SAMJ Vol 104, No 6 (2014) by HMPG

JUNE 2014

WEEK 4

WEEK 8

Legalising medical use of cannabis

387, 399

SAMA – past, present and future Founder genes and Parkinson’s disease Children’s eyes and ears ART initiation targets CME: Sexual health in the South African context

410 th

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SAMF

JUNE 2014 VOL. 104 NO. 6 385-450

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VOL. 104 NO. 6

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JUNE 2014

GUEST EDITORIAL

387

Medical marijuana and beyond J P de V van Niekerk

388

EDITOR’S CHOICE

VOL. 104 NO. 6

EDITOR Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA) EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG MD (Hon), FCM (Hon) CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

CORRESPONDENCE 389

Importance of shielding blood donors from harm E Klug, M Gebka, F Hellig, M Alison, B Townsend, V Naidoo

389

Are all fish oil supplements safe during pregnancy? M Opperman, S Benade

390

A meaningful and sustainable outreach programme in southern Gauteng K R L Huddle, G Chita, N Naicker

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB EDITORIAL SYSTEMS MANAGER Melissa Raemaekers, BSc (Hons), PhD

IZINDABA 391 394 395

E Cape illegal immune-booster given ‘false’ approval – officials suspended SAMA grasps the racial nettle, winning huge majority vote Netcare – KPMG breached client privilege to boost Competitions Commission probe

397

OBITUARY/HULDEBLYK Christian George Albertyn

398 398

BOOK REVIEWS 273 Amazing Days: The Story of Life Before Birth Across the Wide Zambezi: A Doctor’s Life in Africa

SAMJ FORUM

399

OPINION Legalising medical use of cannabis in South Africa: Is the empirical evidence sufficient to support policy shifts in this direction? C D H Parry, B J Myers

401

CLINICAL ALERT Haemophagocytic lymphohistiocytosis: A fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock B Price, J Lines, D Lewis, N Holland

407

ISSUES IN PUBLIC HEALTH ‘Urban insight’: A high level of undiagnosed need reflects limited access to and availability of eye-care services in South Africa A Mathee, A de la Rey, A Swart, S Plagerson, N Naicker

408

ADVANCES IN MEDICINE Additive manufacturing: From implants to organs T S Douglas

SCIENTIFIC EDITOR Ingrid Nye, BSc TECHNICAL EDITORS Paula van der Bijl, BA, HDipLib Emma Buchanan, BA NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za HEAD OF PUBLISHING Robert Arendse PRODUCTION ASSISTANT Neesha Hassan ART DIRECTOR Brent Meder

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EDITORIALS 410

A reflection on the South African Medical Association – past, present and future M Grootboom, M Sonderup

411

A putative founder effect for Parkinson’s disease in South African Afrikaners J Carr, R van Coller

413

RESEARCH

420

No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry population of South Africa Z Vergotine, A P Kengne, R T Erasmus, T E Matsha

Identification of a common founder couple for 40 South African Afrikaner families with Parkinson’s disease G Geldenhuys, B Glanzmann, D Lombard, S Boolay, J Carr, S Bardien

385

DTP & DESIGN Anelia du Plessis | Carl Sampson

June 2014, Vol. 104, No. 6

ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

424

The prevalence of hypotension and hypoxaemia in blunt traumatic brain injury in the prehospital setting of Johannesburg, South Africa: A retrospective chart review W Stassen, T Welzel

428

Setting ART initiation targets in response to changing guidelines: The importance of addressing both steady-state and backlog C Martin, N P Naidoo, W D F Venter, A Jaﬀer, P M Barker

431

Paediatric otitis media at a primary healthcare clinic in South Africa L Biagio, D W Swanepoel, C Laurent, T Lundberg

435

Tick-box admission forms improve the quality of documentation of surgical emergencies, but have limited impact on clinical behaviour G L Laing, J L Bruce, D L Clarke

GUEST EDITORIAL

Members of SAMA receive the SAMJ only on request, as part of their membership beneﬁt.

The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA.

Sexual health in the South African context M M Campbell, D J Stein

REVIEW 440

SAMJ SUBSCRIPTION RATES Local subscriptions R1 144.00 p.a. Foreign subscriptions R2 580.00 p.a. Single copies R95.00

Subscriptions: Tel. 012-481-2071 E-mail: members@samedical.org

CONTINUING MEDICAL EDUCATION 439

CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Web of Knowledge Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Current Contents/Clinical Medicine

Sexual dysfunction: A systematic review of South African research M M Campbell, D J Stein

ARTICLES 445

An integrative treatment model for patients with sexual dysfunctions P Ramlachan, M M Campbell

446

Female sexual dysfunction R Boa

447

Male sexual dysfunction P Ramlachan, M M Campbell

448

Hypersexual disorder in general practice M M Campbell, D J Stein

449

Transgender issues in South Africa, with particular reference to the Groote Schuur Hospital Transgender Unit D Wilson, A Marais, A de Villiers, R Addinall, M M Campbell, The Transgender Unit

450

Sexual function and ageing L Geﬀen

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CPD QUESTIONS

Tree and the Milky Way seen from Sutherland in South Africa. Photo and text: Eric Nathan Email: eric@ericnathan.com

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June 2014, Vol. 104, No. 6

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FIRST PUBLISHED IN 1884

Medical marijuana and beyond ‘Legalise marijuana for medical purposes’ was the cry in Parliament that prompted the response by Charles Parry and Bronwyn Myers in this issue of SAMJ.[1] Much parliamentary and public sentiment favoured such an action. But is this the wisest course to follow? The abuse of drugs is harmful to the individual, families and communities. Declaring war on drugs, as US President Nixon did in 1971, therefore has emotional appeal. However, despite this escalating war, the use of drugs has increased worldwide. While the war had noble intentions, it resulted in harmful unintended consequences. Criminalisation of drug use had the effect of hugely increasing the number of prisoners, who are later likely to resort to other criminal activities. The USA, the leader of the war, has the world’s highest proportion of jailed citizens (707/100 000, as opposed to South Africa at 294/100 000 and India at 30/100 000).[2] The huge profits from the drug trade corrupt users, politicians, police and financial institutions – the fight for turf by drug cartels in Mexico for drugs destined for the USA has been responsible for tens of thousands of murders and disappearances. While the effects of drugs are harmful, the consequences of the war on drugs are far worse. Recognition that the war on drugs has failed has resulted in a worldwide shift to review drug policies.[3] These include medi calisation of the use of marijuana in several US states and elsewhere in the world.[1] The change in approach in South Africa is also apparent in the National Drug Master Plan (NDMP) 2013 - 2017[4] compared with the preceding 2006 - 2011 plan. The latest version aspires to a society free from drug abuse rather than the previous vision of a drug-free society, which does not reflect reality. The NDMP correctly aspires to use evidence of studies concerning the nature of drugs and of policies to manage them. However, clinical trials are lacking, and the Medicines Control Council would be hard pressed to prepare for medical approval and to identify appropriate indications for it. Furthermore, the approval of marijuana for medical purposes will inevitably result in some fraudulent ‘patients’, and complicit doctors who provide their scripts. The NDMP has called for further research, but we already know a great deal.[5] There have been advances in the understanding of addiction and its treatments; drug classification based on its harms can be rational and evidence based; and there are examples of countries that have changed their drug policies with beneficial effects, such as Portugal, which decriminalised the use of all drugs in 2001 with overall improvement across all parameters,[6] and Holland, with its success in making marijuana available through designated ‘coffee shops’.[7] However, commonly voiced concerns about relaxing the war on drugs include: • South Africa is a developing country and does not have the resources to manage decriminalisation or legalisation. Despite service delivery of all kinds requiring improvement, such a stance invites the obvious rejoinder that we should then give up regulating alcohol and tobacco and policing our traffic laws. Imperfect regulation is better than none. • Those who want to abolish the war on drugs have not experienced the horrors of addiction. The reality is that addiction occurs, and is increasing, despite increasing intensity of the war on drugs. The stigma resulting from criminalising users and addicts reduces their chances of receiving treatment, and jailing them much increases their chances of becoming habitual criminals.

387

• The police do not support relaxing the war on drugs. This is understandable, as police are required to enforce existing laws and are promoted for doing so with zeal. But if laws are unjust, they should be changed. Freeing up the police from pursuing innocent users would enable them to focus on more important issues. • Marijuana is a gateway to the use of more serious drugs. Nutt[5] has noted that ‘While it is true that most people who become addicted to heroin and crack have used cannabis, their first drug experiences tend to be alcohol and tobacco,’ and that ‘If anything, prison is the biggest gateway of all.’ In a previous comment on the March 2011 Anti-Substance Abuse Summit in Durban, Parry and Myers[8] recommend that the government should ‘start the real work of formulating and implementing an evidence-based drug policy that learns from the experiences of other countries around decriminalising drug use; takes into account differences in the harms resulting from different classes of drugs; adopts a rights-based, public health approach to policy; and identifies a single (accountable) agency that has the authority to oversee policy implementation’. Mario Oriani-Ambrosini’s recent impassioned plea in Parliament was another wake-up call for action. However, it is probably wiser to get beyond the legalisation of marijuana for medical purposes, which is likely to be a long and complicated process. There is good evidence that decriminalisation of the use of drugs reduces the harms of drugs, reduces the power of the drug lords, and generates revenue for the government. Marijuana is much less harmful than the two legalised drugs, alcohol and tobacco, and has potential medical benefits. A good case can be made for its legalisation and regulation. This would also enable the longer and more complicated medical research to proceed legally, and for those who use marijuana for medical or social purposes to do so of their own accord and without persecution. Bold leadership and action, rather than further revisions of the NDMP, are required. J P de V van Niekerk Consulting Editor jpvn@iafrica.com

1. Parry CDH, Myers BJ. Legalising medical use of cannabis in South Africa: Is the empirical evidence sufficient to support policy shifts in this direction? S Afr Med J 2014;104(6):399-400. [http://dx.doi. org/10.7196/SAMJ.8135] 2. International Centre for Prison Studies. http://www.prisonstudies.org/highest-to-lowest (accessed 6 April 2014). 3. Report of the Global Commission on Drug Policy. 2011. http://www.globalcommissionondrugs.org (accessed 8 April 2014). 4. National Drug Master Plan 2013-2017. http://www.dsd.gov.za/index2.php?option=com_ docman&task=doc_view&gid=414&Itemid=3 (accessed 6 May 2014). 5. Nutt D. Drugs Without the Hot Air: Minimising the Harms of Legal and Illegal Drugs. Cambridge: UIT Cambridge, 2012. 6. CATO Institute. Drug Decriminalization in Portugal: Lessons for Creating Fair and Successful Drug Policies. http://www.cato.org/publications/white-paper/drug-decriminalization-portugal-lessons-creating- fair-successful-drug-policies (accessed 10 April 2014). 7. Grund J-P, Breeksma J. Coffee Shops and Compromise: Separated Illicit Drug Markets in the Netherlands. http://www.opensocietyfoundations.org/about/programs/global-drug-policy-program (accessed 12 April 2014). 8. Parry C, Myers B. Beyond the rhetoric: Towards a more effective and humane drug policy framework in South Africa. S Afr Med J 2011;101(10):704-706.

S Afr Med J 2014;104(6):387. DOI:10.7196/SAMJ.8335

June 2014, Vol. 104, No. 6

EDITOR’S CHOICE

CME: Sexual health

Sexual health is a topic that is seldom discussed, and hardly covered in the current medical curriculum. However, the World Health Organization (WHO) has said that sexual health is one of the basic rights of every person. This issue of CME, compiled by Megan Campbell and Dan Stein, addresses sexual health in the South African (SA) context, from a community perspective. Research shows that people are reluctant to bring up sexual health concerns with their doctors, and hope and expect that the doctor will address these issues as part of holistic care. There are few centres of excellence for sexual health in low- and middle-income countries, which is where most of the world’s population live, and such resources are badly needed. Few SA doctors currently receive the training required to address sexual dysfunction comprehensively, and there are no accredited SA training programmes in this area. This gap is also pertinent to the lesbian, gay, bisexual, transgender and intersex community. We hope that this issue of CME will start to fill some of these gaps.

Evidence for a founder effect for Parkinson’s disease in SA Afrikaners

Afrikaners, a unique ethnic group mainly descended from Dutch, German and French settlers to SA in the 17th and 18th centuries, suffer several disorders that occur at relatively high frequencies owing to founder gene effects. Some of these diseases can be traced back to specific founder couples. Research at the Movement Disorders Clinic at Tygerberg Hospital in Cape Town has shown that Parkinson’s disease (PD) can be added to this list, with 40 PD families identified in which there was only a single most recent ancestral couple common to all of the families.[1] An accompanying editorial[2] outlines the promise that the identification of mutations such as these holds for understanding the cause of the disease and the mechanisms of cell injury and death, and for developing appropriate therapies.

Insulin receptor substrate-1 Gly972Arg variant and type 2 DM

In contrast, a direct genetic basis, specifically carriage of Gly972Arg (the most common single-nucleotide polymorphism in the insulin receptor substrate (IRS1) gene), associated with a 25% increased risk for developing diabetes, does not account for the high prevalence of type 2 diabetes mellitus (T2DM) in the mixed-ancestry population of SA. In Vergotine et al.’s study,[3] the first of its kind in Africa, 237 participants (24.7%) had T2DM. The overall prevalence of IRS1 Gly972Arg was 7.9%, with a higher occurrence of the variant found in non-diabetics, and it was not associated with obesity, insulin resistance/sensitivity or T2DM.

Our children deserve better

As part of student in-service training programmes, the Department of Optometry of the University of Johannesburg supplements the rudimentary optometry services to the community in one of the poorer suburbs of the city. In their Forum article, Mathee et al.[4] report a high level of undiagnosed optometric need. Poorer urban communities, perhaps surprisingly, have limited availability of public sector eye-care services, and cannot manage the high costs of consultations, spectacles and transport. The simple provision of spectacles provided dramatic improvements in quality of life for schoolchildren and adults, transforming their school performance and earning power, respectively. The experience of this clinic raises the issue of access and availability of eye-care services in urban SA. Uncorrected visual impairment in urban children is of particular concern. Poor vision has obvious detrimental impacts on children’s

388

learning ability. Similarly, poor vision limits adults’ ability to fulfil their potential for health and productivity.

The burden of otitis media

The burden and characteristics of otitis media differ greatly between developed and developing regions. India and sub-Saharan Africa (SSA) account for most deaths from complications arising from otitis media. The incidence of acute otitis media is several-fold higher in SSA than in the rest of the world, and SSA has the second-highest incidence of chronic suppurative otitis media (CSOM). A study at a primary healthcare clinic[5] employed otomicroscopy to ascertain the point prevalence of otitis media in a paediatric population in a public health clinic in Diepsloot, a densely populated settlement north of Johannesburg. The prevalence of CSOM for the total paediatric sample was 6.6%, which is classified by the WHO as high. The CSOM prevalence of 9.3% measured among 6 - 15-yearolds in the current study would be rated as the highest prevalence, according to the WHO classification system. In a recent study on the otological, audiological and bacteriological findings in children with CSOM in an SA tertiary hospital, HIV infection was present in 54.6% of participants with CSOM. Many of the risk factors that are attributed to high rates of CSOM could be identified in the population sampled, including short-term breastfeeding, overcrowding, poor hygiene, poor nutrition, and exposure to tobacco, wood and charcoal smoke. Measures that may reduce the burden of otitis media include routine otological screening of schoolchildren and increased referral of children with recurrent ear disease for specialist opinion.

Hypotension and hypoxaemia in blunt traumatic brain injury

Each year, ~89 000 (180/100 000) new cases of head injury are reported in SA. Most patients are in the economically active population. Hypotension and hypoxaemia significantly increase morbidity and mortality after traumatic brain injury (TBI). Cerebral tissue is parti cularly vulnerable to these secondary insults immediately after a TBI, emphasising the importance of prehospital care. Most TBIs are followed by an epsiode of apnoea, even if just for a brief period. Hypoxaemia was associated with a near-doubling in mortality from 27% to 50%. The prevalence of hypotension and hypoxaemia associated with TBI in the greater Johannesburg area reported by Stassen and Welzel[6] is comparable with that observed in international studies. Hypotension was associated with midazolam dosage and the presence of injuries that could result in significant haemorrhage. Similarly, hypoxaemia was associated with injuries to the chest. This study highlights the need for the development of a national TBI protocol for prehospital care providers that is based on sound clinical evidence and can guide decision-making on the most appropriate interventions in the prehospital setting to optimise outcome. JS 1. Geldenhuys G, Glanzmann B, Lombard D, Boolay S, Carr J, Bardien S. Identification of a common founder couple for 40 South African Afrikaner families with Parkinson’s disease. S Afr Med J 2014;104(6):413-419. [http://dx.doi.org/10.7196/SAMJ.7747] 2. Carr J, Van Coller R. A putative founder effect for Parkinson’s disease in South African Afrikaners. S Afr Med J 2014;104(6):411-412. [http://dx.doi.org/10.7196/SAMJ.8390] 3. Vergotine Z, Kengne AP, Erasmus RT, Matsha TE. No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry population of South Africa. S Afr Med J 2014;104(6):420-423. [http://dx.doi.org/10.7196/SAMJ.7419] 4. Mathee A, de la Rey A, Optom B, Swart A, Plagerson S, Naicker N. ‘Urban insight’: A high level of undiagnosed need reflecting limited access to and availability of eye-care services in South Africa. S Afr Med J 2014;104(6):407-408. [http://dx.doi.org/10.7196/SAMJ.8100] 5. Biagio L, Swanepoel DW, Laurent C, Lundberg T. Paediatric otitis media at a primary healthcare clinic in South Africa. S Afr Med J 2014;104(6):431-435. [http://dx.doi.org/10.7196/SAMJ.7524] 6. Stassen W, Welzel T. The prevalence of hypotension and hypoxaemia in blunt traumatic brain injury in the prehospital setting in Johannesburg, South Africa: A retrospective chart review. S Afr Med J 2014;104(6):424-427. [http://dx.doi.org/10.7196/SAMJ.7494]

June 2014, Vol. 104, No. 6

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CORRESPONDENCE

Importance of shielding blood donors from harm

To the Editor: An adequate and safe blood supply remains a challenge in South Africa (SA), and voluntary blood donors are a vital section of our healthcare system. Regular donors (people who make ≥3 donations in a year) are of key importance, because they are the source of a constant flow of blood to the South African National Blood Service (SANBS). The donor gives one unit of whole blood, which involves a venesection of approximately 480 ml (SA law prohibits more). The donor loses approximately 180 mg of iron per donation.[1] The upper limit of frequency of blood donation for both men and women is 6 units/year. By law in SA, a donor cannot donate more frequently than every 56 days. During the 2013 SANBS financial year,[2] 797 623 donations were collected, of which 756 358 were whole-blood collections. A risk of frequent blood donation is iron deficiency anaemia. The REDS-II Donor Iron Status Evaluation (RISE) study documents that among frequent US blood donors, two-thirds (66%) of the women and almost half (49%) of the men were iron deficient.[3] More frequent donation, resulting in greater iron losses, was the main factor leading to iron deficiency.[3] We were unable to find data on the prevalence of iron deficiency in regular SA blood donors. Before people can donate blood they must pass a haematocrit (HCT) test, which determines the percentage of blood volume that is made up of red blood cells. The normal range for HCT is 38.8 - 50% for men and 34.9 - 44.5% for women. The SANBS uses the copper sulphate specific gravity method for primary screening – it is cheap and easy, and widely used in blood centres worldwide. Should the donor’s blood fail this test, a HemoCue test is done. This system uses a portable battery-operated photometric device for rapid determination of haemoglobin (Hb).[4] The cut-off value is 12.5 g/dl for both sexes in SA. No monitoring of donors’ iron store status is routinely done by the SANBS. Iron deficiency, even in the absence of anaemia, is associated with decreased physical endurance and work capacity, fatigue, and impairment of concentration and other cognitive functions.[5-8] The maximum iron absorption from a typical Western diet is at most 3 - 4 mg/day. Consequently, restoring the Hb concentration to predonation concentrations may require an average of 12 - 18 weeks in men, and 14 - 24 weeks or more in women of childbearing age. Some authors have supported the idea that some degree of iron deficiency may be cardioprotective.[9] The only prospective, randomised clinical trial of phlebotomy to reduce body iron stores, the Iron (Fe) and Atherosclerosis Study (FeAST),[10] however, found no significant reduction in all-cause mortality or in death plus nonfatal myocardial infarction and stroke. In our clinical cardiological practice, we have seen six male patients (mean age 50.1 years) presenting with no anaemia or a mild reduction in Hb (mean 14.36 g/dl; range 11.7 - 17.7) and normal or reduced mean corpuscular volume (mean 80.41 fl; range 70 - 94.6), all with reduced serum ferritin (mean 13.4 ng/ml; range 9 - 18) pointing to reduced iron stores, who were regular blood donors (6 times/year, mean age of first donation 28.6 years). It was estimated that the group had donated an average of 119 units of blood per individual (range 12 - 304). None volunteered that they were blood donors, and some had ascribed their fatigue or reduced sport performance to being stressed or getting older. Our conclusion is that the current SANBS donor approach is failing to protect regular blood donors from iron deficiency. Iron deficiency may also result in ‘donor loss’ to the SANBS. The impact on the healthcare system of investigating donors who present to their doctors with reduced red cell indices on the full blood count (FBC),

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with associated reduced ferritin, with or without anaemia, must be considered, especially as in our experience patients often fail to inform their doctor that they are active blood donors. It is clear that all patients presenting with an abnormal FBC must be asked whether they are blood donors. Even then, what are the implications for a patient when the ‘regular blood donor’ explanation is accepted as the most likely cause of the iron deficiency, and an occult gastrointestinal malignancy is not activly excluded? We seek to draw attention to this not uncommon clinical scenario, and encourage the SANBS to monitor serum ferritin levels (and not be satisfied with only the HCT test) in their regular blood donors. If this is deemed potentially too expensive, longer intervals between donations should be recommended, or regular donors should be reminded to have their serum ferritin checked at their own expense, at a time interval still to be determined. Advice on oral iron supplementation should also be offered – none of our patients had been given this advice. Blood donation is an altruistic action by our citizens, and they should be shielded from potential harm. Eric Klug Marek Gebka Farrel Hellig Michael Alison Barbara Townsend Vaman Naidoo

Sunninghill Hospital, Sunninghill, Johannesburg, South Africa eklug@global.co.za 1. Canadian Blood Services. http://www.blood.ca (accessed 2 March 2014). 2. SANBS Annual 2013 Report. http://www.sanbs.org.za (accessed 2 March 2014). 3. Cable RG, Glynn SA, Kiss JE, et al. Iron deficiency in blood donors: Analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study. Transfusion 2012;52(4):702-711. [http:// dx.doi.org/10.1111/j.1537-2995.2011.03401.x] 4. Tondin R, Verma A, Pandey P, et al. Quality evaluation of four haemaglobin screening methods in a blood donor setting along with their comparative cost analysis in an Indian scenario. Asian J Transfus Sci 2009;3(20):66-69. 5. Falkingham M, Abdelhamid A, Curtis P, Fairweather-Tait S, Dye L, Hooper L. The eﬀects of oral iron supplementation on cognition in older children and adults: A systematic review and meta-analysis. Nutr J 2010;9(1):4. [http://dx.doi.org/10.1186/1475-2891-9-4] 6. Murray-Kolb LE, Beard JL. Iron treatment normalizes cognitive functioning in young women. Am J Clin Nutr 2007;85(3):778-787. 7. Hinton PS, Sinclair LM. Iron supplementation maintains ventilatory threshold and improves energetic eﬃciency in iron-deficient non-anaemic athletes. Eur J Clin Nutr 2007;61(1):30-39. 8. Newman B. Iron depletion by whole-blood donation harms menstruating females: The current wholeblood-collection paradigm needs to be changed. Transfusion 2006;46(10):1667-1681. [http://dx.doi. org/10.1111/j.1537-2995.2006.00969.x] 9. Sullivan JL. Blood donation may be good for the donor: Iron, heart disease, and donor recruitment. Vox Sang 1991;61(3):161-164. [http://dx.doi.org/10.1111/j.1423-0410.1991.tb00940.x] 10. Zacharski LR, Chow BK, Howes PS, et al. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: A randomized controlled trial. JAMA 2007;297(6):603-610. [http://dx.doi.org/10.1001/jama.297.6.603]

S Afr Med J 2014;104(6):389. DOI:10.7196/SAMJ.8211

Are all fish oil supplements safe during pregnancy?

To the Editor: Few consumers are aware of the ethyl ester (EE) content of South African (SA) omega-3 fatty acid supplements. We wish to draw the attention of SAMJ readers to the findings of a recent survey on the omega-3 fatty acid content of fish oil supplements available on the SA market. This survey revealed that 20 of the 63 supplements analysed (31.7%) contained omega-3 fatty acids in EE form, or a combination of EEs and triglycerides (TGs).[1] In pure fish oils the omega-3 fatty acids are almost exclusively in the form of TGs. EEs are esterified products of fatty acids and ethanol. During the esterification process the glycerol backbone of TGs is removed by substituting it with ethanol. Omega-3 EEs are then separated from other EEs by molecular distillation. This process enables selective concentration of eicosapentaenoic acid and docosahexaenoic acid,

June 2014, Vol. 104, No. 6

ADVERTORIAL

RED MEAT AND NUTRITION

NOT ALL FATS ARE CREATED EQUAL DIFFERENT TYPES OF FAT:

WHY ARE FATS IMPORTANT? Not all fats are created equal. The types of fat from the diet affect a person’s blood lipid profile to a greater extent than the amount of cholesterol from the diet. Fats and fatty acids have various beneficial properties: • Essential to development and survival during the early stages of life from embryonic development and early growth after birth on through infancy and childhood. • Provide the medium for the absorption of fat-soluble vitamins. • Primary contributors to the palatability of food.

Fats are generally classified or grouped according to the number of double bonds in their chemical structure, i.e. saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA)9 Type

Main food source

Level of evidence

Total fat

All foods containing fats and oils

Probable evidence - No relation between total fat intake and coronary heart disease, fatal coronary heart disease or cancer development.

SFA

Mainly animal sources and coconut oil

Convincing evidence – Raises low-density lipoprotein (LDL) and total/high-density lipoprotein (HDL) ratio in comparison to PUFA and MUFA, but no effect on total/HDL ratio in comparison to carbohydrates.

FATS AND HEALTH – RECENT SCIENTIFIC EVIDENCE Fats have remained one of the most complex and controversial areas of investigation in nutrition science.1 Fats are energy-dense, yet the health consequences of dietary fats go well beyond their role as energy sources. The knowledge of the role of particular fatty acids in determining health and nutritional well-being and how they exert these effects has expanded substantially. Several recent studies report no or minor association between total dietary fat intake and obesity, weight gain, coronary heart disease and cancer2,3,4,5,6 Low-fat, high-carbohydrate diets do not favourably affect serum lipids, fasting serum glucose, serum insulin, or blood pressure, compared with higher fat diets7,8 Consistent associations have been found between high intakes of specific dietary fats, and substituting carbohydrates with fats, with lower risk of heart disease4,8 RECOMMENDATIONS (expressed as a percentage of total dietary energy9) Fatty acid

Acceptable range

Total fat

20-35% 10%

MUFA

By difference up to 15-20%*

PUFA

6-11%

n-6 PUFA

2.5-9%

n-3 PUFA

0.5-2%

TFA

<1%

Content (g/100g) Lamb

Mutton

Beef

LDL-cholesterol raising

4.2

3.62

3.64

Lauric acid C12:0

0.08

0.01

Myristic acid C14:0

0.85

0.34

0.37

Palmitic acid C16:0

3.27

Cholesterol neutral

1.91

3.01

2.99 2.99

Stearic acid C18:0

1.91

3.01

LDL-cholesterol lowering

5.22

5.40

5.4

Oleic acid C18:1

4.79

4.95

5.12 0.24

Linoleic acid (Omega 6) C18:2

0.36

0.29

Alpha-linolenic acid (Omega 3) C18:3

0.07

0.14

Arachidonic acid C20:4

0.00

0.02

0.04

HealthyMeatZA

MUFA

Canola, peanut, and olive oils, avocados, nuts, and seeds such as pumpkin and sesame seeds

Convincing evidence – Lowers LDL and total/ HDL ratio when substituted for SFA.

Plant oils such as those derived from sunflower, corn, soybean and flax seeds, as well as walnuts, fish and meat

Convincing evidence – Essential for human health and development (linoleic acid (LA), alpha-linolenic acid (ALA); Lowers LDL and total/HDL ratio in comparison to SFA; Decreases risk of coronary heart disease when PUFA replaces SFA.

Possible evidence – Decreases risk of metabolic syndrome components. Insufficient evidence - Effect on diabetes risk, body weight, adiposity, coronary heart disease and cancer.

Possible evidence - Decreases risk of metabolic syndrome components; Increases lipid peroxidation with high consumption, especially when tocopherol intake is low. Insufficient evidence – Risk of body weight, adiposity or cancer.

Despite common reference to animal fats as ‘saturated’, red meat contains saturated and mono- and polyunsaturated fats. South African lamb, mutton and beef contain nearly as much cholesterol lowering fatty acids than cholesterol raising fatty acids10,11,12

Healthy Meat

Insufficient evidence – Increased risk of hypertension, body weight and adiposity.

PUFA

SFA

Fatty Acids

Possible evidence - Increases risk of Type 2 diabetes.

Omega 6 Plant oils, nuts PUFA and meat

Convincing evidence – Essential for human health and development (LA) Probable evidence – Decreases risk of metabolic syndrome components and diabetes Insufficient evidence – Risk of body weight, adiposity, cancer

Omega 3 EPA and DHA PUFA are found in fatty fish such as salmon, tuna, mackerel and sardines ALA is found in canola and soybean oil, walnuts and flaxseed

Convincing evidence – Essential for human health and development (alpha-Linolenic acid (ALA)); Decreased risk of fatal coronary heart disease (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) Possible evidence – Decrease risk of total coronary health disease and stroke

REFERENCES 1. Nishida et al. 2009. EJCN, 63: 51-54. 2. Field et al. 2007. Obesity, 15(4): 967976. 3. He et al. 2003. BMJ, 327(7418): 777-782. 4. Hu et al. 2001. J. Am. Coll. Nutr., 20(1): 5-19. 5. Koh-Banerjee et al. 2003. Am. J. Clin. Nutr., 78(4): 719-727. 6. WCRF/AICR. 2007. Report. Washington DC. 7. Appel et al. 2005. JAMA, 294(19): 2455-2464. 8. Gardner et al. 2007. JAMA, 297(9): 969-977. 9. FAO. 2010. Fats and Fatty Acids in Human Nutrition. FAO Paper 91. Rome. 10. Mozaffarian et al. 2007. Curr. Atheroscler. Rep., 9(6): 486-493. 11. Schönfeldt et al. 1996. Composition of South African beef. ARC Report, Irene. 12. Schönfeldt et al. 2012. ISBN 9780-620-52922-8.

www.healthymeat.co.za

An educational campaign translating current science into consumer friendly messages. Supported by the Red Meat Industry of South Africa.

SAMJ-07_RM_Apr2014

Lamb & Mutton South Africa

CORRESPONDENCE

in excess of levels in natural fish oil. These preparations are typically marketed as fish oil concentrates. Pregnant women are advised not to use EEs, since their safety during pregnancy has not been established.[2] Importantly, none of the labels of the supplements surveyed declared the presence of EEs, and none of the labels warned against using EEs during pregnancy and lactation – there was even one supplement containing EEs that was specifically recommended during pregnancy. During digestion, EEs are converted back to TGs and ethanol is released. Even though the quantity of ethanol released after taking a typical dose of fish oil for supplementation is small, at-risk groups such as pregnant and lactating women, as well as young children, should avoid using omega-3 fatty acid supplements that contain EEs. In some countries (although not in SA), fatty acid EEs are used as prescription medications to reduce very high blood TG levels (≥5.65 mmol/l). However, these preparations provide pharma cological amounts of omega-3 fatty acid EEs and are used under strict supervision by a physician. It is unfortunate that the same procedures are not applied to ensure the safety of omega-3 fatty acid supplements. We suggest that all manufacturers should indicate on the labels the forms in which omega-3 fatty acids are present in the fish oil/ omega-3 supplements they produce, and that the labels should also warn pregnant women about the use of supplements containing EEs. Doctors should familiarise themselves with the contents of the various fish oil supplements. This information can be accessed on the website of the Cancer Association of South Africa.[3] Maretha Opperman Spinnler Benade

Functional Foods Research Unit, Faculty of Applied Science, Cape Peninsula University of Technology, Cape Town, South Africa oppermanm@cput.ac.za 1. Opperman M, Benade AJS. Analysis of the omega-3 fatty acid content of South African fish oil supplements – a follow-up study. Cardiovasc J Afr 2013;24(8):323-328. [http://dx.doi.org/10.5830/ CVJA-2013-074] 2. Bays H. Clinical overview of Omacor: A concentrated formulation of omega-3 polyunsaturated fatty acids. Am J Cardiol 2006;98(Suppl. 1):71-76. [http://dx.doi.org/10.1016/j.amjcard.2005.12.029] 3. Cancer Association of South Africa. http://www.cansa.org.za/files/2013/02/Fish-oil-Analyses-26-22013.pdf (accessed 5 May 2014).

Medicine had too few subspecialty training posts to accommodate the large number of applicants; and the three cluster hospitals (Sebokeng, Leratong and Edenvale) served by the department were unable to fill their vacant specialist posts. The solution agreed to was that the three cluster hospitals would second their unfilled specialist posts to the Department of Medicine for filling in exchange for a continuous specialist service at the hospitals. The subspecialty training was extended by 1 year to a total of 3 years (already in existence for cardiology subspecialty training) to allow for 1 year of outreach. This was a win-win solution that allowed the Department of Medicine to expand its pool of posts for subspecialty training in exchange for providing muchneeded specialist services at these hospitals. A similar model was adopted by both CHBAH and HJH, whereby two to three physicians (subspecialty fellows) rotate through the Department of Medicine at Sebokeng Hospital (the responsibility of CHBAH) and Leratong Hospital (the responsibility of HJH) for periods of 3 - 4 months for each of the 3 years. These are both large regional hospitals each with approximately 800 beds. The rotating physicians participate fully in the clinical activities of the respective departments of medicine. They also have administrative and teaching responsibilities. Senior physicians visit the cluster hospitals on a weekly basis. The programme is now in its 5th year and has proved to be a great success. The regional hospitals have benefited by having a continuous on-site specialist service. The junior staff in these hospitals have responded very positively to having on-site specialist supervision and teaching. The rotating physicians have also benefited by being made aware of the importance of outreach in the context of South African healthcare. For the first time in their careers they have been given substantial responsibilities without senior supervision being immediately at hand. The majority of them have responded admirably to these challenges and have contributed meaningfully to these hospitals. The positive spiral created at these two hospitals has also resulted in the recent appointment of permanent specialists at both. It is our view that this type of outreach model could be implemented in other centres in South Africa, with the specific intention of improving the quality of care at regional hospital level. This would fit in very well with the National Health Insurance plan.

S Afr Med J 2014;104(6):389-390. DOI:10.7196/SAMJ.8242

K R L Huddle

A meaningful and sustainable outreach programme in southern Gauteng

G Chita

Department of Medicine, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa kenneth.huddle@wits.ac.za

To the Editor: In 2009 a meeting took place between the then Chief of Operations of the Gauteng Health Department, Dr A Rahman, and the academic and clinical heads of Internal Medicine at the three academic hospitals of the University of the Witwatersrand, Chris Hani Baragwanath Academic Hospital (CHBAH), Helen Joseph Hospital (HJH) and Charlotte Maxeke Johannesburg Academic Hospital. Two problems were highlighted: the Department of Internal

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Department of Medicine, Helen Joseph Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

S Naicker

Graduate Studies Committee, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa S Afr Med J 2014;104(6):390. DOI:10.7196/SAMJ.8179

June 2014, Vol. 104, No. 6

Air Liquide Southern Africa Tel: +27 (0)11 389 7262, Celeste Gopaul (Executive Healthcare Assistant) Fax: +27 (0)11 389 7394 www.airliquide.co.za

IZINDABA

E Cape illegal immune-booster given ‘false’ approval – oﬃcials suspended An official in the Medicines Control Council (MCC)’s national law enforcement inspectorate and a Port Elizabeth district health manager have been suspended following an illegal trial of an unregistered Californianmanufactured ‘immune-boosting’ spray on public sector clinic patients. This was confirmed to Izindaba by both Ms Precious Matsoso, National DirectorGeneral of Health, and the Registrar of the Medicines Control Council (MCC), Ms Mandisa Hela, who added that the local importers/distributors of Immutides Spray, Saulez Agencies CC, also face potential criminal charges. A consignment of the spray, with an estimated value of nearly R1.4 million, was effectively impounded by the MCC four days before a second Eastern Cape health department-‘sanctioned’ 1 March ‘trial’ involving 90 HIV/tuberculosis (TB) patients at the three main TB hospitals in the province was due to begin. The national health leadership duo rejected earnest claims by Saulez Agencies CC CEO Guy Saulez that he had met every application criterion pertaining at the time and merely followed official advice. Saulez said he took an MCC law enforcement ‘permission to sell’ document at face value and described a partially completed trial of Immutides Spray, plus the aborted prospective trial, as ‘case studies, not medical trials’. Matsoso, herself a former MCC Registrar, said that any research involving medicines needed MCC approval (which Hela confirmed had not been sought). Hela reiterated that Saulez Agencies’ application for registration of Immutides as a complementary medicine had been turned down by both an MCC complementary medicines committee and an MCC veterinary committee, both citing ‘genuine safety concerns’. She said the data collection sheets for Immutides Spray used at the Nelson Mandela Region’s primary health clinics made it a clinical trial, emphasising that ‘we don’t know what the protocol of the trial was, or even who the principal investigators were’. The first trial, at several municipal health clinics over a protracted period, preceded by several months a directive from the recently appointed Nelson Mandela Region’s District Health Manager,

Precious Matsoso, National DirectorGeneral of Health. Picture: Chris Bateman.

Dr Lulekwa Mayekiso. Mayekiso ordered all senior managers involved in caring for patients in the province’s three TB hospitals to dispense the spray to all patients – and issue scripts for it on discharge from hospital. Her edict, effective from 1 March this year, included a provision that the roll-out include the compilation and evaluation of a ‘research report’ on Immutides. This project was halted four days before it was due to start after the Treatment Action Campaign (TAC) was tipped off by a concerned healthcare practitioner and fired off letters to the top provincial and national regulatory authorities. Eastern Cape Director-General of Health Dr Thobile Mbengashe confirmed that Mayekiso had been suspended on full pay in terms of the Public Service Act pending a disciplinary enquiry, expected to be complete by June. Mbengashe, who was head of the national HIV/AIDS department before taking his current post in September 2013, said the enquiry would focus only on the directive Mayekiso issued in the face of an unregistered, unproven drug that had no ethical approval. The other provincial officials involved were not part of the enquiry, but he would not rule out that they might be. ‘The MCC and the NDoH [National Department of Health] have their own probes – we’re going with the strongest evidence we have.’ He said that neither Mrs Nomalanga Makwedini, at the time

391

Eastern Cape Director-General for Clinical Management Services, nor Dr Francois Fourie, in charge of primary healthcare clinics in the Nelson Mandela Bay district, had ‘ordered anyone to use the drugs’. While Izindaba has, independently of the MCC, established that the ‘immuneboosting’ Immutides Spray remains scientifically unproven, its distributor says he met every requirement health officials threw at him – and obtained what he thought was official permission to sell it. Documents supplied to Izindaba by Saulez, who admits having distributed the spray to thousands of people in the Eastern Cape, hoping to distribute it nationally, provide no evidence of efficacy, nor do they justify any clinical trials, according to a top pharmacologist we consulted. However, another set of documents Saulez supplied appear to support his contention that he followed all official advice and abided by regulatory requirements pertaining at the time. A possible fly in the ointment, Hela admits, is that she could find no record that Saulez Agencies was notified that their registration was turned down. ‘But nothing stopped them from contacting us and enquiring as to the status of their application,’ she said.

Mayekiso ordered all senior managers involved in caring for patients in the province’s three TB hospitals to dispense the spray to all patients – and issue scripts for it upon hospital discharge. Her edict, effective from 1 March this year, included a provision that the roll-out include the compilation and evaluation of a ‘research report’ on Immutides. This project was halted four days before it was due to start. It is possible that Saulez may have been given faulty advice – but virtually certain that approval of Immutides by national and provincial health officials was either fraudulent or deeply flawed. The legislative evolution included an obligatory 2002 ‘callup’ notice for complementary medicines

June 2014, Vol. 104, No. 6

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whereby importers and local manufacturers had to submit information to the MCC to enable a national audit of a chaotic market. However, this was replaced by a comprehensive set of stricter revisions promulgated in November 2013. Prof. Andrew Gray, one of the country’s top pharmacologists and a senior lecturer in the subject at the School of Health Sciences at the Nelson Mandela School of Medicine, University of KwaZulu-Natal, said it was possible that Saulez Agencies was given contradictory advice by national and provincial officials. Gray, a research associate and consultant at the Centre for AIDS Programme of Research in South Africa (CAPRISA, based on his own campus), said that despite all protestations to the contrary, what was envisaged by Eastern Cape district health officials and Saulez Agencies CC was a clinical trial involving human subjects. No such trial could proceed without prior permission from the MCC, as well as from an accredited ethics committee. Not only were no data on the quality of Immutides Spray provided by the company, but the product was unregistered and the manufacturer had not demonstrated compliance with good manufacturing practices (one of the new requirements), as confirmed by a South African MCC inspection (the full scientific documentation on Immutides Spray as supplied by Saulez, with Professor Gray’s detailed analysis, is available upon request). The spray did not meet the updated requirements for registration as a complementary medicine. Gray said that one document provided by Saulez to back the efficacy of the spray was devoted to a description of the operation of the normal immune system, and then to laboratory, in vitro and animal studies conducted on transfer factor, various colostrum concentrates (ovine and bovine), prolinerich polypeptides and lactoferrin. ‘While useful as background data, and establishing some degree of proof of concept, none can be considered as evidence of the efficacy or safety of the extract commercialised as Immutides Spray,’ he said. Hela said of Immutides’ bovine origin, ‘we could not even substantiate the claim on the protein they claimed’.

New broom meant to sweep snake-oils clean

Last year’s beefed-up complementary medi cine compliance regulations were an attempt to clean up the production, marketing and retailing of sub-standard complementary medicines, using amendments to over 20

Guy Saulez, CEO of Saulez Agencies CC.

of the general regulations to improve public safety. From 15 November last year, any new complementary medicine entering the market had to be fully registered before going on sale to the public – with a ‘responsible pharmacist’ overseeing and taking responsibility for all processes within the manufacturing chain and submitting reports to the MCC and the Pharmacy Council. The regulations for products under the new definition of ‘complementary medicines’ (‘any substance or mixture of substances that originates from plants, minerals or animals; is used or intended to be used for, or manufactured or sold for use in assisting the innate healing power of a human being or animal to mitigate, modify, alleviate or prevent illness or the symptoms thereof or abnormal physical or mental state; and is used in accordance with the practice of the professions regulated under the Allied Health Professions Act, 1982 (Act No. 63 of 1982)’) have now been structured on a benefit v. risk approach – which is significant in terms of looking at the facilities in which medicines are manufactured.

She said the success of any provincial probe would ‘depend on the political will’. Hela confirmed that a long-serving Ms Petra Bekker in the Inspectorate of Law Enforcement of the Pharmaceutical and Related Products Regulation Management Unit had signed an outdated form on an NDoH letterhead, granting permission for Immutides Spray to be ‘imported and sold as a complementary medicine in accordance with

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June 2014, Vol. 104, No. 6

Government Gazette Notice 23128’. Bekker had been suspended pending an internal disciplinary hearing. She had gone ‘way beyond’ her delegated powers – using NDoH stationery instead of official MCC forms. Matsoso said her suspicions were aroused when she saw the NDoH letterhead. She had instructed Hela to begin an internal inquiry immediately. Hela confirmed that Bekker had been asked to handle the Immutides port clearance by a Port Elizabeth Port Health Authority official when the shipment first arrived. ‘What used to happen is our law enforcement officers had an arrangement with customs that anything not registered with the MCC that looks like a medicine, or is a suspicious cosmetic or such, will call them and clear out whether it’s for regulation or not. If the ingredients and claims look safe, the company is given a number and form under which the consignment can be released from the harbour to save them storage fees – that’s all.’ She emphasised that none of this could circumvent the legal requirement for MCC registration. ‘It looks like that when Saulez Agencies found out they were not coming right with the MCC, they were advised to work via Bekker.’ A hard-done-by Saulez said he had been ‘put through the mill’ by the MCC’s law enforcement officers after complaints by the TAC, with ensuing widespread publicity over what appeared to be a cynical money-making scam. Saulez said that far from attempting to sidestep regulatory requirements, he had in 2011 met with the national Director of Nutrition, one Lynn Moeng, who advised him to register Immutides with the MCC. This had led to a meeting with the very law enforcement officers dispatched to the Eastern Cape by Matsoso in March to probe the aborted official provincial rollout. Added Saulez: ‘They (initially) told us what forms to fill in and how to go about things, recommending we hire a private medical consultant to submit all our product information.’ He provided Izindaba with a copy of his 17-page application to the MCC for registration of Immutides as a medicine, plus correspondence with Medreg, the private medical consultant that facilitated it. He also produced his non-surgical (ethical) request for a new NAPPI code and his NDoH ‘codification of supplier details’ report. (A NAPPI code is a unique identifier for a given ethical, surgical or consumable product which enables electronic transfer of information throughout the healthcare delivery chain.) Curiously, some eight months after submitting analysis sheets and samples to the MCC, Saulez received the

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IZINDABA

now made a ruling and that ‘as far as this product goes, it’s done in this country – under no circumstances may it be sold’. He added, ‘If Fourie had told us after six months that this is totally ineffective, we would have said fine, but we were really confident and he was excited – there was also the possibility of a national contract. Now I’m basically finished and all I want to do is clear my name.’ He denied any suggestion that his business partner, Mr Mike Xego, a former ANC chairperson of the Nelson Mandela Bay region and former provincial MP, used his name to gain any advantage. He said Immutides was not manufactured by Micro Basics in the USA (as reported by Izindaba), but in Arizona, and distributed to Saulez Agencies by Immutrition Inc. in San Diego, California.

now-suspect approval letter from its law enforcement inspectorate. On the strength of this, Makwedini issued an ‘acknowledge ment of approval’, confirming that Saulez Agencies CC had ‘applied to the NDoH for approval to register and supply Immutides Spray as a complementary medicine’. Saulez said he had genuinely believed that this cleared the way for a roll-out.

Immutides Spray widely used

‘We had also registered on the electronic suppliers databases of the Free State, Northern Cape and Western Cape,’ Saulez revealed. He disclosed that his company had sold ‘just under’ 5 000 bottles of Immutides Spray across the board ‘over about a year or so’ (one bottle lasts a single patient one month, taking four sprays in the morning and four in the evening), and claimed that an article in a top magazine for runners had resulted in numerous runners susceptible to colds and flu using the product before and after competitions, ‘with very good results – a lot of women were also giving it to their schoolchildren’, he added.

‘I said to the MCC law enforcement people when they arrived that their actions meant that Lynn Moeng, plus their own person who gave authorisation and Mrs Makwedini, had all made a mistake – and we were being punished!’ – Guy Saulez Saulez said Dr Fourie had told him that Immutides Spray was the only immune modulator he’d seen that actually supported the immune system. Fourie declined to speak to Izindaba, citing official media protocols and referring Izindaba to his senior, Dr Mayekiso. Saulez said Fourie and his pharmaceutical and therapeutic committee decided to issue the spray to ‘certain groups of AIDS/TB coinfected patients with CD4 cell counts below 200 who had already been on antiretroviral

Prof. Andrew Gray, senior lecturer in pharma cology at the School of Health Sciences, Nelson Mandela School of Medicine, University of KwaZulu-Natal.

drugs for 12 months’. This was to be done by attaching the MCC law enforcement department ‘approval’ to the local directive signed by Dr Mayekiso.

‘I jumped through all the hoops’ – Saulez

Saulez said emails were sent to Lynn Moeng in Pretoria informing her of the decision, and that Moeng had asked to be kept abreast of developments – which she was. He said Fourie wanted to trial about 30 patients at each TB hospital, but the project was dropped like a hot potato upon the announcement of a criminal investigation (in terms of the Medicines Act and the Public Service Act). ‘I said to the MCC law enforcement people when they arrived that their actions meant that Lynn Moeng, plus their own person who gave authorisation and Mrs Makwedini, had all made a mistake – and we were being punished! We’ve not put a foot wrong, but we’ve been absolutely castigated and our company name emblazoned all over the place … it’s not a scam, we’re not corrupt and there are no tenders involved,’ he said. Saulez said he accepted that the MCC had

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HIV clinician slams tardy controls

Professor Francois Venter, Deputy Executive Director at the Wits Reproductive Health and HIV Institute, said that, in general, ‘we repeatedly see snake-oil salespeople taking advantage of scared and confused patients, with (historically) little or no regulation or protection from the various agencies. Provincial health departments often seem to confuse things further by encouraging distribution. There are no short cuts for these supplements, especially now that many vitamin and other trials into so-called safe interventions affecting the immune system have actually demonstrated harm.’ Asked by Izindaba whether Makwedini would be included in the provincial probe and about her confidence in such an investigation, Hela referred us to the provincial Health MEC, Dr Mbengashe, whom she said she had instructed to ‘ensure it’s done by a competent authority’. She said the success of any provincial probe would ‘depend on the political will’. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(6):391-393. DOI:10.7196/SAMJ.8085

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SAMA grasps the racial nettle, winning huge majority vote An internal wrangle over how all racial groups are fairly represented in the South African Medical Association (SAMA) led to all-time record attendance at an Extra ordinary General Meeting in Pretoria last month, where an 89% majority backed a pragmatic redefinition of non-racialism. The catalyst for the unusual gathering was vociferous objections by a minority of members of the former ‘Partner Organisations’ (POs) after the current SAMA President, Prof. Ames Dhai, changed the wording of the 2013 Memorandum of Incorporation (MOI). This MOI reflected the historic 1997 Agreement of Understanding (AOU) between the POs and the former predominantly white Medical Association of South Africa (MASA). With her Board’s unanimous backing, on 21 February this year Dhai changed the words ‘Founder Groups’ (read Partner Organisations) to ‘Historically Disadvantaged Individuals’ (HDIs) in a paragraph which decrees that they have at least 50% representation. The Board asked her, through a unanimously approved resolution in December last year, to guide them and make a determination on the nonresolution of the MOI and Company Rules that they had been grappling with for some time. The POs were the Dispensing Family Practitioners Association, the Eastern Cape Medical Group, the South African Medical and Dental Practitioners, the Society for Dispensing Family Practitioners and the Progressive Doctors Group. The latter had dissolved soon after the AOU had been signed. A majority of Board members maintains that the original agreement was a transitional instrument to enable a more equitable, demographically evolving and representative organisation. A group claiming to represent the POs, calling itself the National Medical Forum (NMF) and led by current SAMA Board member Dr Mohamed Adam, said Dhai’s intervention legally and technically altered the bed-rock transformation of SAMA, labelling it a politically inspired conservative regression ‘back to the apartheid MASA’. The NMF is demanding, on threat of legal action, that SAMA stick to the definition of the original POs when ensuring 50% representation in all SAMA

Prof. Ames Dhai, SAMA President.

structures. However, backed by her Board (and the subsequent 89% vote for the new MOI), Dhai says she cannot find proof that the various POs are still legally viable and functioning with constituent memberships and constitutions. She cited contacting one of the NMF’s list of PO executive members, who told her that the last time members of that organisation had met was 10 years ago and that it was ‘in actual fact, defunct’. Dhai, a leading bioethicist with a master’s degree in law, said she found herself ‘challenged with the ethics and morality of including shadow entities in the MOI, a founding document of the SAMA processes’. SAMA’s dilemma was this: had it stuck to the atrophied original MOI and AOU, the voting rights of branch and therefore Council members would be over-ridden by the 50% PO representivity clause, rendering powerless doctors who had long served their constituencies. Said Dhai: ‘It’s very sad that you have a small group of individuals that, under the guise of transformation, want to autocratically rule the SAMA membership. We have a beautiful constitution in our country and we’re 20 years into our democracy. SAMA has transitioned towards a pluralistic, multiracial and multicultural membership that is rich in its diversity and is well into the process of transformation, as evidenced by the trend in its demographic

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composition since 1998. Any revision of its MOI and Company Rules must be reflective and supportive of this growth.’ The NMF’s inflexible position ignored these positive shifts and would take SAMA back to its preconception phase, she added. A sustained NMF internet and email campaign that questioned Dhai’s comp etence and qualifications, queried SAMA Chairman Dr Mzukizi Grootboom’s honesty and cast suspicion on his and his deputy Dr Mark Sonderup’s motivation led to an all-time attendance record at the 12 April Extraordinary General Meeting in Pretoria – in terms of both proxy votes and physical presence of members. Grootboom rejected ‘the disgraceful endeavour by a few individuals to win favour for their distorted objectives via smear campaigns in the social and online media, with the contempt it deserves’. He said the overwhelmingly supportive vote meant that SAMA could now confidently and unambiguously move forward to tackle the country’s pressing social issues, knowing that all its structures reflected representation of HDIs by at least 50%. Asked by Izindaba about SAMA’s current membership demographics, Dhai said estimates were ‘50% people of colour and 50% white’. ‘SAMA does not include race when capturing the demographic details of its members, so transformation status will be derived from surnames. This is not ideal and almost certainly under-represents

SAMA Chairman Dr Mzukisi Grootboom.

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people of colour in the Association,’ she added. She explained that the transition from apartheid in training doctors, regardless of colour, was a process. Medical schools in the country had not yet reached the stage at which graduating doctors were reflective of the country’s current racial demographic profile. The NMF accused Dhai of flouting her mandate and being legally unqualified, and described the Board resolution as ‘a Trojan horse’, passed under false pretenses. It alleged that Board members Drs Zameer Brey and Sonderup helped craft the ‘hastily worded’ resolution, rendering it binding on the Board. The NMF said the ‘new model’ effectively disempowered the five predominantly black organisations that helped give birth to SAMA and called it ‘ultra vires and unlawful’, threatening to hold the relevant Board members personally liable. Dhai denied all allegations, adding that Dr Adam was present at the Board meeting and

that he also voted for the resolution, which was approved unanimously. Prof. Denise White, vice-chair and interim chair of SAMA during some of its most turbulent years (2002 - 2009) and herself a former target of a social media vilification campaign, said she was getting calls from confused and annoyed non-SAMA members asking how their emails were accessed by the NMF and what was going on, after reading the NMF’s recent cyber campaign material. She said that even during her tenure, extracting membership lists from the POs was a recurring problem – which begged the question of whether the POs were being leveraged for personal agendas. ‘Even in those days, they didn’t have the transparency to come up with a list of, say, 100 people,’ she said. White said that, ironically, SAMA’s current leadership was ‘totally transformed, demographically’, while the executives of the junior doctors’ and registrars’ associations were ‘more than’ demographically repre

sentative. The cyber-smear campaign had ‘clearly backfired’, frustrating members who wanted the organisation to focus on more urgent healthcare delivery and professional issues. An elective SAMA National Council meeting was held on 23/24 May (beyond the deadline of this article), at which the controversy was expected to be thoroughly aired and ‘put to bed’ to enable ‘more pressing matters’, including the Competitions Commission probe into the private health care industry, National Health Insurance implementation, the controversial ‘Certi ficate of Need’ and labour relations/trade union matters, to be engaged with as a matter of urgency. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(6):394-395. DOI:10.7196/SAMJ.8436

Netcare – KPMG breached client privilege to boost Competitions Commissions probe Private hospital giant Netcare claims that its former auditors, KPMG, cynically breached client privi lege by sharing det ailed information they had obtained from Netcare with the Competitions Commission – after silently agreeing to help the Commission with its probe. Melanie da Costa, Director of Strategy and Policy at Netcare (and chairperson of the Hospital Association of South Africa), said that a KPMG team had spent three years helping Netcare prepare itself for the healthcare market inquiry. It had unfettered access to Netcare’s strategy, planning, competitive positioning and other business data. This auditing team then allegedly shared this data with another KPMG team, which had, unknown to Netcare, taken on the Competitions Commission advisory and data-gathering brief – raising serious conflict-of-interest issues. She said that the wrangle was between Netcare and KPMG, not the Competitions Commission,

and that it was not a delaying tactic, as a KPMG executive claimed, adding: ‘We have nothing to hide – I can tell you that, hand on heart – KPMG are disingenuously trying to portray that, but it’s most definitely not the issue.’ Da Costa was referring to the ‘totally irresponsible’ accusation by KPMG’s head of legal services, Olaff Abraham van Niekerk, that Netcare’s court action was part of an ‘Operation Kotov’ (a chess move allegedly designed to delay the opponent, in this case ostensibly the Commission, thus hurrying them into a blunder). She said that when KPMG refused to provide Netcare with assurances that it would abide by accepted confidentiality rules, Netcare took them to court. On 29 October last year, the High Court in Gauteng ordered all KPMG staff assisting the Competitions Commission to provide ‘affidavits of assurance’ that KPMG’s internal ‘Chinese walls’ had not been breached – in other words, to swear under oath that they had not breached confidence by obtaining privileged information from

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their colleagues who worked for Netcare. Da Costa said that KPMG belatedly provided Netcare with these affidavits in December last year – revealing that its staff had in fact breached the court order. She claims that KPMG had up to 50 000 documents referencing Netcare (which KPMG refused to hand over). Far from Netcare stalling any Competitions Commission probe, it was KPMG who on 6 January this year requested a court postponement to 20 May.

Simple solution – hand over info to independent attorneys, says Netcare

‘They could have, and still can at any stage, give independent attorneys access to the information they have on Netcare to ensure this matter is speedily resolved, but have chosen not to,’ Da Costa emphasised. Netcare is asking the High Court to rule that: (i) KPMG breached its earlier ruling; (ii) KPMG hand over all relevant documents to independent attorneys to assess their content; and (iii) KPMG cease all work

IT TAKES THE RIGHT COMBINATION TO ACHIEVE SUCCESS.1,2

Introducing the only RAASi/CCB combination with proven all-cause mortality benefits.2,3

Reference: 1. South African Hypertension Guideline 2011. YK Seedat, BL Rayner. S Afr Med J 2012;102:57-84 2. 2013 ESH/ESC Guidelines for the managment of arterial hypertension. Mancia G, Fagard R et al. Euro Heart J. Doi:10.1093/eurheart/eht151 3. Mourad JJ, Jeaune SL et al. Current Medical Research and Opinion. 2010;9:2263-2276 S3 Coveram速 5 mg /5 mg tablets: Perindopril arginine 5 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0933 S3 Coveram速 5 mg/10 mg tablets: Perindopril arginine 5 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0934 S3 Coveram速 10 mg/5 mg tablets: Perindopril arginine 10 mg + Amlodipine 5 mg (as besilate) Reg. No. 43/7.1.3/0935 S3 Coveram速 10 mg/10 mg tablets: Perindopril arginine 10 mg + Amlodipine 10 mg (as besilate) Reg. No. 43/7.1.3/0936 For full prescribing information, refer to the package insert approved by the medicines regulatory authority, Dec 2013. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27 (0)861 700 900. Fax: +27 (0)11 525 3401.

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for the Competitions Commission until the issue is resolved. KPMG’s Van Niekerk claimed in court papers that Netcare went to court ‘as part of Operation Kotov’, adding: ‘Project Kotov seems a very apt name ... Kotov is a Russian surname, the most famous bearer of which was one Alexander Kotov. He was a famous chess grandmaster ... He describes a situation when a player thinks very hard for a long time [about] a complicated position but does not find a clear path, then, running low on time, quickly makes a poor move, often a blunder.’ Van Niekerk maintains that Netcare’s broad strategy is to force the Commission to delay the inquiry for as long as possible and, because of the long delay, cause the Commission to move quickly. He says KPMG’s work for Netcare was ‘technical’ in nature.

KPMG: Netcare ‘hiding something’

Court papers reveal that the Commission suspects that Netcare wants to hide something. The Commission says: ‘Netcare also fears that information provided to the inquiry may lead the commission to initiate a complaint against it or refer it to the tribunal.’ The tribunal has the power to both subpoena evidence and fine companies 10% of their annual turnover for pricefixing or illegal anti-competitive behaviour. Commission spokesperson Trudie Makhaya told Izindaba that any fines would be a byproduct of the wider investigation, which was aimed at ‘bigger competition policy problems’. ‘If we suspect price fixing we can open a new probe and run with it (via the Competition Tribunal), imposing penalties, but that’s not our primary purpose.’ Explaining the Kotov reference, Da Costa told Izindaba that in 2011 Netcare engaged a professional external company to work with its management to assess strategy in the context of various possible future South African healthcare scenarios. They had used chessboard analogies to depict these scenarios, named Kotov, Stalemate, Gambit and Grandmaster. In the UK, where Netcare provides substantial services to the National Health Service set-up, this scenario planning was analysed in the context of the Olympics soon to be hosted in London (scenario analogies being Gold, Silver, Bronze and Off the Podium). ‘The local Kotov scenario was not a response to the more recently announced market inquiry here. KPMG are simply seeking to deflect attention away from their own inappropriate behaviour by making unfounded allegations,’ she said. The

Melanie da Costa, Director of Strategy and Policy at Netcare. Picture: Chris Bateman.

name ‘Project Kotov’ arose from Netcare’s constructive engagement with various external stakeholders, including senior government officials, politicians, academics, opinion formers and business executives, with the aim of stimulating ideas on how to increase access to quality healthcare in South Africa. The ‘Kotov scenario’ was intended to reflect a potential narrative of economic growth, but low social cohesion – with the likelihood of additional regulation perceived to be relatively high. ‘The issue has nothing to do with the Competitions Commission. It’s actually about a professional services firm (KPMG) and its client. It’s about the breach of good faith and the duty of care a professional services firm has to its client. It’s unacceptable behaviour, and we’ll protect our proprietary information and intellectual capital in the interests of Netcare and its shareholders,’ she added.

Commission aims to restore order to ‘law of the jungle’ market

Amended legislation for the first time gives the Commission powers of subpoena with attendant fines for non-co-operation – unlike the probe into the banking sector in 2008, which depended entirely on companies’ voluntary participation and resulted in some impact on bank charges but little change to the way banks do business. The health sector probe is a long-awaited response to a ‘law of the jungle’ situation that has evolved in the unevenly regulated private sector where, among other things, specialists can charge up to 500% of medical aid prices and patients must cough up the payment shortfall, in addition to their everrising medical aid subscriptions. Medical

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schemes argue that they are unable to act in the best interests of their members because of their lack of bargaining power relative to the powerful hospital groups (a controversial Competitions Commission ruling in 2005, aimed at preventing collective price setting without any regulatory oversight, halted price negotiations between the Board of Healthcare Funders, the Hospitals Association of South Africa and the South African Medical Association). New research by economics consultancy Econex on the market concentration of private hospitals, medical schemes and administrators purports to show that, contrary to concerns over growing concentration, the private hospitals market has in fact remained flat since price negotiations were banned. Econex said it had constructed a bed database that allowed it to calculate market share accurately, and found that most consolidation in the hospital market took place before the ban.

Setting tariff guidelines – no consensus

With the Health Professions Council of South Africa and the national health department reluctant to grasp the volatile issue of setting patient tariff guidelines, stakeholders have been operating in a void with, among other legal battles, court applications seeking the ‘proper’ legal interpretation of ‘pay in full’ for Prescribed Minimum Benefits bogging down in technicalities. It’s become a ‘zerosum game’, with each stakeholder operating at the expense of the other and the patient all but forgotten in the mix. As medical inflation soars, medical aids blame collusion between specialists and private hospitals, plus complicity between patients and doctors in abusing hospital plans. They cite the explosion of powerful but expensive new medicines and technologies and the fee-forservice payment system, plus the fragmented structure in which doctors, hospitals and all other providers work in silos, with almost no co-ordination between them. Specialists, on their side, point to almost intolerable workloads resulting from serious shortages in their numbers, rampant brokerage and administration and managed-care costs in medical aids, plus soaring litigation insurance costs. It’s a toxic, society-unfriendly mix that has placed huge pressure on the Competitions Commission to come up with provisional findings and recommendations by its target date of October 2015. Briefing stakeholders in mid-May, the Chairman of the Health Inquiry, former Chief Justice Sandile Ngcobo, said that its success was inextricably linked to the

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open and transparent airing of views and information. He said his hand-picked team of experts was developing a set of ideas about how harmful effects of competition might arise in the relevant markets. Dubbed ‘theories of harm’, these were hypotheses or tools enabling them to identify whether there were features that might prevent, distort or restrict competition in the private healthcare markets. He emphasised that theories of harm were not findings of harm, but simply analytical tools to guide analysis. ‘They will be deepened and revised as the

inquiry’s thinking develops,’ he added. Harm to competition could come from market power, including market concentration, barriers to entry and expansion, imperfect information, regulatory framework and vertical relationships. Judge Ngcobo said the issuing of ‘information requests’ would be done by August this year. The first round of public hearings would be held between 1 March and 30 April next year. Beginning in May next year, the inquiry would analyse and review all information gathered, putting provisional findings and recommendations

out for public comment by October 2015. Quizzed on how the Netcare court challenge to its auditors might affect these timelines, Competitions Commissioner Tembinkosi Bonakele would only say that ‘the probe is live and happening, just slower than anticipated’.

George had a wonderful memory, and until the month before he died, despite his virtual blindness, he kept up to date with events and read avidly using his Merlin magnifier. He could do complex mathematical calculations in his head, and remembered the names of people he had met in his childhood and every telephone number he had ever had in his long life. If anyone wanted to know something from the past, George would invariably supply the answer. He adapted to new inventions, taking to the computer and later his iPad with alacrity, and could learn new languages with ease. He spoke English, Afrikaans and Dutch fluently, and picked up some isiZulu, Italian and Greek. He did cryptic crosswords every day until the day before he died. A keen sportsman, George swam for Natal, captained the Wits university water polo team, and played tennis into his 70s and golf until the age of 90. He loved rugby and cricket and continued to take an interest in these sports until his death. George was an enthusiastic man. He loved his music, mostly jazz from the 1930s and 1940s, he loved to read, he loved learning about new things, and he always enjoyed stories and hearing about things other people were doing. He loved the game reserve and going on holiday with his family, he loved the sea and surfed until he could no longer manage the beach, he loved to bake and cook, he loved to teach, he loved to entertain, he loved travelling, and he adored his wife, children, grandchildren and greatgrandchildren. He was a tolerant and stoical man, and never liked to show that he was in pain or discomfort. He had a wonderful sense of humour and loved to laugh. He had enormous energy and zest for life, especially

revealed by his interest in other people. He listened with focused attention, genuinely interested in their stories, and his politeness and respectful attention to others, whatever their age or station in life, was a wonderful example to everyone he encountered. George was not one-dimensional; he may have been cheerful company when enter taining friends, but he was also a methodical and careful professional and parent. He was blessed with the talent to use his energy astutely and effectively, achieving many things in his long life on a very wide front. As a medical doctor, George sometimes had the sad task of helping families over their grief at the passing of a loved one. He was a district surgeon at Sharpeville after the shootings, a bitter and terrible experience for a war veteran. This could have made a lesser man become cynical, but he knew and acted upon the knowledge that ultimately everyone is responsible for their own happiness. George used his close relationships to express his life and dreams. He and his wife Helen, also a radiologist, had a remarkable and exemplary marriage. Helen was his companion, guiding star, great passion and support. He had four children, ten grand children and two great-grandchildren, and had a special relationship with them all. George Albertyn has left us a rich and brilliantly lit path and example. He took hold of life with both hands and shared his journey with us all. He died peacefully in his sleep on 20 March 2014.

Chris Bateman chrisb@hmpg.co.za S Afr Med J 2014;104(6):395-397. DOI:10.7196/SAMJ.8438

OBITUARY Christian George Albertyn

Christian George Albertyn was born on 13 December 1920 in Bethal, Transvaal. He started studying medicine at the University of the Witwatersrand in 1939. His studies were interrupted by World War II, and he joined up in 1941 and served in Egypt and Italy. He returned home in 1945, graduated in 1949, and did his internship at Edenvale Hospital. George worked as a general practitioner in Vereeniging until 1966, when he started to specialise in radiology at the University of Pretoria, qualifying in 1969. He worked as a radiologist in private practice until he retired at the age of 65, and then continued to work as a radiologist at Steve Biko Academic Hospital, where he was involved in teaching registrars, until the age of 75. During his career as a radiologist he served as President of the Radiological Society.

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Lynda Albertyn-Cross Child, Adolescent and Family Unit, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa drlcross@telkomsa.net

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BOOK REVIEWS 273 Amazing Days: The Story of Life Before Birth

poetry, examples of which have appeared in the SAMJ, and grooks – originally a form of short, pithy Danish poetry). Here is an example. Blastocyst – life already planned Life already planned Like writing in the sand Half-mum, half-dad I will be And in larger part, just me J P van Niekerk Consulting Editor, SAMJ jpvn@iafrica.com

By Peter Folb. AuthorHouse UK, 2014. ISBN (paperback) 978-1 4918-8814-8; ISBN (ebook) 978-1-4918-8815-5. Author email: peterfolb@gmail.com This is a story of the marvel of human life from conception to birth. Although the book was designed for young readers, it is suitable for use by anybody who wishes to know about our conception, development and birth. It can be appreciated at several levels. Firstly, it is a fascinating story, told simply and with wise interspersed comments; secondly, the author’s numerous colourful illustrations and line drawings are works of art (created on his iPad – previously he was noted for his woodcut art); and thirdly, and perhaps most importantly, the main messages are conveyed by exquisite poetry (mainly haiku, a Japanese form of

Across the Wide Zambezi: A Doctor’s Life in Africa By Warren Durrant. London: PublishNation, 2013. ISBN 978-1-291-44343-1.

Leaving his GP practice in the UK at age 39, Warren Durrant took a medical officer post in Ghana. This was followed by an appointment at a mine hospital in Zambia and a trip home via the Congo River. Realising that Africa had got under his skin, he settled in what was then Rhodesia, where he married much later and had a family. This story of a colonial doctor is packed with details of many interesting or bizarre cases that Durrant had to handle on his own or with the help of a range of colleagues in the various hospitals in which he found himself. We also meet many interesting characters. The Rhodesian ‘war of liberation’

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washes over his many medical experiences and includes a gunfight at the Troutbeck Inn. Following liberation of the country, his financial circumstances result in his going into private practice at the age of 60 and then returning to England with his family. Although the bush war is not discussed in political terms, the horrors of its social and medical results are graphically described. It is sad that a doctor who made such a valuable contribution and enjoyed himself so much was not able to remain in the country because of deteriorating circumstances. J P van Niekerk Consulting Editor, SAMJ jpvn@iafrica.com

FORUM

OPINION

Legalising medical use of cannabis in South Africa: Is the empirical evidence sufficient to support policy shifts in this direction? C D H Parry, B J Myers Charles Parry is Acting Vice-President (Intramural Research) at the South African Medical Research Council (MRC), Director of the Alcohol, Tobacco and Other Drug Research Unit (ATODRU) at the MRC, and an Extraordinary Professor in the Department of Psychiatry at Stellenbosch University, Tygerberg, Cape Town, South Africa. His interests include substance abuse epidemiology, alcohol and drug policy, and the effect of substance abuse on HIV and AIDS. Bronwyn Myers is a Chief Specialist Scientist in the ATODRU and an Honorary Associate Professor in the Department of Psychiatry and Mental Health at the University of Cape Town, South Africa. Her interests include alcohol and drug intervention and services research, and drug policy. Corresponding author: C Parry (cparry@mrc.ac.za)

Inkatha Freedom Party MP Mario Oriani-Ambrosini’s impassioned plea to legalise the medical use of cannabis must be understood in the context of his own condition as well as legislative changes in at least ten countries. This article argues that any decisions to shift policy must be based on a consideration of the evidence on the risks and benefits associated with the medical use of cannabis for the individual and broader society. It concludes that there are important gaps in the evidence base, particularly in human trials supporting the efficacy of cannabis use for treating and preventing medical conditions and alleviating negative symptoms associated with these conditions. South African researchers should be enabled actively to support development of the necessary evidence base by conducting preclinical and clinical research in this area. Human trials to establish the efficacy of the use of cannabis/cannabinoids in addressing AIDS wasting syndrome and other negative sequelae of HIV and AIDS are especially needed. S Afr Med J 2014;104(6):399-400. DOI:10.7196/SAMJ.8135

On 19 February 2014, Inkatha Freedom Party MP Mario Oriani-Ambrosini made an impassioned plea to President Zuma and the South African (SA) government to legalise the medical use of cannabis and informed Parliament that he was introducing a private member’s bill, the Medical Innovation Bill, to move this agenda forward.[1] The President responded by indicating that he had asked the Minister of Health to look into the matter. Medical cannabis refers to the use of cannabis and its constituent cannabinoids, including Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), as therapy to treat or alleviate symptoms of medical conditions. In some countries synthetic cannabinoids, such as nabilone (Cesamet) and dronabinol (Marinol), are available for these purposes. Cannabinoids are delivered through various mechanisms, the most obvious being through smoking. However, smoking cannabis can be hazardous to health over the long term because toxic compounds are created in the combustion process. In addition, it is difficult to regulate the amount of cannabinoids being ingested. However, users report that smoking relieves symptoms quickly. Cannabinoids can also be ingested orally, inhaled through vapourisers (Nabidiolex), and used transdermally and via suppositories. Synthetic cannabis is most often delivered in pill form. Obviously these delivery mechanisms vary in cost and ease of access. In SA, smoking is the cheapest and most easily accessible delivery mechanism as cannabis is widely available to purchase, though not without risk of arrest. Cannabis oil is also available on the black market, and there are recipes on the internet for people seeking to make their own.[2] Medical use of cannabis is now legal in Austria, Canada, Finland, Germany, Israel, Italy, the Netherlands, Portugal and Spain.

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Furthermore, medical users of cannabis in 20 states and the District of Columbia in the USA are not prosecuted as long as they are in compliance with the state’s marijuana sale regulations. In contrast, it is currently illegal to possess cannabis or trade in it in SA.[3] We also have no medications approved by the Medicines Control Council that contain THC, other cannabinoids or even synthetic cannabinoids.[4] Cannabis has also not been approved for medical use by the US Federal Drug Administration, largely as a result of three shortcomings: (i) the lack of human clinical trials to show that the benefits outweigh the risks; (ii) inconsistencies in the main chemical compound, particularly when smoked; and (iii) the negative health effects sometimes associated with cannabis use, particularly when smoked.[5] Any decisions on legalising the medical use of cannabis must take into consideration the risk of possible harms that have been demonstrated among some people who regularly use cannabis, the possible effects that legalising medical use of cannabis may have on the non-medical use of the drug, possible impacts on communities and broader society, and the quality of the evidence supporting the medical use of cannabis.

Harms associated with cannabis use

On the first issue, our own research has shown associations between cannabis use and road traffic injuries and other forms of trauma,[6] crime, particularly property crime and murder,[7] and sexual HIV risk behaviours,[8] but the causal mechanisms were not clearly elucidated. Unpublished research conducted in SA using functional magnetic resonance imaging also showed cognitive deficits associated with cannabis use, even after participants had stopped using cannabis for several weeks (Carey P, et al. – ‘Functional magnetic resonance imaging (f-MRI) of abstinent cannabis, cannabis/methaqualone users, and normal controls’,

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presented at the 6-monthly meeting of the South African Community Epidemiology Network on Drug Use, 16 November 2005). In addition, a recent systematic review identified several adverse effects associated with cannabis use, including a dependence syndrome, an increased risk of motor vehicle crashes, impaired respiratory function, cardiovascular disease, and adverse effects of regular use on adolescent psychosocial development and mental health.[9] However, these harms should not be overstated, as they do not affect all people who use cannabis. Certainly, at a community level the harms are a lot fewer than those associated with alcohol and tobacco use.[10,11]

Impact of medical cannabis use on non-medical use

On the second issue, very few studies have examined whether allowing medical use of cannabis impacts on its non-medical use. A large study investigating the relationship between state legalisation of medical cannabis and cannabis use, abuse and dependence in the USA found that states that legalised medical cannabis had higher rates of use, but the authors acknowledged that this association was not necessarily causal.[12] National surveys in Canada have indicated substantial use of cannabis for therapeutic purposes outside of the Health Canada programme, with an order of magnitude of between 13 and 33 persons for every one person in the programme.[13]

Quality of the evidence supporting medical use of cannabis

The third important issue when considering whether to legalise the medical use of cannabis is the quality of the evidence in support of its effects on medical conditions. In his speech in Parliament, OrianiAmbrisoni referred to studies from Harvard cited in a Cannabis Position Paper presented to the Central Drug Authority in November 2013.[14] This paper highlights various studies, mainly preclinical but some involving human subjects, that showed positive effects on a variety of conditions including Alzheimer’s disease, amyotrophic lateral sclerosis, chronic pain, multiple sclerosis, diabetes mellitus, dystonia, fibromyalgia, incontinence, gastrointestinal disorders and various cancers, including lung cancer, the condition affecting OrianiAmbrisoni. Other conditions that have reportedly been positively affected by cannabis use include atopic dermatitis, brain injuries, eating disorders, epilepsy, glaucoma, Huntington’s disease, neuromuscular disorders, rheumatoid arthritis, sleep disorders and Tourette’s syn drome, though in many cases the supportive evidence is equivocal.[15] Cannabinoids are used for symptom management in cancer, while there is emerging evidence that cannabinoids may have anticancer effects, particularly antitumour effects.[16] However, few human clinical trials have been published in this area, and more trials are required to achieve certainty that cannabis or cannabinoids can be used as anticancer agents.[16] With regard to pain relief in cancer patients, in experimental models of acute pain, inhaled cannabis resulted in dose-dependent pain relief. In patients with chronic pain, both cannabis and cannabinoids outperformed placebo treatment. However, few studies have compared cannabis or cannabinoids with conventional medications used to manage pain in cancer.[16] The effects of cannabis or cannabis extracts on AIDS wasting syndrome or weight loss from AIDS have been studied, mainly because cannabis or cannabinoids reportedly stimulate the appetite. A Cochrane review found that the seven studies included in the review suffered from bias and small sample size and lacked longitudinal data, limiting the extent to which conclusions could be drawn.[17] The evidence is stronger regarding the positive effect of cannabinoids in treating chemotherapy-induced nausea and vomiting in cancer patients.[16,18] Human studies suggest efficacy of cannabinoids in

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the management of chemically induced nausea and vomiting, but further research aimed at developing new endocannabinoid-based antinausea and antiemetic therapies is still warranted.[18]

Conclusions

There appears to be a divide between the reported medical benefits of cannabis use and well-executed studies on the benefits and risks of such use.[13] Although evidence from preclinical studies points to the potential for cannabinoids to contribute to symptom alleviation and possible effects on disease status for a number of medical conditions, there are significant gaps in our understanding of the potential benefits and risks associated with their use. Most notable is the lack of evidence from human trials. That said, and in line with part of the reasoning behind the proposed legislation,[1] the SA government should make it easier for researchers to conduct studies on the medical use of cannabinoids (including synthetic cannabinoids), and funding should be made available to support this research, especially where it could lead to medical innovation. This research should include: (i) an investigation of factors that led to the policy shifts in countries that have legalised the medical use of cannabis, and what their experiences have been of this policy shift; (ii) maintaining a watching brief on the literature in this area, as advances in scientific knowledge are taking place rapidly; (iii) establishing surveillance systems to assess the poss ible influences of medical cannabis use on non-medical cannabis use; and (iv) conducting both preclinical and human studies to study the effects of cannabinoids on symptom alleviation and disease status. For the latter, longitudinal studies that investigate the effects of cannabinoid inhalation and ingestion on the quality of life of patients with HIV/AIDS, where SA should lead the way, are especially needed. In conclusion, while in principle we are open to the idea of cannabis use for medical conditions, we need to strengthen the empirical evidence base in support of the benefits of such use, and find ways to minimise the risk of harms, before we can recommend legalising medical cannabis use in SA. 1. Oriani-Ambrosini MGR. Medical Innovation Bill: Publication and invitation for public comment (Notice 100 of 2014). Government Gazette No. 37349, 18 February 2014, Vol. 584. 2. Kellzzy. Making cannabis oil in South Africa. http://kitchencures.wordpress.com/2013/06/16/104/ (accessed 26 February 2014). 3. The Drugs and Drug Trafficking Act, 1992 (Act No. 140 of 1992). 4. Medicines and Related Substances Act, 1965 (Act No. 101 of 1965). 5. National Institute on Drug Abuse. DrugFacts: Is marijuana medicine? http://www.drugabuse.gov/publications/ drugfacts/marijuana-medicine (accessed 25 February 2014). 6. Parry CDH, Plüddemann A, Donson H, Sukhai S, Marais S, Lombard C. Cannabis and other drug use among trauma patients in Cape Town, Port Elizabeth and Durban, South Africa, 1999-2001. S Afr Med J 2005;95(6):429-432. 7. Parry CDH, Plüddemann A, Louw A, Leggett T. The 3-Metros Study of Drugs and Crime in South Africa: Findings and policy implications. Am J Drug Alcohol Abuse 2004;30(1):167-185. [http://dx.doi.org/10.1081/ ADA-120029872] 8. Parry CDH, Petersen P, Carney T, Dewing S, Needle R. Rapid assessment of drug use and sexual HIV risk patterns among vulnerable drug using populations in Cape Town, Durban and Pretoria, South Africa. SAHARA-J: Journal of Social Aspects of HIV/AIDS 2008;5(3):52-58. [http://dx.doi.org/10.1080/17290376.2 008.9724909] 9. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009;374(9698):1383-1391. [http://dx.doi.org/10.1016/S0140-6736(09)61037-0] 10. Lim SS, Vos T, Flaxman AD, et al. The burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions 1990-2010: A systematic analysis. Lancet 2012;380(9859):2224-2260. [http://dx.doi. org/10.1016/S0140-6736(12)61766-8] 11. Nutt DJ, King LA, Phillips D. Drug harms in the UK: A multicriteria decision analysis. Lancet 2010;376(9752):1558-1565. [http://dx.doi.org/10.1016/S0140-6736(10)61462-6] 12. Cerdá M, Wall M, Keyes KM, Galea S, Hasin D. Medical marijuana laws in 50 states: Investigating the relationship between state legalization of medical marijuana and marijuana use, abuse and dependence. Drug Alcohol Depend 2012;120(1-3):22-27. [http://dx.doi.org/10.1016/j.drugalcdep.2011.06.011] 13. Walsh Z, Callaway R, Belle-Isle L, et al. Cannabis for therapeutic purposes: Patient characteristics, access, and reasons for use. Int J Drug Policy 2013;24(6):511-516. [http://dx.doi.org/10.1016/j.drugpo.2013.08.010] 14. Du Plessis A, Visser I, Smit A (on behalf of the South African Cannabis Working Group). Cannabis Position Paper 2013. https://www.daggacouple.co.za/wp-content/uploads/2013/11/SANCWG-Cannabis-PositionPaper-of-2013.pdf (accessed 25 February 2014). 15. Mayo Clinic. Drugs and supplements: Marijuana (Cannabis sativa). http://www.mayoclinic.org/drugssupplements/marijuana/evidence/hrb-20059701 (accessed 26 February 2014). 16. Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliviera LMQ, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: Systematic review and meta-analysis. Eur J Cancer Care 2008:17(5):431-443. [http://dx.doi.org/10.1111/j.1365-2354.2008.00917.x] 17. Lutge, EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev 2013; Issue 4. Art. No.: CD005175. [http://dx.doi. org/10.1002/14651858.CD005175.pub3] 18. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 2014;722:134-146. [http://dx.doi.org/10.1016/j.ejphar.2013.09.068]

Accepted 12 March 2014.

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CLINICAL ALERT

Haemophagocytic lymphohistiocytosis: A fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock B Price, J Lines, D Lewis, N Holland Brendon Price, Jennifer Lines and Nicole Holland are based in the Department of Haematology, and Dorothy Lewis in the Department of Histopathology, at Lancet Laboratories, Johannesburg, South Africa Corresponding author: B Price (pricebrendon@yahoo.com)

Acquired haemophagocytic lymphohistiocytosis (HLH) is a condition involving cytokine overproduction by defective cytotoxic T lymphocytes and natural killer cells, resulting in life-threatening cytopaenias and multiorgan infiltration and dysfunction. Triggers for acquired HLH vary and include viruses, malignancies and autoimmune conditions. Recent reports suggest that HLH may be underdiagnosed owing to variable clinical presentations, diagnostic criteria and a low level of awareness on the part of medical personnel, thus delaying prompt treatment and contributing to high mortality rates. Five patients in whom acquired HLH was diagnosed, following bone marrow investigations, during the period of May - September 2013 are presented. All were at an advanced stage of their disease at time of diagnosis. The three patients who were HIV-positive had a coexisting malignancy at the time of HLH diagnosis, which may have triggered HLH. A definite trigger was not identified in the remaining two HIV-negative patients despite early concerns regarding autoimmune disease. Two patients received timeous diagnosis, started chemotherapy and are currently improving. The remaining three succumbed to their illness. Aquired HLH in adults may be more common in the acute care setting than currently appreciated. As awareness of this condition and its treatment is currently low, it may remain undiagnosed until the disease has evolved into multiorgan failure. Fever in the absence of infectious agents, marked hyperferritinaemia, unexplained cytopenias, organomegaly or liver dysfunction should raise the suspicion of HLH. Timeous introduction of therapy will improve outcomes. S Afr Med J 2014;104(6):401-406. DOI:7196/SAMJ.7810

Haemophagocytic lymphohistiocytosis (HLH) is a condition in which there is pathological, unregulated cytokine-mediated stimulation of the immune system by functionally defective cyto toxic T lymphocytes (CTLs) and natural killer (NK) cells.[1-4] Massive amounts of proinflammatory cytokines (interleukins 1, 6 and 10, granulocyte macrophage colony stimu lating factor, tumour necrosis factor-α and interferon-γ (IFN-γ)) released by CTLs result in increased production of non-neoplastic lymphocytes and macrophages/histiocytes, along with unremitting fever. Thereafter, haemophagocytosis and infiltration of organs by cytokine-activated histiocytes result in organomegaly, multiorgan dysfunction, life-threatening cytopenias and sepsis.[1] HLH may be classified as primary/genetic or secondary/acquired (Table 1). In genetic HLH, a mutation occurs in one of the proteins responsible for intracellular vesicle docking and release of preformed proapoptotic granzyme and perforin.[1-4] This in turn reduces the ability of CTLs and NK cells to induce apoptosis of antigenpresenting cells and clonally expanded T lymphocytes. In acquired HLH, the exact cause of depressed CTL and NK cell activity is less well understood, but it is strongly associated with specific viral infections, malignancies and autoimmune disorders.[3,5] It is postulated that patients who develop acquired HLH may in fact have an underlying (as yet unidentified) genetic predisposition.[6] Genetic HLH arises in childhood, usually before 1 year of age, but there are reports of adults presenting with primary HLH at advanced

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ages.[1,7] As it is due to a genetic mutation, the only chance of cure is stem cell transplantation. Acquired HLH can occur at any age and is treated with combination chemotherapy via the HLH-94 trial protocol,[8] along with treatment for the suspected trigger (e.g. infection). In cases with a clear trigger for acquired HLH (e.g. cytomegalovirus (CMV), HIV), reports of complete cure (using immunoglobulins or antiretrovirals) without the need for additional chemotherapy have been described.[9-11] Patients who are diagnosed with acquired HLH that does not respond to the HLH-94 chemotherapy regimen or relapse post-chemotherapy are referred for stem cell transplantation.[8] Much of our knowledge about HLH is derived from Swedish paediatric studies in the context of primary HLH, where an incidence of 0.12/100 000/year has been estimated.[6] The exact incidence of acquired HLH in adults is unknown, although a single-institution retrospective analysis of malignancy-associated acquired HLH puts the estimate at 0.36/100 000/year.[12] The diagnostic criteria for HLH are published by the Histiocyte Society (http://www.histiocytesociety.org) and require either a confirmed molecular diagnosis of genetic mutations known to be associated with HLH or the presence of at least 5/8 clinical and laboratory criteria. These include: • prolonged fever • splenomegaly • haemophagocytosis (in bone marrow, lymph node or spleen) • cytopenias

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Table 1. Types of HLH* Type

Subtype

Underlying cause/trigger

Genetic/primary

Familial

Autosomal and X-linked recessive genetic mutations of proteins involved in granzyme/perforin-mediated cytolytic function in CTL/NK cells: PRF1, UNC13D, STXBP2, RAB27A, STX11, SH2D1A, XIAP

Immune deficiency-associated

Chédiak-Higashi syndrome Griscelli syndrome X-linked lymphoproliferative syndrome

Infection-associated

Viral (EBV, HSV, HIV, CMV, B19V) Bacterial, protozoal, mycobacterial

Malignancy-associated

Lymphoma Leukaemia (particularly T- and NK-cell types) Solid tumours (rare)

Rheumatic disease-associated (macrophage activation syndrome)

SLE, scleroderma, Sjögren’s syndrome, mixed connective tissue disorders

Acquired/secondary

HLH = haemophagocytic lymphohistiocytosis; CTL = cytotoxic T-lymphocyte; NK = natural killer; PRF1 = perforin 1 gene; UNC13D = unc-13 homolog D gene; STXBP2 = syntaxin binding protein 2 gene; RAB27A = Ras-related protein Rab-27A gene; STX11 = syntaxin 11 gene; SH2D1A = SH2 domain protein-1A gene, XIAP = X-linked inhibitor of apoptosis gene; EBV = EpsteinBarr virus; HSV = herpes simplex virus; HIV = human immunodeficiency virus; CMV = cytomegalovirus; B19V = parvovirus B19; SLE = systemic lupus erythematosus. [1]

*Adapted from Lehmberg and Ehl,

• • • •

[2]

Usmani et al.,

[3]

Janka and zur Stadt

[6]

and Arceci.

fasting hypertriglyceridaemia or hypofibrinogenaemia hyperferritinaemia low/absent NK cell activity elevated soluble CD25 (interleukin-2 receptor) levels.

HLH can mimic many other conditions in its early stages (Table 2). It may therefore be underdiagnosed in patients with infection or malignancy who present with systemic inflammatory response syndrome (SIRS) and acute multiorgan dysfunction.[13,14] A high index of suspicion is required to promptly initiate therapy in these patients. Because awareness of acquired HLH is limited, it typically has a high mortality rate (50 - 100%), partly as a reslt of delayed diagnosis and treat ment.[14] Recent studies suggest that acquired HLH is an under-recognised cause of death in adult intensive care units (ICUs).[13,15] Patients usually present with features of SIRS (including pyrexia of unknown origin, tachycardia and leucopenia) and disseminated intravascular coagulation (DIC), organomegaly (specifically splenomegaly with or without hepatomegaly), and may additionally exhibit hepatic dysfunction, neurological deficits or septic features.[1-3,6,13,15] As not all diagnostic features may be present initially, it is essential to monitor patients clinically and biochemically at regular intervals. In the early stages, there may be mild manifestations (e.g. skin rashes) that resolve spontaneously with subsequent exacerbations.[1] Importantly, haemophagocytosis is not specific to HLH and can be demonstrated in various non-HLH conditions such as post-blood transfusion, haemolysis, myelodysplasia/bone marrow failure or sepsis.[4,5,13,15] Moreover, haemophagocytosis may not be seen in up to 20% of initial bone marrow biopsies[16] and therefore, despite the nomenclature, can neither be diagnosed nor excluded solely on the basis of presence or absence of haemophagocytosis.[1,15] We describe five cases of acquired HLH that were diagnosed over the course of 5 months (May - September 2013 ) in private hospitals in the greater Johannesburg area, South Africa (SA), with the aim of raising awareness and increasing the diagnostic pickup rate of acquired HLH in adult patients admitted to wards and ICUs with multiorgan dysfunction and/or presumed sepsis/SIRS. Although only three patients in this series were HIV-positive, the high burden of HIV in SA may make this condition more common,

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potentially triggered by coexisting HIV-associated infections and malignancies. All patients were diagnosed with acquired HLH following bone marrow aspiration and trephine (BMAT). Clinical information (viz. presenting signs and symptoms, temperature trends, organomegaly) was obtained either from the bedside at time of BMAT or alternatively via communication with the treating physician. All laboratory data were accessed on the password-protected Meditech software system at Lancet Laboratories. The clinical and laboratory details of the cases are shown in Table 3. Four cases fulfilled the diagnostic criteria for HLH. These include at least 5/8 criteria (listed as B1 - B8). No genetic mutational analyses were performed (A). Individual results that fit the HLH diagnostic criteria are highlighted in bold. Case 2 fulfilled only four criteria, but was included in the case series in view of her markedly raised ferritin level (24 370 µg/l), hepatomegaly and active haemophagocytosis. (Had NK cell activity and/or CD25 assays been available, these may have been able to confirm the diagnosis conclusively.) All patients were young adults. Cases 2 and 4 tested positive for HIV prior to admission and were receiving treatment. During admission, a drug-resistance polymerase chain reaction (PCR) screen performed on case 2 showed resistance to efavirenz. Case 1, who was initially HIV-negative according to an enzyme-linked immunosorbent assay (ELISA) and p24 antigen assay, seroconverted during the course of treatment. Cases 1 and 2 were diagnosed with diffuse large B-cell lymphoma at the time of HLH diagnosis. Neither had undergone chemotherapy for lymphoma prior to HLH diagnosis. Case 2 additionally had a prior history of high-grade ductal carcinoma. Case 4 had been treated for Kaposi’s sarcoma (KS) prior to HLH diagnosis. All patients had prolonged fever prior to the diagnosis of HLH. This feature is consistent among HLH patients and is due to CTL/ NK-mediated hypercytokinaemia rather than to specific infectious agents.[1,4] Fevers generally do not resolve despite the use of empiric antibiotics. Splenomegaly was assessed either clinically or radiologically, absence of splenomegaly in cases 2 and 4 being confirmed on radiological imaging. Splenomegaly is a fairly consistent feature in HLH and is due to organ infiltration by activated histiocytes and

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Table 2. Mechanisms involved and differential diagnoses of typical clinical and laboratory findings in HLH* Pathology

Mechanism

Differential diagnosis

Cytopenia/s

Haemophagocytosis via activated histiocytes

Bone marrow hypoplasia/ failure Bone marrow infiltration (malignant, infective) Drug-induced myelotoxicity (e.g. HAART, chemotherapy) Sepsis ITP/TTP Sequestration (e.g. splenomegaly)

Liver dysfunction

Infiltration by activated histiocytes Hepatocyte damage

Viral hepatitis Drug-induced hepatitis Warfarin toxicity DIC Sepsis

Fever

Pro-inflammatory cytokine release by CTL/NK cells

Infection

Neurological deficit/s

Demyelination

Infections (meningitis, encephalitis) CVA, space-occupying lesion

Hyperferritinaemia

Released from activated histiocytes ? Released from damaged hepatocytes Ferritin receptor down-regulation

Sepsis Anaemia of chronic disorders Iron overload disorders SLE Fulminant hepatic failure

Hypertriglyceridaemia

Liver infiltration by histiocytes Decreased levels of lipoprotein lipase

Dyslipidaemia Diabetes Nephrotic syndrome Drugs

Hypofibrinogenaemia

Liver infiltration

DIC Liver failure

Hepatomegaly/splenomegaly

Organ infiltration by activated histiocytes

EPTB Malignancies (e.g. CML, hepatic metastases) Infections (e.g. malaria) Haemolytic states Extramedullary haematopoiesis Storage disorders

Cutaneous manifestations (commonly panniculitis and/ or purpura)

Histiocytic and lymphocytic infiltration

Eczema Erythema nodosum Panniculitis Drug-related Kawasaki disease

HLH = haemophagocytic lymphohistiocytosis; HAART = highly active antiretroviral therapy; ITP = idiopathic thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura; DIC = disseminated intravascular coagulation; CTL = cytotoxic T-lymphocyte; NK = natural killer; CVA = cerebrovascular accident; SLE = systemic lupus erythematosus; EPTB = extrapulmonary tuberculosis; CML = chronic myeloid leukaemia. [1]

*Adapted from Lehmberg and Ehl,

[2]

Usmani et al.,

[4]

Jordan et al.,

[13]

Okabe et al.,

[15]

Raschke and Garcia-Orr

lymphocytes.[1,2] Hepatomegaly may similarly develop and commonly results in deranged liver enzymes secondary to hepatocyte damage. Organomegaly was been shown to be present in 90% of HLH patients in a recent Indian case series.[14] All patients exhibited cytopenias during their stay, although cell counts often fluctuated markedly, most commonly following transfusion of blood products. As a result, the diagnostic bi-/pancytopenia may not be present following blood/platelet transfusion, a fact to be borne in mind when working up a patient for suspected HLH. Importantly, underlying neutropenia may be masked if recombinant growth factors (e.g. filgrastim ) have recently been administered. All the patients demonstrated haemophagocytosis in the bone marrow, probably because all were at an advanced stage of illness at the time of BMAT and their haemophagocytosis was well established. The presence of haemophagocytosis signalled the possibility of HLH

403

[17]

and Morrell et al.

and prompted urgent communication with the treating physicians and additional focused laboratory investigations including ferritin, fibrinogen and triglyceride levels. Three patients had raised triglycerides above the diagnostic 3 mM level, although the remaining two showed levels closely approaching this (2.91 mM and 2.95 mM). Fasting hypertriglyceridaemia is seen in ~70% of HLH patients and is thought to be the result of cytokine-mediated lipoprotein lipase inhibition.[1,13] Caution should be applied when interpreting this parameter in patients known to be dyslipidaemic, when a fibrinogen level should preferentially be tested as it is scored under the same diagnostic criterion. Ferritin and fibrinogen are liver-derived positive acute-phase reactants. In the normal inflammatory response, levels of both should increase. However, markedly raised ferritin levels in HLH denote excessive production by activated histiocytes and possibly release

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Table 3. Case series of patients diagnosed with acquired HLH* Case 1

Case 2

Case 3

Case 4

Case 5

32, male

34, female

25, female

47, male

29, female

. Molecular diagnosis for HLH-associated A genetic mutations

B1. Fever

Present

B2. Splenomegaly

Present

Absent (mild hepatomegaly)

Present

Absent

Present

B3. Cytopenia (≥2/3 lineages)

Present

Age (yrs), gender HLH diagnostic criteria

Anaemia (Hb ≤9 g/dl)

8.2

15.4

7.3

7.7

8.8

Absolute neutropenia (≤1×109/l)

0.71

0.24

0.1†

8.62

16.8

Thrombocytopenia (≤100×109/l)

4. Haemophagocytosis present in BM, B spleen or lymph node

Present (BM)

Present (BM and lymph node)

Present (BM)

Present (BM and lymph node)

B5. Fasting hypertriglyceridaemia (≥3 mmol/l) and/or

4.22

2.91

4.20

2.95

7.79

hypofibrinogenaemia (≤1.5 g/l)

0.94

3.70

0.6

B6. Hyperferritinaemia (≥500 µg/l)

11 427

24 370

19 115

4 072

147 952

B7. Increased soluble CD25 (≥2 400 U/ml)

B8. Low/absent NK cell activity

Additional investigations HIV status

Positive

Negative

Positive

Negative

Herpesvirus (EBV, CMV, HHV-8)

EBNA-positive on trephine‡

EBV serologynegative CMV-negative

Known HHV-8 positive (KS)

Negative

Fungal

Positive

Negative

Blood cultures

Negative

CoNS

PCR

Negative for P. jiroveci

Negative for CMV

Negative for H1N1, influenza A and B

Autoimmune screen

Negative for CTD

Negative for c-ANCA, antiglomerular base

Associated malignancy

Yes

Likely trigger of HLH

Diffuse large B-cell lymphoma ? HIV

B-cell lymphoma EBV ? HIV

Uncertain infection

Sepsis ? HIV ? HHV-8

? Autoimmune

Clinical outcome

Alive

Died

Alive

HLH = haemophagocytic lymphohistiocytosis; ND = not done; Hb = haemoglobin; BM = bone marrow; NK = natural killer; HIV = human immunodeficiency virus; EBV = Epstein-Barr virus; CMV = cytomegalovirus; HHV-8 = human herpesvirus-8; EBNA = Epstein-Barr virus nuclear antigen 1; KS = Kaposi’s sarcoma; TB = tuberculosis; CoNS = coagulase-negative Staphylococcus; PCR = polymerase chain reaction; CTD = connective tissue disease; c-ANCA = cytoplasmic anti-neutrophil cytoplasmic antibody. *Individual results that fit the HLH diagnostic criteria are highlighted in bold. †

Total white cell count. A valid differential count could not be performed because there were too few leucocytes.

‡

Determined by in situ hybridisation.

from hepatocytes in the presence of liver infiltration.[13] Ferritin levels were markedly raised in all cases. Though the diagnostic threshold is 500 µg/l, reports show that levels >3 000 µg/l should raise strong suspicion and initiate prompt investigation for HLH. Levels >10 000 µg/l have been shown to be >90% specific for HLH,[1]

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though they may also be associated with fulminant hepatic failure. Ferritin is a useful, rapid and relatively cost-effective parameter to measure, especially in resource-limited settings.[18] The rate of ferritin decline following treatment has been shown to be an important prognostic factor for mortality in children.[19] Hypofibrinogenaemia

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(in the absence of liver failure or laboratory features of DIC) suggests immune dysregulation and should arouse suspicion of HLH, especially if associated with splenomegaly. Importantly, the presence of DIC does not preclude HLH as it is common in these patients.[15] Fibrinogen levels were measured in cases 3 - 5 only (as part of DIC screening) with cases 3 and 5 showing diagnostically low levels. Neither NK cell activity nor CD25 assays were performed, as neither assay is widely available locally. Owing to technical aspects of the assays, if available, and delay in obtaining results, it is recommended that blood be taken at the earliest possible opportunity during work-up for suspected HLH. For all the patients in this series, NK cell or CD25 assays may have been of limited use owing to the advanced stage of disease at time of BMAT. NK cell and CD25 assays may, however, assist in raising the diagnostic pickup rate of HLH, especially if patients do not meet the criteria for the remaining parameters. Additional investigations were performed on all patients in the search for a trigger for suspected sepsis/SIRS before the diagnosis of HLH was made. These investigations varied between treating physicians and were probably focused according to individual clinical symptoms and comorbidities. The search for infective triggers involved testing for herpesviruses, tuberculosis (TB), aerobic micro-organisms and fungi. Members of the herpesvirus family coincidentally are the most frequent triggers of viral-associated HLH.[5,6,20] These include Epstein-Barr virus (EBV), the reactivation of which has been implicated the most in viral-associated HLH,[21] CMV and human herpesvirus 8 (HHV-8). EBV was detected by in situ hybridisation of the trephine in case 2. EBV serology was negative in case 3. TB investigations were carried out on peripheral blood (case 1), ascitic fluid (adenosine deaminase measurement only, case 4), sputum (cases 2 and 3), urine (case 2), bone marrow aspirate (cases 1 and 4). All yielded negative results. Cases 3 and 4 yielded positive fungal results on peripheral blood cultures. Case 3 had a severe neutropenia of 0.04×109/l at the time of fungal culture sampling, while case 4 had normal absolute neutrophil and lymphocyte counts of 5.19×109/l and 3.07×109/l, respectively. It is therefore likely that the fungaemia identified in case 3 resulted from HLH-related severe neutropenia and was considered unlikely as an initial trigger. Blood cultures from case 4 yielded a coagulase-negative staphylococcal infection while negative cultures were obtained from the other cases. Cultures of catheter tips, urine and skin swabs were all negative. PCR assays for potential HLH triggers, Pneumocystis jiroveci, CMV and influenza were performed on cases 2, 3 and 5, respectively and were all negative. CMV is an infrequent trigger of HLH, but has been shown to respond well to intravenous immunoglobulin thereby avoiding the need for chemotherapy.[21] A connective tissue disease screen was performed on case 3, as she presented with a history of erythema nodosum that responded well to steroids. Biopsy of the lesion revealed septal panniculitis. She subsequently deteriorated clinically upon withdrawal of steroid therapy. Results of the connective tissue disease screen were negative. Cytoplasmic anti-neutrophil cytoplasmic antibody and glomerular membrane base antibody screens were performed on case 5 as she presented with features of vasculitis and malar rash at time of admission. The results were also negative. Three of the five cases had a malignancy at the time of diagnosis. In malignancy-associated HLH, HLH can precede the malignancy diagnosis, occur after diagnosis or manifest during chemotherapy. It is largely associated with T-/NK cell lymphomas or leukaemias.[2,5] However, an association with large B-cell lymphomas has been described.[22] It has been postulated that HLH is triggered by release of IFN-γ and CD25 from neoplastic cells, causing significant macrophage activation.[5]

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HIV has been listed as a trigger of HLH in the literature, but the exact mechanism/s by which this occurs is not yet understood.[9,23] HLH is common during the period of seroconversion, though it may occur at any time.[9] There is a paucity of information regarding optimal treatment of HIV-positive patients presenting with HLH. A French retrospective study of 58 HIV-positive patients showed that reactive haemophagocytic syndrome was diagnosed in patients with a median CD4+ count of 91 cells/µl, with 35% of patients having viral loads (VLs) of <50 copies/ml at diagnosis.[23] Single case reports from Japan reported cures with antiretroviral therapy alone.[9,10] Case 3 had a CD4+ count of 50 cells/µl with a VL of 459 444 copies/ml. Case 4 had CD4+ count of 586 cells/µl with a VL of <20 copies/ml, but he had previously been treated for KS, according to clinical information provided. HHV-8 has been shown to act as an HLH trigger in HIVpositive cases in a limited case series. However, the median CD4+ counts of the patients was significantly lower (200 cells/µl).[20] Case 1 was HIV-negative on ELISA and p24 antigen-negative at admission. Recent repeat HIV testing revealed that he is HIV-positive with a CD4+ count of 371 cells/µl and a VL of 104 copies/ml. Hence, HLH may have been triggered by either seroconversion or malignancy. The treating physicians were contacted immediately after the diagnosis of HLH was made and were advised to urgently seek treatment advice from a clinical haematologist. Unfortunately, all patients were at advanced stages of disease at the time of BMAT and cases 2 - 4 succumbed to their illness shortly thereafter. Cases 1 and 5 received appropriate treatment after diagnosis and were alive at time of writing. The normal immune response to antigenic stimuli (viz. viruses, bacteria or malignancies) involves the clonal expansion of specific CD4- and CD8-positive T-lymphocytes along with the generation of cytokines to recruit macrophages to the site of concern. A defect in CTL and NK cell-directed apoptosis (via perforin and granzyme) of these activated clonal lymphocytes once the stimulus has been removed forms the common pathway of familial and acquired HLH. Defective apoptosis results in increasing production of pro inflammatory cytokines, resulting in a catastrophic cascade of events, terminating in multiorgan failure and death. HLH is considered to be rare, and much of what is known in the literature is found in paediatric journals concerned with the familial form. As such, acquired HLH remains a largely unknown entity in adult medicine and its diagnosis is frequently missed in ICU settings. This limited case series suggests that adult acquired HLH may be a common pathology in acute care settings, where it may masquerade as sepsis or SIRS. Unless it is diagnosed early and appropriate treat ment is instituted, the mortality rate is high. Much of the information regarding chemo-/immunotherapy has been gleaned from the HLH94 protocol where children under 16 years of age were administered etoposide, dexamethasone and cyclosporine (while awaiting a stem cell transplant if diagnosed with familial HLH or relapsing/nonresponding secondary HLH). A 5-year survival rate of 54% (standard deviation ±6) was achieved with the HLH-94 trial – a remarkable improvement when previously the mortality rate approached 100%.[8] Given the complex nature of the condition, treatment requires the expertise of a clinical haematologist or medical oncologist well versed in the complexity and challenges of HLH if cure is to be achieved. The concept of using chemotherapy to treat a non-neoplastic condition may seem drastic to medical personnel not familiar with the disease, but its use is essential to induce apoptosis in the defective NK cells and CTLs and quell the cytokine storm. Establishing a diagnosis of HLH may be difficult in the early stages of disease, as most diagnostic parameters (apart from the gene-specific assays) are in themselves fairly nonspecific. In the

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case of oncology patients or those with HIV, the list of differential pathologies is considerable. Only when seen together does a picture of immune hyperstimulation and resulting multiorgan failure emerge. Possible methods to increase the diagnostic pick-up rate of acquired HLH include auto-flagging of haematological results that exceed upper limits for certain diagnostic criteria (e.g. raised ferritin in the presence of low fibrinogen levels). Alternatively, a standard algorithm for work-up of cases of suspected sepsis with unresolving pyrexia and organomegaly could be instituted in acute care settings. Though not part of the HLH diagnostic criteria, the absence of liver dysfunction in a suspected HLH patient should prompt treating physicians to consider alternative diagnoses. It is important to note that in this case series, patients received a diagnosis of HLH only after BMATs were performed to further investigate cytopenias or possible septic foci. It is not known how many HLH cases may have gone undiagnosed in patients who revealed no haemophagocytosis on aspirates/trephines. Reports on the role of flow cytometry in diagnosing HLH on bone marrow aspirates show promise and may assist in increasing the pick-up rate.[1,24] It is hoped that this case series raises awareness of adult acquired HLH in intensivists, oncologists, physicians and infectious disease experts. 1. Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 2012;160(3):275-287. [http://dx.doi.org/10.1111/bjh.12138] 2. Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol 2013;161(5):609-622. [http://dx.doi.org/10.1111/bjh.12293] 3. Janka G, zur Stadt U. Familial and acquired haemophagocytic lymphohistiocytosis. ASH Education Book 2005;2005(1):82-88. [http://dx.doi.org/10.1182/asheducation-2005.1.82] 4. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118(15):4041-4052. [http://dx.doi.org/10.1182/blood-2011-03-278127] 5. Canna SW, Behrens EM. Making sense of the cytokine storm: A conceptual framework for understanding, diagnosing and treating hemophagocytic syndromes. Pediatr Clin North Am 2012;59(2):329-344. [http:// dx.doi.org/10.1016/j.pcl.2012.03.002] 6. Arceci RJ. When T cells and macrophages do not talk: The hemophagocytic syndromes. Curr Opin Hematol 2008;15(4):359-367. [http://dx.doi.org/10.1097/MOH.0b013e3282f97f88] 7. Machaczka M. Hemophagocytic lymphohistiocytosis in adults. Ups J Med Sci 2013;118(3):201-203. [http:// dx.doi.org/10.3109/03009734.2013.795634]

8. Trottestam H, Horne A, Aricó M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long term results of the HLH-94 treatment protocol. Blood 2011;118(17):4577-4584. [http://dx.doi. org/10.1182/blood-2011-06-356261] 9. Adachi E, Koibuchi T, Imai K, et al. Hemophagocytic syndrome in an acute human immunodeficiency virus infection. Intern Med 2013;52(5):629-632. [http://dx.doi.org/10.2169/internalmedicine.52.7544] 10. Gotoh M, Matsua J, Gohchi K, Sanaka T, Kawasugi K. Successful recovery from human immunodeficiency virus (HIV)-associated haemophagocytic syndrome treated in highly active anti-retroviral therapy in a patient with HIV infection. Br J Haematol 2001;112(4):1090. [http://dx.doi.org/10.1046/j.1365-2141.2001.02622-7.x] 11. Hot A, Madoux MH, Viard JP, Coppéré B, Ninet J. Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins. Am J Hematol 2008;83(2):159-162. [http:// dx.doi.org/10.1002/ajh.21008] 12. Machaczka M, Vaktnäs J, Klimkowska M, Hägglund H. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: A retrospective population-based analysis from a single center. Leuk Lymphoma 2011;52(4):613-619. [http://dx.doi.org/10.3109/10428194.2010.551153] 13. Okabe T, Shah G, Mendoza V, et al. What intensivists need to know about hemophagocytic syndrome: An underrecognized cause of death in adult intensive care units. J Intensive Care Med 2012;27(1):58-64. [http:// dx.doi.org/10.1177/0885066610393462] 14. Rajagopala S, Singh N, Agarwal R, Gupta D, Das R. Severe hemophagocytic lymphohistiocytosis in adults – experience from an intensive care unit from north India. Indian J Crit Care Med 2012;16(4):198-203. [http:// dx.doi.org/10.4103/0972-5229.106501] 15. Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: A potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in Adults. Chest 2011;140(4):933-938. [http://dx.doi.org/10.1378/chest.11-0619] 16. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunotherapy and bone marrow transplantation. Blood 2002;100(7):2367-2373. [http://dx.doi. org/10.1182/blood-2002-01-0172] 17. Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol 2002;138(9):1208-1212. [http://dx.doi.org/10.1001/archderm.138.9.1208] 18. Switala JR, Hendricks M, Davidson A. Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world. J Pediatr Hematol Oncol 2012;34(3):e89-e92. [http://dx.doi. org/10.1097/MPH.0b013e31824227b9] 19. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer 2011;56(1):154-155. [http://dx.doi.org/10.1002/pbc.22774] 20. Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003;37(2):285-291. [http://dx.doi. org/10.1086/375224] 21. Mishra B, Varma N, Appannanavar S, et al. Viral markers in patients with hemophagocytosis: A prospective study in a tertiary care hospital. Indian J Pathol Microbiol 2012;55(2):215-217. [http://dx.doi.org/10.4103/03774929.97876] 22. Altaf S, Atreaga GM, Joshi AY, Rodriguez V. Diffuse large B-cell lymphoma in an adolescent female presenting with Epstein-Barr virus-driven hemophagocytic lymphohistiocytosis: A case report. J Med Case Rep 2012;6:141-146. [http://dx.doi.org/10.1186/1752-1947-6-141] 23. Fardet L, Lambotte O, Meynard JL, et al. Reactive haemophagocytic syndrome in 58 HIV-1 infected patients: Clinical features, underlying diseases and prognosis. AIDS 2010;24(9):1299-1306. [http://dx.doi.org/10.1097/ QAD.0b013e328339e55b] 24. McCall CM, Mudali S, Arceci RJ, et al. Flow cytometric findings in hemophagocytic lymphohistiocytosis. Am J Clin Pathol 2012;137:786-794. [http://dx.doi.org/10.1309/AJCPP40MEXWYRLPN]

Accepted 9 December 2013.

This month in the SAMJ ... Charles Parry* is Director of the South African Medical Research Council (MRC)’s Alcohol, Tobacco and Other Drug Research Unit. He was educated in South Africa and the USA (MSc Mathematical Statistics, MA Clinical Psychology, PhD Community Psychology) and completed a postdoctoral fellowship in clinical services research at the Western Psychiatric Institute and Clinic in Pittsburgh. He is registered with the Health Professions Council of South Africa as a clinical and research psychologist, has an appointment as Extraordinary Professor in the Department of Psychiatry at Stellenbosch University, and since November 2012 has been Acting Vice-President: Intramural Research at the MRC. In 2006 he was appointed to the World Health Organization (WHO)’s Expert Panel on Drug Dependence and Alcohol Problems, and in 2010 to the Technical Advisory Group of the United Nations Office on Drugs and Crime/WHO joint programme on drug dependence, treatment and care, and the Board of the Global Alcohol Policy Alliance. * Parry CDH, Myers BJ. Legalising medical use of cannabis in South Africa: Is the empirical evidence sufficient to support policy shifts in this direction? S Afr Med J 2014;104(6):399-400. [http://dx.doi.org/10.7196/SAMJ.8135]

Jonathan Carr*,† is a neurologist with a particular interest in movement disorders. He completed his under graduate training at the University of Cape Town, and then did a neurology residency at the Mount Sinai Medical Centre in New York. After returning to South Africa, he took up a post in the Division of Neurology at Tygerberg Hospital and Stellenbosch University. He subsequently did a sabbatical at the University of British Columbia and thereafter, together with Professor Soraya Bardien, helped to set up a laboratory at Stellenbosch University to investigate the genetic causes of Parkinson’s disease. *Carr J, Van Coller R. A putative founder effect for Parkinson’s disease in South Africa. S Afr Med J 2014;104(6):411-412. [http://dx.doi.org/10.7196/SAMJ.8390] eldenhuys G, Glanzmann B, Lombard D, Boolay S, Carr J, Bardien S. Identification of a common founder couple for 40 South African Afrikaner families with Parkinson’s G disease. S Afr Med J 2014;104(6):413-419. [http://dx.doi.org/10.7196/SAMJ.7747]

†

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ISSUES IN PUBLIC HEALTH

‘Urban insight’: A high level of undiagnosed need reflects limited access to and availability of eye-care services in South Africa A Mathee, A de la Rey, A Swart, S Plagerson, N Naicker Prof. Angela Mathee, PhD, is based at the Environment and Health Research Unit, South African Medical Research Council, and holds honorary professorial positions at the School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, and the Faculty of Health Sciences, University of Johannesburg. Ansunel de la Rey, BOptom, is based at the Department of Optometry, Faculty of Health Sciences, University of Johannesburg, Prof. Andre Swart, PhD, is the Dean of the Faculty of Health Sciences, University of Johannesburg, and Dr Sophie Plagerson, PhD, is based at the Centre for Social Development in Africa, Faculty of Social Sciences, University of Johannesburg. Dr Nisha Naicker, MB BCh, FCPHM, PhD, is based at the Environment and Health Research Unit, South African Medical Research Council, and is a honorary lecturer at the School of Public Health, University of the Witwatersrand. Corresponding author: N Naicker (nisha.naicker@mrc.ac.za)

Findings from an urban community optometry clinic in a poor area of Johannesburg, South Africa (SA), highlighted a high level of undiagnosed need, raising questions concerning access to and availability of eye-care services in SA. It is imperative that we understand vision as a requisite for poverty alleviation, and the need for a public health approach to service delivery. S Afr Med J 2014;104(6):407-408. DOI:10.7196/SAMJ.8100

Poor vision impairs children’s and adults’ ability to fulfil their potential for health and productivity. Preventable disabling visual impairment and the overall lack of eyecare services are often both the cause and the result of social, economic and developmental challenges such as poverty, lack of education, inadequate healthcare services and lack of opportunity for people to control or influence their healthcare.[1] Uncorrected visual impairment is often viewed as an issue pertaining to remote rural areas, where access to eye care and corrective eyewear is difficult. However, a research project in a Johannesburg community has highlighted a high level of undiagnosed optometric need, particularly among children, with severely impaired quality of life resulting from undetected refractive error, raising the issue of access to and availability of eye-care services in urban South Africa (SA).

The Health, Environment and Development study

The World Health Organization Collaborating Centre for Urban Health (WHOCCUH) is a partnership of academic, governmental and research institutions. For 8 years the WHOCCUH partnership has been conducting the Health, Environment and Development (HEAD) study in five deprived areas of Johannesburg. In one of these areas, Riverlea, the HEAD study highlighted a number of health issues, including high rates of diabetes.[2] Because of the known high prevalence of correctable visual impairment in diabetics, the Department of Optometry of the University of Johannesburg was requested to supplement the rudimentary, treatment-based response to diabetes at the local clinic with additional optometry, podiatry and environmental health promotion services, as part of student in-service training programmes. Results from the first 6 months of optometry services are reported in Table 1.

Optometry clinic findings

Optometry screening has been offered weekly since February 2010. During the first 6 months of the service, clients’ ages ranged from 6 to

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84 years, and for 60% it was their first-ever optometry screen. Table 1 sets out the patient profile according to age category, diagnoses and intervention status. For all the children (n=7), the test represented their first vision examination. All required spectacles and/or referral for further treatment. The vast majority (99.2%) of clients aged ≥40 years required treatment for cataracts or spectacles for near or far vision. For the first 6 months of the clinic’s operation, the intervention requirement rate was 98%. Individuals have described remarkable improvements in quality of life outcomes; for example, a 13-year-old girl who was struggling at school reported a dramatic improvement in her vision, and consequently her school performance, after receiving her first-ever pair of spectacles. An older woman whose visual deterioration had prevented her from sewing reported being able to resume incomegenerating activities. Research conducted in other urban areas suggests that the findings in this study are not limited to one community but represent a wider concern.[3] This study suggests that, in addition to lack of services, lack of awareness among parents and teachers may provide an additional barrier to children accessing eye care, even where services are available. World Health Organization Vision 2020 recommended that all schoolchildren have a simple vision-screening examination service provided through school health programmes.[4] However, the National Vision Screening Programme has been discontinued in many provinces of SA, owing to a lack of resources.[5] Child screening through schools often occurs on an ad hoc basis, implemented by non-governmental bodies such as the South African Optometric Association. In the light of budgetary constraints preventing school vision screening programmes by optometrically trained staff, it is crucial that basic sight screening skills be introduced into standard teacher training curricula, in order to raise consciousness of the association between learning difficulties and compromised vision and to prevent the avoidable disabling effects of uncorrected vision. Given the low levels of educational attainment in SA schools, and the implications for

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Table 1. Riverlea optometry clinic patient profiles Age groups (yrs) 0 - 17 (N=7) n (%)

18 - 39 (N=15) n (%)

≥40 (N=129) n (%)

Total (N=151) n (%)

Required intervention

7 (100.0)

13 (86.7)

128 (99.2)

148 (98.0)

Previously screened/received intervention

2 (13.3)

58 (45.0)

60 (39.7)

Intervention status

Diagnosis* (among those who required intervention) Refractive error

5 (71.4)

10 (66.7)

128 (99.2)

143 (94.7)

Accommodative/binocular disorders

2 (28.6)

2 (1.3)

Cataract

2 (13.3)

11 (8.5)

13 (8.6)

Macula/other pathology

2 (13.3)

9 (7.0)

11 (7.3)

*Some patients had multiple diagnoses.

quality of life, it is vital that the issue of children’s eyesight be elevated on the national public health and education agendas.

Conclusion

In Riverlea, a poor urban area of Johannesburg, a high level of undiagnosed optometric need was identified. Simple interventions such as provision of spectacles resulted in dramatic improvements in quality of life. Preliminary investigations highlighted limited availability of public sector eye-care services, and high costs of consultations, spectacles and transport. Cases of uncorrected visual impairment among urban children are of particular concern, the small numbers of children attending the clinic suggesting a lack of awareness of eye-care needs among parents and teachers. Lack of screening among school-age children is the

key barrier preventing earlier access to eye care, and poor vision has detrimental impacts on children’s learning ability. Similarly, poor vision limits adults’ ability to fulfil their potential for health and productivity. In urban SA there is a need for raised awareness of, and improved access and availability to, eye-care services. 1. Naidoo K. Poverty and blindness in Africa. Clin Exp Optom 2007;90(6):415-421. [http://dx.doi. org/10.1111/j.1444-0938.2007.00197.x] 2. Mathee A. Indicators of Health, Environment and Development: A Longitudinal Study in Johannesburg 2006-2008. Johannesburg: World Health Organization Collaborating Centre for Urban Health, 2009. 3. Mabaso R, Oduntan A, Mpolokeng M. Refractive status of primary school children in Mopani district, Limpopo Province, South Africa. South African Optometrist 2005;65(4):125-133. 4. Gilbert C, Foster A. Childhood blindness in the context of VISION 2020 – The Right to Sight. Bull World Health Organ 2001;79(3):227-232. 5. Moodley V. Amplitude, facility and accuracy of accommodation in a primary school population. South African Optometrist 2008;67(4):147-154.

Accepted 26 March 2014.

ADVANCES IN MEDICINE

Additive manufacturing: From implants to organs T S Douglas Tania Douglas is Deputy Dean for Research in the Faculty of Health Sciences and Professor of Biomedical Engineering at the University of Cape Town, South Africa Corresponding author: T S Douglas (tania.douglas@uct.ac.za)

Additive manufacturing (AM) constructs 3D objects layer by layer under computer control from 3D models. 3D printing is one example of this kind of technology. AM offers geometric flexibility in its products and therefore allows customisation to suit individual needs. Clinical success has been shown with models for surgical planning, implants, assistive devices and scaffold-based tissue engineering. The use of AM to print tissues and organs that mimic nature in structure and function remains an elusive goal, but has the potential to transform personalised medicine, drug development and scientific understanding of the mechanisms of disease. S Afr Med J 2014;104(6):408-409. DOI:10.7196/SAMJ.7915

Additive manufacturing (AM) has been labelled a disruptive technology for its ability to produce customised geometrically complex objects in small quantities at low cost.[1] The Economist has called it the third industrial revolution. Unlike traditional manufacturing, which is

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subtractive in that large volumes of material are reduced to desired shapes by removing excess, AM constructs 3D objects by adding materials layer by layer under computer control based on 3D models. AM creates complex shapes yet makes efficient use of raw materials, [2] producing minimal waste and requiring minimal tools. The

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geometric flexibility of the process, mostly attributable to its additive nature, has led to various non-industrial applications, notably those in medicine. Some medical applications of AM include construction of anatomical models for surgery planning, and design and construction of customised prosthetic implants. The raw materials used in AM for these applications include plastics, resins, alloys, stainless steel, titanium, polymers and ceramics.[1] Layers of material can be built and consolidated in a variety of ways. 3D printing is a fast form of AM and is available in low-cost, low-resolution format. It places production capability in the hands of the designer, facilitated by the availability of computing technology that translates 3D designs into printable files. 3D printers operate similarly to traditional laser or inkjet printers, but with the ink replaced by the materials from which the objects are to be built. They deposit material layer by layer and bind it chemically using a binder sprayed through a nozzle; further strengthening may be achieved with the application of heat. The unbound material is removed chemically. The printer interfaces with computer-aided design (CAD) software to specify the shape of the object. Patient-specific physical models of anatomical structures serve as an aid for surgical planning to highlight areas of interest and for surgery rehearsal to determine possible complications and reduce operating time.[3] Such models are produced using AM after CAD translation of volumetric images from 3D modalities such as computed tomography and magnetic resonance imaging. Although 3D visualisation using specialised viewers is available for surgical planning,[4] 3D images are typically viewed on 2D screens. This limitation can be overcome using physical 3D models. The ability of images to differentiate softtissue types remains a constraint, and models of hard tissue are more commonly reported than those of soft tissue.[5] Physical models have been used successfully in cranio- and maxillofacial, pelvic, neuro-, spine, cardiovascular and visceral surgery.[3] Among its potential medical applications, the use of AM in the production of implants, particularly to replace bony structures, is perhaps the best known. AM techniques allow the design of patientspecific prosthetic implants to suit individual anatomy for improved fit, functionality and aesthetics, and to reduce the likelihood of implant failure. Examples include customised mandibles, hips, knees and cranial plates. AM is commonly used in dentistry, and a variety of dental products, such as bridges and crowns, are commercially available.[2] AM has also influenced the production of hearing aids, devices that require a high degree of customisation for individual fit. Greater ease of regulatory approval for devices worn on the body than for implants has assisted widespread adoption of AM-produced hearing aids, with the result that AM accounts for 99% of those that are placed in the ear.[6] In addition to the implantation of fabricated prostheses, surgical techniques adopted to repair defects and replace bone and other tissue that the body is unable to produce include autologous bone grafts (the gold standard – originating from another site in the same patient), allografts (from human donors) or xenografts (from animals). Autografts are associated with long recovery periods, donor site morbidity and a complex graft-shaping process to achieve biomechanical coupling; allografts and xenografts carry the possibility of immuno-rejection, inflammation and disease transmission, as well as poor mechanical performance.[7] For these reasons, tissue regeneration or engineering approaches are being explored. AM has been used as a tool in tissue regeneration through the production of biocompatible or biodegradable scaffolds – structures that serve as a platform to guide the growth of new tissues to replace damaged or defective ones.[5] Scaffolds act not only as passive matrices to support cell adhesion or proliferation, but also as vehicles for the delivery of bioactive molecules, nutrients and waste products.[7] Their functional specifications translate into fabrication requirements for spatially varying structures with high geometric complexity coupled with different biomaterials. Such ‘biofabrication’ can

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be accommodated by AM techniques in combination with CAD and medical imaging.[8] While tissue engineering is still in its technological infancy, scaffolds have been clinically successful in building bladder and bronchus,[9] bone, osteochondral tissue, cartilage and skin. Techniques to develop new vasculature are being explored.[8] Scaffolding is the traditional tissue engineering approach but has limited ability for cell manipulation and control of cell placement. Incorporating viable cells into biofabricated structures remains a challenge.[8] Organ printing through controlled deposition of cells or cell aggregates is an alternative to scaffolds, offering more precise cellular positioning.[10] Manufactured organs are, however, an elusive goal. Patches of organ tissue – including liver, kidney and heart – that have been printed to date have generally not exceeded a few millimetres in area and a few layers in cell depth. Thicker structures would require a vascular system to supply nutrients and oxygen; the requirement for an embedded vasculature and limits to the current understanding of interactions between cells and their environment are challenges to the production of viable organs.[11] Nonetheless, the ultimate possibility of organ printing in vivo, with the aid of a biofabrication device as a surgical tool, has been suggested.[12] More immediate applications of tissue engineering transcend its traditional purpose of generating tissues for repair or restoration and lie in the discovery, development and testing of drugs. Biofabrication can produce models of both health and disease. Fabricated tissues can provide a more realistic platform for preclinical testing of pharmaceuticals than the cultured cells and animal models that are currently used. Tissue models can be designed to answer very specific research questions and used as test platforms for new treatments and vaccines.[13] Personalised therapy is another potential application, e.g. printed models of tumours can be subjected to therapies in vitro and their responses used to design patient-specific cancer treatment.[11] Engineered tissue models can also be valuable research tools. They have the potential to provide the heterogeneity of mechanics and structure that are lacking in the cellular aggregates currently used in biological studies of disease. They can be used to examine complex cellular pathways and behaviours in a variety of biological conditions to aid the understanding of disease progression and the design of approaches for prevention.[13] The ability of AM technology to deliver customised products to suit individual needs holds great promise for personalised healthcare. There have been some clinical successes with AM-based surgical planning, implants, assistive devices and scaffold-based tissue engineering. Biofabrication of tissues and organs that mimic in vivo structure and function remains fraught with challenges, but offers exciting prospects and may contribute in significant ways to the ‘century of biology’. 1. Berman B. 3-D printing: The new industrial revolution. Business Horizons 2012;55(2):155-162. [http://dx.doi. org/10.1016/j.bushor.2011.11.003] 2. Huang S, Liu P, Mokasdar A, Hou L. Additive manufacturing and its societal impact: A literature review. Int J Adv Manuf Technol 2013;67(5-8):1191-1203. [http://dx.doi.org/10.1007/s00170-012-4558-5] 3. Rengier F, Mehndiratta A, von Tengg-Kobligk H, et al. 3D printing based on imaging data: Review of medical applications. Int J Comput Assist Radiol Surg 2010;5(4):335-341. [http://dx.doi.org/10.1007/s11548-0100476-x] 4. Moscatiello F, Jover J, Ballester M, Hernandez E, Piombino P, Califano L. Preoperative digital threedimensional planning for rhinoplasty. Aesthetic Plast Surg 2010;34(2):232-238. [http://dx.doi.org/10.1007/ s00266-009-9455-4] 5. Giannatsis J, Dedoussis V. Additive fabrication technologies applied to medicine and health care: A review. Int J Adv Manuf Technol 2009;40(1-2):116-127. [http://dx.doi.org/10.1007/s00170-007-1308-1] 6. Banks J. Adding value in additive manufacturing: Researchers in the United Kingdom and Europe look to 3D printing for customization. IEEE Pulse 2013;4(6):22-26. [http://dx.doi.org/10.1109/MPUL.2013.2279617] 7. Domingos M, Intranuovo F, Russo T, et al. The first systematic analysis of 3D rapid prototyped poly(εcaprolactone) scaffolds manufactured through BioCell printing: The effect of pore size and geometry on compressive mechanical behaviour and in vitro hMSC viability. Biofabrication 2013;5(4):045004. [http:// dx.doi.org/10.1088/1758-5082/5/4/045004] 8. Melchels F, Domingos M, Klein T, Malda J, Bartolo P, Hutmacher D. Additive manufacturing of tissues and organs. Prog Polym Sci 2012;37(8):1079-1104. [http://dx.doi.org/10.1016/j.progpolymsci.2011.11.007] 9. Mironov V, Trusk T, Kasyanov V, Little S, Swaja R, Markwald R. Biofabrication: A 21st century manufacturing paradigm. Biofabrication 2009;1(2):022001. [http://dx.doi.org/10.1088/1758-5082/1/2/022001] 10. Drake C, Kasyanov V, Markwald R, Mironov V. Organ printing: Promises and challenges. Regen Med 2008;3(1):93-103. [http://dx.doi.org/10.2217/17460751.3.1.93] 11. Fischer S. The body printed. IEEE Pulse 2013;4(6):27-31. [http://dx.doi.org/10.1109/MPUL.2013.2279618] 12. Campbell P, Weiss L. Tissue engineering with the aid of inkjet printers. Expert Opin Biol Ther 2007;7(8):11231127. [http://dx.doi.org/10.1517/14712598.7.8.1123] 13. Burg T, Cass C, Groff R, Pepper M, Burg K. Building off-the-shelf tissue-engineered composites. Philos Trans A Math Phys Eng Sci 2010;368(1917):1839-1862. [http://dx.doi.org/10.1098/rsta.2010.0002]

Accepted 16 January 2014.

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EDITORIAL

A reflection on the South African Medical Association – past, present and future The recent adoption of the Memorandum of Incor poration (MOI) and Rules of the South African Medical Association (SAMA) represents an appro priate time to pause and reflect. For purposes of compliance with the new Companies Act, the MOI and Rules were in fact adopted in 2013, with recent amendments needing to be added. This does, however, provide an opportunity to critically evaluate where the Association is in the year in which, as a country, we celebrate 20 years of democracy. It is often said that to understand the present one needs to look to the past. Two articles from 1996 by Mlisana et al.[1] and Hanekom et al.[2] provide a useful context of the situation just before the formation of SAMA, as well as insights into the development of the process of unity in the profession. Furthermore, the ideals of a professional association stated at that time provide a measure by which we can assess our progress. The medical profession after 1994 remained largely divided along both ethnic and partisan lines. The largest grouping of the time, the Medical Association of South Africa (MASA), predominantly represented the interests of white doctors in the private sector. Its major counterpart was the National Medical and Dental Association, formed in the early 1980s as the result of deep dissatisfaction with the position and silence of MASA on several matters, most notably the death in detention of Steve Biko. The National Medical and Dental Forum, formed from mostly black general practitioners, was established at around the time when there was talk of a unified medical profession under a single association. An interesting perspective was that, despite the existence of these various bodies, many doctors still felt alienated, reflecting an innate dissonance within the profession. Over the ensuing 18 months a process was followed, sometimes rocky, that led to the formation of the new medical association, the South African Medical Association or SAMA. On 21 May 1998, SAMA was formally established and continued as a section 21 company, with some of the remaining groupings joining by April 1999. The initial agreement of understanding, signed in September 1997, tasked the new Association with producing a constitution that would encapsulate the principles enshrined in the so-called founding document. A key principle came to be known as the 50:50 principle. This implied that representation of the different organisations, with particular reference to the first National Council, the Board of Directors and the Standing Committees, would be on the basis of 50% from MASA and 50% from the signatories of the original agreement of understanding document. The latter included the Dispensing Family Practitioners Association, the Eastern Cape Medical Guild, the Family Practitioners Association, the South African Medical and Dental Practitioners, the Society for Dispensing Family Practitioners, and the Progressive Doctors Group. The 50:50 principle became enshrined in the Memorandum and Articles of the Association and was the principle underpinning the first National Council. It was always understood and accepted that ex-members of MASA and what were now called the Partner Organisations (POs) would fully integrate into SAMA, exercising their participation at branch level in particular and not just at a national level. PO involvement at National Council level declined significantly, reflecting the de facto dissolution of these organisations over time, as might have been anticipated with the formation of SAMA as the broader collective. Some of the organisations evolved

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into independent practitioner-type associations. Importantly, MASA ceased to exist. By 2009 it was already apparent that an entirely new generation of doctors were participating in SAMA. These members knew no affiliation to what had been MASA or to the POs, and vehemently expressed the need to reform the association of which they were now members and in which they participated. The 2009 National Council tasked the Constitutional Transformation Task Team (later to become the Constitutional Matters Committee or CMC) to deal with this reform as a matter of urgency. Among other proposals, removal of the 50:50 clause with respect to the POs and acceptance of the principle of historically disadvantaged South Africans were requested. This principle was adopted at the 2010 National Council. The advent of the new Companies Act, promulgated in 2008, provided the impetus to realign the Articles of the Association with the requirements of the new Act. This process has been lengthy and inclusive and effectively started after the 2009 National Council. Compliance-based changes were incorporated into the 2013 adopted MOI and Rules. The CMC also debated a demand from the POs that they retain a strict 50% veto over members attending National Council and occupying positions in Standing Committees of the Board. No consensus was achieved. This position was maintained despite the fact that all but two of the original POs were either non-functional or no longer existed. The main protagonist persisted with the view that there still had to be a MASA and POs within the present SAMA, despite the formation of a new organisation 17 years ago. They insisted, furthermore, that the current SAMA was in fact MASA, and that it did not matter that, if their demands were acceded to, the vast majority of the fee-paying members of SAMA would be disenfranchised. In an attempt to break the deadlock, an opinion from a senior counsel was sought to clarify conflicting clauses in the proposed Memorandum of Incorporation and Rules of SAMA. The opinion was clear and unambiguous – conflicting clauses would need to be removed, and the areas of concern that were highlighted needed to be attended to in order to avoid a dysfunctional MOI and Rules. Given that the opinion did not fully satisfy all concerned, the SAMA Board took a unanimous decision that the President of SAMA, a titular, non-partisan and non-voting member of the Board, be tasked to consider all inputs and documents and provide the Board with a binding opinion. The President was mandated and empowered to accept and consider each and every input provided. The President took almost two months to complete this task, and in February 2014 provided the Board with what has now become the new MOI and Rules of SAMA. Due process having been followed, these were adopted by a significant majority at an Extraordinary General Meeting in April 2014. Two important perspectives warrant mention: firstly, the principle of historically disadvantaged individuals occupying a minimum of 50% of positions in the National Council, Board and Standing Committees has been incorporated into the new MOI; and secondly, a transformation task team has been advised to look at ongoing issues of transformation in a far broader manner than has been done to date. The intention is not to forget those who founded SAMA, but rather to realise fully what was always intended by the founders – a united professional association serving its members.

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Despite the above process, it is extremely unfortunate that some, although they were wholly part of the above Board decisions, have taken measures not only to undermine what has been achieved but also to attempt to discredit those involved in the process. The purpose of their agenda would need to be explained by those involved, but will not alter the fact that SAMA is now rightly positioned to be a home to all doctors irrespective of their affiliations, past or present. It also gives the new throng of doctors the opportunity to join a diverse and representative professional association that maintains a transformative agenda at its core. More importantly, the members will decide who should represent them, ensuring that all those in leadership positions in SAMA are from within its ranks and not imposed on them. This will ensure that the leadership remains answerable to the membership. SAMA has achieved much for an organisation that has just moved out of its teenage years, but many challenges remain. The organisation restructured itself in the past few years and consolidated into being primarily member focused. The longstanding trade union function for employed doctors was fully realigned, as required by the Labour Relations Act, into the SAMA Trade Union in 2013. This focuses all its energies on doctors in the public sector, as well as other employed doctors. Provincial and local structures are being formed and will be fully realised in time. The Private Sector Department can be very proud of its wealth of expertise in the areas of coding; its capacitation with new skills and growth is an ongoing process so as to provide a complete service to those members in the private sector. Our branches must remain the bedrock of the organisation.

A notable concern remains the lack of cohesion within the profession, cutting across all sectors in the profession and including the specialist societies – interestingly, an issue that was lamented before the formation of SAMA. The need for the profession – public, private, general practitioner and specialist – to remain united should be a core purpose of SAMA, which at all times needs to provide the requisite leadership in this regard. Only as a united profession will we be able to address the issues that lie ahead, which include our role and contribution in building the National Health Insurance, capacitating the public sector, ensuring a viable private sector, and standing up for the rights of our members. After all, a motivated and satisfied doctor is good for healthcare delivery, and ultimately the people who will benefit are those we serve, our patients. Mzukisi Grootboom, Chairman Mark Sonderup, Vice-Chairman South African Medical Association, Pretoria, South Africa Corresponding authors: M Grootboom (mzukisi@mweb.co.za), M Sonderup (msonderup@samedical.co.za) 1. Mlisana ZS, Mahlathi PM, Soni PN. Unity in the medical profession. S Afr Med J 1996;86(4):328-329. 2. Hanekom HA, Mahlati MP, Chetty A. The ideal professional association. S Afr Med J 1996;86(10):12471248.

S Afr Med J 2014;104(6):410-411. DOI:10.7196/SAMJ.8408

A putative founder effect for Parkinson’s disease in South African Afrikaners Neurodegenerative diseases are important causes of disability and death, with prominent examples including Alzheimer’s disease, Parkinson’s disease (PD) and motor neuron disease. Although familial clustering of these illnesses was well known before the advent of modern molecular genetics, meaningful strides in identifying the origin of neurodegenerative diseases have really only begun to be made in the past two decades. All these disorders are characterised by a small percentage of affected patients whose disease is clearly the result of Mendelian inherited genetic illness, either recessive or dominant. In particular, dominant disease is exemplified in the case of Alzheimer’s disease by presenilin 2 mutations that arose in German immigrants from the Volga river region in the 17th century,[1] and in PD by mutations in the LRRK2 protein that are linked to a founder effect dating back to the 2nd century, probably in Ashkenazi Jews.[2] Such autosomal dominant families enable a crucial aspect of neurodegenerative disease to be addressed, namely the identification of biomarkers that can serve to identify the earliest features of the onset of disease. These biomarkers range from proteins in cerebrospinal fluid, such as amyloid and tau, to magnetic resonance imaging scans of the brain volumes of cortex and temporal lobe

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structures, and positron emission tomography scans of markers of neurodegeneration, such as amyloid.[3,4] It is clear, certainly in the case of Alzheimer’s disease, that by the time even mild memory impairment has developed there is wide spread pathological change that is highly likely to be irreversible.[5] Similarly, although tremor may the best-appreciated manifestation of dopaminergic cell loss in PD, it is clearly preceded by a slowly progressive process that gradually ascends up the brainstem and may produce features of brainstem dysfunction as long as 25 years before the onset of classic PD.[6,7] In general, it would probably be most useful to identify individuals who are genetically at risk for developing neurodegenerative illness, and monitor particular biomarkers, in the event that successful therapies become available. After the initial euphoria when the first genes associated with Alzheimer’s disease and PD were identified, a major issue has been the extrapolation of these findings to the much more common situation of sporadic disease in individuals who lack a clear-cut family history. So far, although genome-wide association studies (GWASs) have shown much promise, they have failed to deliver many significant advances with regard to the genetic cause of neurodegenerative disease. In particular, the power of such studies has been limited, and not uncommonly GWASs have only served

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EDITORIAL

to confirm genetic targets already identified by other methods.[8] It could be argued that a sporadic case is more likely to have an environmental cause, but the evidence for the environment playing an important role in the causation of neurodegenerative disease is not particularly strong. A major advantage of genetic studies is not only that they identify the cause of illness, but also that they shed light on the various molecular pathways implicated in the causation of neurodegenerative disease.[9] This clearly has significant implications for the development of treatments that would potentially be of benefit for patients harbouring preclinical or manifest mutations, as well as for patients with sporadic disease. To reiterate, the identification of mutations has profound implications for understanding the cause of disease, and it is likely that it will only be through the understanding of the mechanisms of cell injury and death in neurodegenerative disease that advances will be made in therapeutics. One major issue regarding the utility of genetics when applied to neurodegenerative disease is that age is a major risk factor, and many patients may not develop illness simply because they die before the disease manifests. Confirmation of a family history of an illness being inherited in a particular pattern may therefore be difficult. Over and above mutation analysis, genealogical studies can be very useful in populations where there are common founder effects and church records. Such is the case for the original Dutch population that settled in the Cape from the mid-1600s, and with the admixture largely of German and French immigrants, ultimately developed into the South African (SA) Afrikaner population. As is well known, this population has well-established founder effects for a wide range of conditions, of which the best-known examples are familial hypercholesterolaemia and variegate porphyria. Furthermore, the Afrikaner population has genealogies that range from the 1600s through the early 1800s and later, and are well documented and recorded.[10] Interestingly, with respect to neurodegenerative disease, there is some evidence for a founder effect for Huntington’s disease in SA, possibly arising from an early Dutch settler, since there is a common haplotype indicative of a European origin.[11,12] In the study by Geldenhuys et al.[13] published in this issue of the SAMJ, genealogies of 12 Afrikaner families were investigated in detail using the records of the Genealogical Institute of South Africa in Stellenbosch and other sources. The genealogical research concentrated on those with a family history suggestive of either dominant or recessive inheritance of PD. The 12 families were shown to be linked to a single ancestral couple, and this finding was further supported by confirmation of ancestral lines to the putative founder couple in an additional 28 families, also of Afrikaner origin and with a history of PD. The affected family members had a mean age of onset of PD of only 52 years, which is considerably less than that in typical idiopathic disease and suggests a genetic origin for the illness.[14] The

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founder couple was of Dutch and German ancestry and married in the Cape in 1668. This finding is of importance for two reasons. Firstly, given that established genetic causes of PD have not been identified in the Afrikaner population, it appears likely that this population carries unique mutations that remain to be identified by genome-wide screening.[15,16] Secondly, in the event that effective treatments are developed, particularly for presymptomatic patients, the Afrikaner population may be considered to be at risk and requiring careful assessment with accurate biomarkers. Jonathan Carr Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Riaan van Coller Wilgers Medical Centre, Pretoria, South Africa Corresponding author: J Carr (jcarr@sun.ac.za) 1. Yu C, Marchani E, Nikisch G, et al. The N141I mutation in PSEN2: Implications for the quintessential case of Alzheimer disease. Arch Neurol 2010;67(5):631-633. [http://dx.doi.org/10.1001/archneurol.2010.87] 2. Bar-Shira A, Hutter CM, Giladi N, Zabetian CP, Orr-Urtreger A. Ashkenazi Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries. Neurogenetics 2009;10(4):355-358. [http://dx.doi.org/10.1007/s10048-009-0186-0] 3. Mosconi L, Murray J, Tsui WH, et al. Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD. Neurology 2014;82(9):752-760. [http://dx.doi.org/10.1212/ WNL.0000000000000181] 4. Fagan AM, Xiong C, Jasielec MS, et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci Transl Med 2014;6(226):226ra30. 5. Markesbery WR. Neuropathologic alterations in mild cognitive impairment: A review. J Alzheimers Dis 2010;19(1):221-228. 6. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007;130(11):2770-2788. [http://dx.doi.org/10.1093/brain/awm056] 7. Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24(2):197-211. [http://dx.doi. org/10.1016/S0197-4580(02)00065-9] 8. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461(7265):747-753. [http://dx.doi.org/10.1038/nature08494] 9. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, Mccomb RD, Stoessl AJ. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;62(9):1619-1622. [http://dx.doi. org/10.1212/01.WNL.0000125015.06989.DB] 10. Greeff JM. Deconstructing Jaco: Genetic heritage of an Afrikaner. Ann Hum Genet 2007;71:674-688. [http://dx.doi.org/10.1111/j.1469-1809.2007.00363.x] 11. Hayden M, Hopkins H, Macrae M, Beighton P. The origin of Huntington’s chorea in the Afrikaner population of South Africa. S Afr Med J 1980;58(5):197-200. 12. Baine FK, Kay C, Ketelaar ME, et al. Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. Eur J Hum Genet 2013;21(10):1120-1127. [http:// dx.doi.org/10.1038/ejhg.2013.2] 13. Geldenhuys G, Glanzman B, Lombard D, Boolay S, Carr J, Bardien S. Identification of a common founder couple for 40 South African Afrikaner families with Parkinson’s disease. S Afr Med J 2014;104(6):413-419. [http://dx.doi.org/10.7196/SAMJ.7747] 14. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: An etiologic study. JAMA 1999;281(4):341-346. [http://dx.doi.org/10.1001/jama.281.4.341] 15. Bardien S, Lesage S, Brice A, Carr J. Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson’s disease. Parkinsonism Relat Disord 2011;17(7):501-508. [http://dx.doi. org/10.1016/j.parkreldis.2010.11.008] 16. Blanckenberg J, Bardien S, Glanzmann B, Okubadejo NU, Carr JA. The prevalence and genetics of Parkinson’s disease in sub-Saharan Africans. J Neurol Sci 2013;335(1-2):22-25. [http://dx.doi. org/10.1016/j.jns.2013.09.010]

S Afr Med J 2014;104(6):411-412. DOI:10.7196/SAMJ.8390

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RESEARCH

Identification of a common founder couple for 40 South African Afrikaner families with Parkinson’s disease G Geldenhuys,1 PhD; B Glanzmann,2 MSc; D Lombard,3 BCur; S Boolay,2 PhD; J Carr,3 MB ChB, PhD; S Bardien,2 PhD ivision of Applied Mathematics, Department of Mathematical Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa D Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa 3 Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa 1 2

Corresponding author: S Bardien (sbardien@sun.ac.za) Background. Afrikaners are a unique ethnic group in South Africa (SA) with well-documented ancestral records spanning a period of over 350 years. They are mainly descended from Dutch, German and French settlers to SA in the 17th and 18th centuries. Today several disorders in this population occur at relatively high frequencies as a result of founder effects. Objective. To determine whether a founder effect for Parkinson’s disease (PD) is present in the Afrikaner population. Methods. Study participants were recruited from the Movement Disorders Clinic at Tygerberg Hospital in Cape Town, SA, and from support groups of the Parkinson’s Association of South Africa. Standard methods for genealogical research in SA on hereditary diseases were used including interviews and searches in sources such as state archives, the Huguenot Museum in Franschhoek, marriage and baptismal records, and tombstone inscriptions. Results. For 40 of the PD families, there was only a single most recent ancestral couple common to all of the families. On average there are between three and four ancestral lines to the founder couple per proband (range 1 -14). Conclusion. If genetic studies confirm the presence of a founder effect for PD in Afrikaners, this would imply that there is a large number of individuals from this ethnic group who may potentially be at risk of developing this debilitating condition. This study illustrates and reinforces the concept that genealogical analysis is a powerful tool for identification of founder effects for various disorders in the Afrikaner population. S Afr Med J 2014;104(6):413-419. DOI:10.7196/SAMJ.7747

Afrikaners in South Africa (SA) are a recognisable group with a relatively small gene pool and excellent family records over a period of >350 years. The foundations of this group were laid mainly from 1652 until 1807. Afrikaners are derived from settlers from The Netherlands (roughly one-third), Germany (slightly less than onethird) and France (roughly one-quarter), with smaller contributions from other countries, imported slaves and indigenous peoples,[1] the exact proportions differing for each present-day Afrikaner. To illustrate this, a ‘deconstruction’ of one specific Afrikaner individual who has an incomplete ancestral chart of 926 individuals shows contributions of 37.5% from The Netherlands, 27.4% from Germany and 26.4% from France in his make-up, with 2.2% from people ‘van die Kaap’ (‘from the Cape’, an expression which usually refers to female slaves born in the Cape), 1.9% from Britain and the rest from other countries.[2] There could be a perception that in isolated areas such as the Gamkaskloof more frequent intermarriages might have had an influence on the occurrence of hereditary diseases. However, there is no clear evidence that the people in these areas differed significantly from those in less isolated rural Afrikaner communities.[3] Several disorders among Afrikaners occur at relatively high frequencies due to founder effects.[3,4] A founder effect results when a small subset of a large population establishes a new population. The new population may differ significantly from the original population, both in terms of its genotypes and phenotypes. In the case of Afrikaners, the disorders that occur at an unusually high frequency may indicate that the original Dutch, French and German colonists

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who settled in the Cape carried those disease-causing genes at high frequency. In some cases the diseases can be traced back to specific founder couples, e.g. for familial colonic polyposis,[4,5] porphyria variegata,[6] progressive familial heart block,[7] Huntington’s disease (HD),[8] osteogenesis imperfecta,[9] pseudoxanthoma elasticum (PXE),[10] schizophrenia,[11] long QT syndrome[12,13] and Fanconi’s anaemia.[14] Given the evidence of founder effects for other disorders in the Afrikaner population, we sought to determine whether a founder effect for Parkinson’s disease (PD) also occurs in this population. PD is a debilitating neurodegenerative condition arising as a result of the progressive loss of dopaminergic neurons in the brainstem associated with proteinaceous inclusions termed Lewy bodies. Cardinal clinical features include resting tremor, rigidity, bradykinesia, postural instability and responsiveness to levodopa. A genetic aetiology has been found in ~10 - 15% of PD cases and a number of genes (and corresponding proteins) have been implicated, including parkin, PINK1 (PTEN-induced putative kinase 1), DJ-1 (DJ-1), SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), VPS35 (vacuolar protein sorting 35) and EIF4G1 (eukaryotic translation initiation factor 4 γ1). For the genetic forms of PD, both autosomal dominant (AD) and autosomal recessive (AR) patterns of inheritance are evident. Our research team has been investigating the genetic causes of PD in local SA populations since 2007. Noting that a significant proportion of our PD patients were self-identified as Afrikaner, we undertook a genealogical study to investigate the presence of a possible founder effect for PD.

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Fig. 1. Pedigree of the 40 individuals with Parkinsonâ&#x20AC;&#x2122;s disease illustrating their ancestral lines to a common founder couple (labels listed as year of birth, family number, order on pedigree from 1 - 40).

1946 ZA 272 5

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Affected? = Yes

RESEARCH

Methods

Study participants were recruited from the Movement Disorders Clinic at Tygerberg Hospital in Cape Town, SA, and from various support group meetings around SA of the Parkinson’s Association of South Africa. All study participants gave written informed consent. When the genealogical study was started in June 2009, 193 PD probands had been recruited, and of these approximately one-third (62/193; 32.1%) were self-identified as Afrikaner. Afrikaner probands were selected for further genealogical analysis on the basis of having a young age at onset of PD (mostly ≤60 years) and a positive family history of the condition (at least one first-, second- or third-degree relative presenting with similar symptoms). By February 2013, 48 Afrikaner families had been investigated and for each of these a proband was chosen for whom an ancestral chart was drawn. Methods that have become standard in SA genealogical research on hereditary diseases were used.[11,13] These include interviews with probands and their relatives, and searches in various sources such as state archives, the Huguenot Museum in Franschhoek, marriage and baptismal records, death notices, published genealogies, tombstone inscriptions, voters’ rolls, telephone directories and the internet. It is well known that the three mainstream Afrikaans churches, the Nederduitse Gereformeerde Kerk, the Gereformeerde Kerk and the Nederduitsch Hervormde Kerk van Afrika, keep detailed records of marriages and baptisms. Many of these records are available in film or microfiche form at the Genealogical Institute of South Africa in Stellenbosch.

Results

In the initial stages of the research the ancestral charts were drawn as completely as possible. For most of the families, their ancestors can be traced back for at least eight generations. A single ancestral chart for one proband could therefore contain at least 511 individuals, corresponding to the eight generations ancestral to the proband. After the genealogical trees of the first 12 families were constructed, it emerged that there was a single ancestral couple common to these families. This couple (couple A) married in SA in 1668. The husband was born in The Netherlands and came to SA in 1661. The wife was born in Germany in 1655, and she and her parents came to SA in the late 1650s. For the remaining families, the genealogical research concentrated on finding at least one line of descent from couple A to the proband. For 40 of the PD probands, at least one such line of descent was found that confirmed ancestry to couple A. On average, there are between three and four ancestral lines for each PD proband, ranging from a minimum of one line to a maximum of 14 lines. From a genealogical viewpoint this is strong evidence of a possible founder effect for PD, with couple A as the founder couple. For the remaining 8/48 families investigated, the information provided was insufficient to determine their ancestry for more than three or four generations, and their relationship to the founder couple is therefore unknown. Selected lines of descent from the founder couple to the 40 probands are shown in Fig. 1. Although couple A had 12 children, the pedigree shows only the five children for whom there are lines of descent to the PD patients in this study. It should be noted that since a single proband may have many different ancestral lines to the founder couple, this diagram may potentially be drawn in many different ways. A summary of the available demographic and clinical information for these 40 families is provided in Table 1. In these families, both AD and AR patterns of inheritance are evident, based on currently available information. Also, it is plausible that

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reduced penetrance and marriage to spouses with a family history of PD could influence the pattern of inheritance observed within specific families.

Discussion

In the present study, we were able to show that 40 Afrikaner PD probands are descended from a common founder couple. After this couple was identified in the first 12 families examined, links to the couple could also be established in an additional 28 families in which there was sufficient genealogical information to trace ancestry. Since some progenitors of Afrikaners, e.g. the Van der Merwe and Ferreira progenitors, have large numbers of present-day descendants it has been suggested that any two present-day Afrikaners might share these progenitors as ancestors.[2] However, this proposal appears not to be correct. In our database there are only two lines of descent from the Ferreira progenitor, and both are linked to the same proband. To put our results in perspective, these genealogical findings were compared with other genealogical data that we have available on Afrikaners for long QT syndrome.[12] Of the 22 families who were shown to share a founder couple for this disorder, 12 complete and ten partial ancestral charts were drawn. In the 12 complete ancestral charts only four were found with ancestral lines to couple A. Given that the total number of male and female progenitors for the Afrikaner population for the period from 1657 until 1806 was ~4 000,[15] the probability that any randomly selected group of 40 Afrikaners would share a common founder couple appears to be remote. We conclude that it is unlikely that couple A’s relationship to our 40 families is a chance finding, and that couple A is likely to be the founder couple for PD in the present-day Afrikaner population. Notably, couple A has also been referred to as the founder couple for HD, lipoid proteinosis, PXE and schizophrenia in the Afrikaner population.[2] However, this statement can be questioned by referring to the original published literature for each of these disorders. In the case of HD, it is actually the eldest daughter of couple A who was shown to be the founder mother of this disorder in SA.[8] With regard to lipoid proteinosis, a study conducted in the Namaqualand region of SA proposed that a brother and his sister who were born early in the 18th century are the common ancestors of present-day lipoid proteinosis patients.[16] This implies that it is the siblings’ parents, and not couple A, who are the founder couple of lipoid proteinosis. For the recessive condition PXE, genetic analysis of the families identified three mutations that are associated with distinct haplotypes. This suggests that these families are derived from at least three founder couples, one of these being couple A.[10,17] With regard to schizophrenia, 87 affected individuals have been shown to be linked to a single founder couple,[11] but there is no documented evidence that couple A is the founder couple. We acknowledge that to confirm our hypothesis of a founder effect for PD in SA, identification of the underlying genetic cause is needed. To this end, high-density genome-wide single-nucleotide polymorphism genotyping will be used to provide additional support for the genealogical data. It has previously been shown that distantly related affected individuals who share the same causal mutation will also share large genomic regions surrounding it.[18] Moreover, 3/40 probands and one affected sibling (from families labelled ZA92, ZA106 and ZA111) (Table 1) have been selected for wholeexome sequencing (WES), a technique that involves the screening of all coding regions of the genome for pathogenic mutations. The WES data are in the process of being analysed using bioinformatics analysis and genetic studies to identify the causative mutation in these families.

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Table 1. Demographic and clinical information on the South African Afrikaner probands with PD (N=40) and their family members Family no.

Family ID

Gender

Relationship

Affected

AAO

Pedigree pattern

ZA64

F M

Proband Son

Y N

ZA95

F M F F

Proband Son Sister Daughter

Y N N N

ZA233

M F F

Proband Mother Sister

Y N N

ZA134

M F

Proband Daughter

Y N

ZA272

Proband

ZA72

Proband

ZA263

Proband

ZA213

M F F

Proband Daughter Wife

Y N N

ZA112

F M M

Proband Son Son

Y N N

ZA89

F M M F F F M

Proband Husband Son Daughter Daughter Sister Son

Y N N N N N N

ZA86

M M F F

Proband Son Daughter Sister

Y N N N

ZA241

M F

Proband Sister

Y N

ZA92

F F M F F M M F F

Proband Daughter Husband Daughter Daughter Nephew Brother Sister in-law Sister

Y N N N N N Y N N

WES

ZA34

Proband

ZA140

M F M F M F M

Proband Daughter Son Mother Brother Daughter Son

Y N N N N N N

ZA252

M M F F

Proband Father Sister Mother

Y N N N

(Continued ...)

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Table 1. (continued) Demographic and clinical information on the South African Afrikaner probands with PD (N=40) and their family members Family no.

Family ID

Gender

Relationship

Affected

AAO

Pedigree pattern

ZA194

M M F

Proband Brother Daughter

Y N N

ZA142

M M M F F M M M M F F

Proband Cousin Brother Sister Mother Son Son Son Son Daughter Sister

Y N N N N N N N N N Y

WES

ZA413

F M

Proband Cousin

Y Y

54 67

ZA103

M F F F M M M M M

Proband Wife Sister Sister Cousin Cousin Cousin Cousin Uncle

Y N N N N N N N Y

ZA116

M F F F F

Proband Sister Daughter Daughter Sister

Y N N N N

ZA68

M F F M F F

Proband Wife Daughter Son Sister Sister

Y N N N N N

ZA5

Proband

ZA190

Proband

ZA76

M M M

Proband Son Son

Y N N

ZA253

M M F M M M M

Proband Nephew Sister Brother Nephew Cousin Brother-in-law

Y Y N Y N N N

40 37

ZA411

Proband

ZA24

F F

Proband Sister

Y Y

69 61

(Continued ...)

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Table 1. (continued) Demographic and clinical information on the South African Afrikaner probands with PD (N=40) and their family members Family no.

Family ID

Gender

Relationship

Affected

AAO

Pedigree pattern

WES

ZA106

M M F F F M F F

Proband Son Daughter Sister Second cousin Second cousin Second cousin Second cousin

Y N N N N N N N

ZA78

M F M F

Proband Daughter Son Wife

Y N N N

ZA4

Proband

ZA216

M F F

Proband Daughter Daughter

Y N N

ZA340

M M M M F M F

Proband Brother Brother Brother Sister Brother Sister

Y Y Y N N N N

68 48 58

ZA175

M F F M

Proband Sister Daughter Brother

Y N N N

ZA316

Proband

ZA111

M F M F M F M F M F F

Proband Daughter Brother Sister Son Sister Son Daughter Twin Niece Wife

Y N N N N N N N N N N

ZA16

F F M F F M M M F

Proband Sister Father Mother Niece Nephew Son Brother Sister

Y Y N N N N N N N

27 27

ZA150

Proband

ZA256

Proband

(Continued ...)

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Table 1. (continued) Demographic and clinical information on the South African Afrikaner probands with PD (N=40) and their family members Family no.

Family ID

Gender

Relationship

Affected

AAO

Pedigree pattern

ZA128

F F F F F

Proband Daughter Daughter Sister Mother

Y N N N N

WES

PD = Parkinson’s disease; ID = identification; AAO = age at onset of Parkinson’s disease (yrs); WES = whole-exome sequencing; F = female; M = male; Y = yes; N = no; AR = autosomal recessive; AD = autosomal dominant.

There is evidence for the presence of founder effects for PD in a number of different populations, including the North African Arab, Basque and Ashkenazi Jewish populations. In the North African Arab population upwards of 30% of PD patients have been shown to harbour the LRRK2 G2019S mutation, and all these individuals share a common haplotype.[19] This same mutation is also present at a relatively high frequency (~20%) in Ashkenazi Jews, implicating a founder effect for the mutation which occurred in the Near East at least 4 000 years ago.[20] In Norway, G2019S mutation carriers could be traced back 10 generations to a common Norwegian ancestor couple living between 1580 and 1650.[21] Similarly, the LRRK2 R1441G mutation has been found in ~20% of familial PD patients from the Basque ethnic group but is rare outside Spain, and it is hypothesised that this mutation originated in the Basque population in about the 7th century.[22] If genetic studies confirm the presence of a founder effect for PD in Afrikaners, this would imply that there is a large number of individuals from this ethnic group who may potentially be at risk of developing this debilitating condition. It is therefore imperative to identify the underlying causative mutations to be able to offer the options of pre-symptomatic and carrier testing with the appropriate genetic counselling to these individuals. In conclusion, given the extent and depth of ancestral information that is available on Afrikaners, genealogical analysis is a powerful tool for identification of genetic founder effects for various disorders in this particular population.

Acknowledgements. We thank the patients and their families for their participation in this study; without their willing assistance this research would not have been possible. We acknowledge the Harry Crossley Foundation, the South African Medical Research Council and Stellenbosch University for financial support.

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References 1. De Bruyn GFC. [Die samestelling van die Afrikanervolk]. Tydskrif vir Geesteswetenskappe 1976;15:39-42. 2. Greeff JM. Deconstructing Jaco: Genetic heritage of an Afrikaner. Ann Hum Genet 2007;71(5):674688. [http://dx.doi.org/10.1111/j.1469-1809.2007.00363.x] 3. Botha MC, Beighton P. Inherited disorders in the Afrikaner population of southern Africa, Part II. Skeletal, dermal and haematological conditions; the Afrikaners of Gamkaskloof; demographic considerations. S Afr Med J 1983;64(17):664-667. 4. Botha MC, Beighton P. Inherited disorders in the Afrikaner population of southern Africa, Part I. Historical and demographic background, cardiovascular, neurological, metabolical and intestinal conditions. S Afr Med J 1983;64(16):609-612. 5. Louw JH, Torrington M. Familial polyposis of the colon: A condition illustrating the importance of genealogy in medicine. Familia 1968;5:42-47. 6. Dean G. The Porphyrias: A Study of Inheritance and Environment. 2nd ed. London: Pitman, 1971. 7. Brink AJ, Torrington M. Progressive familial heart block – two types. S Afr Med J 1977;52(2):53-59. 8. Hayden MR, Hopkins HC, Macrae M, Beighton PH. The origin of Huntington’s chorea in the Afrikaner population of South Africa. S Afr Med J 1980;58(5):197-200. 9. Knoll DP, de Vries WN, de Wet WJ. [Genealogie van ’n familie met osteogenesis imperfecta: Die stamregister van Pieter Willem Adriaan Piek]. Familia 1988;25:46-64. 10. Le Saux O, Beck K, Sachsinger C, et al. Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa. Hum Genet 2002;111(4-5):331-338. [http://dx.doi. org/10.1007/s00439-002-0808-1] 11. Karayiorgou M, Torrington M, Abecasis GR, et al. Phenotypic characterization and genealogical tracing in an Afrikaner schizophrenia database. Am J Med Genet B Neuropsychiatr Genet 2004;124B(1):2028. [http://dx.doi.org/10.1002/ajmg.b.20090] 12. Brink PA, Criotti L, Corfield V, et al. Phenotypic variability and unusual clinical severity of congenital long QT Syndrome in a founder population. Circulation 2005;112(17):2602-2610. [http://dx.doi. org/10.1161/CIRCULATIONAHA.105.572453] 13. Geldenhuys G. [Genealogiese navorsing oor die lang QT sindroom.] Capensis 3 2009:14-29. 14. Tipping AJ, Pearson T, Morgan NV, et al. Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA 2001;98(10):5734-5739. [http://dx.doi.org/10.1073/pnas.091402398] 15. Heese JA. [Die Herkoms van die Afrikaner 1657-1867.] Kaapstad: AA Balkema, 1971. 16. Van Hougenhouck-Tulleken W, Chan I, Hamada T, et al. Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa. Br J Dermatol 2004;151(2):413-423. [http://dx.doi. org/10.1111/j.1365-2133.2004.06076.x] 17. Torrington M, Viljoen DL. Founder effect in 20 Afrikaner kindreds with pseudoxanthoma elasticum. S Afr Med J 1991;79(1):7-11. 18. Van der Zwaag PA, van Tintelen JP, Gerbens F, et al. Haplotype sharing test maps genes for familial cardiomyopathies. Clin Genet 2011;79(5):459-467. [http://dx.doi.org/10.1111/j.1399-0004.2010.01472.x] 19. Benamer HT, de Silva R. LRRK2 G2019S in the North African population: A review. Eur Neurol 2010;63(6):321-325. [http://dx.doi.org/10.1159/000279653] 20. Lesage S, Patin E, Condroyer C et al; French Parkinson's Disease Genetics Study Group. Parkinson’s disease-related LRRK2 G2019S mutation results from independent mutational events in humans. Hum Mol Genet 2010;19(10):1998-2004. [http://dx.doi.org/10.1093/hmg/ddq081] 21. Johansen KK, Hasselberg K, White LR, Farrer MJ, Aasly JO. Genealogical studies in LRRK2-associated Parkinson’s disease in central Norway. Parkinsonism Relat Disord 2010;16(8):527-530. [http://dx.doi. org/10.1016/j.parkreldis.2010.05.005] 22. Mata IF, Hutter CM, González-Fernández MC, et al. Lrrk2 R1441G-related Parkinson’s disease: Evidence of a common founding event in the seventh century in Northern Spain. Neurogenetics 2009;10(4):347-353. [http://dx.doi.org/10.1007/s10048-009-0187-z]

Accepted 26 February 2014.

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No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry population of South Africa Z Vergotine,1,2 MSc; A P Kengne,3 MD, PhD; R T Erasmus,2 FCPath; T E Matsha,1 PhD epartment of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa D Division of Chemical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa 3 National Collaborative Research Programme for Cardiovascular and Metabolic Diseases, South African Medical Research Council, Tygerberg and University of Cape Town, South Africa 1 2

Corresponding author: T E Matsha (matshat@cput.ac.za) Background. The most common single-nucleotide polymorphism in the insulin receptor substrate-1 (IRS1) gene is Gly972Arg, which is associated with a 25% increased risk of developing diabetes. The mixed-ancestry population of South Africa (SA) has one of the highest prevalences of type 2 diabetes mellitus (T2DM) in Africa. Objective. To report the frequency of IRS1 Gly972Arg and investigate its associations with cardiometabolic traits. Methods. DNA from 856 mixed-ancestry adults drawn from an urban community of Bellville South, Cape Town, SA, was genotyped by two independent laboratories. Oral glucose tolerance tests were performed and cardiometabolic risk factors measured. Results. A total of 237 (24.7%) participants had T2DM. The IRS1 Gly972Arg variant was present in 7.9% of the individuals studied and only one participant (non-diabetic) carried the homozygous A/A variant. In linear and logistic regression analyses, Gly972Arg was not associated with obesity, insulin resistance/sensitivity or T2DM. Conclusions. The prevalence of the Gly972Arg variant in the mixed-ancestry population of SA is comparable to that reported in African Americans, but its presence is not associated with cardiometabolic traits. This suggests that the Gly972Arg variant may not aid diabetes risk evaluation in this setting, nor can such information help explain the high prevalence of diabetes previously reported in this population. S Afr Med J 2014;104(6):420-423. DOI:10.7196/SAMJ.7419

Insulin receptor substrate-1 (IRS1) is a wellcharacterised intracellular substrate for insulin receptor tyrosine kinases containing Src homology 2 (SH2) domains, e.g. phosphatidylinositol 3-kinase, growth factor receptor-bound protein 2 and SH2containing protein tyrosine phosphatase in the insulin-signalling cascade.[1] Extensive studies on several amino-acid variations of the IRS1 gene have shown associations with human metabolic disorders such as type 2 diabetes mellitus (T2DM),[2] obesity[3] and insulin resistance in various population studies as well as in animal models.â&#x20AC;&#x160;[4] Gly972Arg (rs1801278) is the most studied singlenucleotide polymorphism (SNP) of the IRS1 gene because it is a functional mutant reported to impair insulin signalling in transfected cell lines and in human cells carrying the variant.[5-7] There are no data currently available for populations in Africa. Therefore, our study objective was to determine the frequency of Gly972Arg and investigate its associations with T2DM, insulin resistance and obesity traits in the mixed-ancestry population of South Africa (SA), which has been found previously to be prone to diabetes.[8]

Methods

Study setting and population

The study setting, survey design and procedures have been described in detail elsewhere.[8,9] Briefly, eligible participants were invited to take part in a community-based survey from January 2008 to March

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2009 (cohort 1), and January to November 2011 (cohort 2) in Bellville South, Cape Town, SA. The study was approved by the research ethics committees of Stellenbosch University and the Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology. All participants gave written informed consent after all the procedures were fully explained in the language of their choice.

Clinical data

All consenting participants received a standardised interview and physical examination during which blood pressure (BP) was measured according to the World Health Organization (WHO) guidelines[10] using a semi-automated digital BP monitor (Rossmax, USA) on the right arm in a sitting position. Other clinical measurements included body weight, height, and waist and hip circumferences. All anthropometric measurements were performed three times and results averaged. Participants with no history of doctor-diagnosed diabetes underwent a 75â&#x20AC;&#x2026;g oral glucose tolerance test (OGTT) as recommended by the WHO.[11]

Laboratory measurements

Blood samples were collected after an overnight fast and processed for further biochemical analysis. Plasma glucose was measured using the enzymatic hexokinase method, and glycated haemoglobin (HbA1c) by turbidimetric inhibition immunoassay (Cobas 6000, Roche Diagnostics, Germany). Total cholesterol (TC), highdensity lipoprotein cholesterol (HDL-C), and triglycerides (TGs)

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were estimated by enzymatic colorimetric methods (Cobas 6000, Roche Diagnostics, Germany). Low-density lipoprotein cholesterol (LDL-C) was calculated using Friedewald’s formula.[12] Insulin was determined using a microparticle enzyme immunoassay (Axsym, Abbott, USA).

SNP genotyping

Genomic DNA was extracted from whole-blood samples collected in an EDTA tube. For quality control purposes, genotyping for IRS1 Gly972Arg (rs1801278) was carried out in two independent laboratories on the ABI Prism 7900HT platform (Applied Biosystems, USA) and a BioRad Optica (BioRad, USA) using Taqman genotyping assay (Applied Biosystems, USA). In all but two cases, there was complete agreement concerning the genotypes. Consensus agreement was achieved by the comparisons of raw data outputs and automated sequencing using ABI 3730.

Definitions

Body mass index (BMI) was calculated as weight (in kg)/m2 and waist-to-hip ratio as waist/hip circumferences (in cm). Diabetes status was based on a history of doctor diagnosis, a fasting plasma glucose ≥7.0 mmol/l and/or a 2-hour post-OGTT plasma glucose ≥11.1 mmol/l. The following calculations were used:

• homeostatic model assessment of insulin resistance (HOMA-IR) = [fasting insulin concentration (µIU/l) × fasting plasma glucose (mmol/l)] ÷ 22.5 • functional β-cells (HOMA-β%) = [20 × fasting insulin (μIU/ml)] ÷ [fasting glucose (mmol/ml) − 3.5] • fasting insulin resistance index (FIRI) = [fasting insulin (μU/ml) × fasting glucose (mM)] ÷ 25 • quantitative insulin-sensitivity check index (QUICKI) = 1 ÷ [log(fasting insulin (μU/ml) × log(fasting glucose (mg/dl))][13]

Statistical analyses

Of the 1 256 participants who took part in the survey, 1 035 consented to genetic studies. Among the latter, 126 were excluded because they were related to the other participants, and 53 were excluded owing to missing data on the genetic or T2DM trait variables. Therefore, 856 had valid data for the current analyses. General characteristics of the study group were summarised as n and % for dichotomous traits, and mean ± standard deviations (SDs) or median and 25th - 75th percentiles for quantitative traits. Traits were log-transformed to approximate normality, where necessary, prior to analysis. SNPs were tested for departure from Hardy-Weinberg Equilibrium (HWE) via a χ2 goodness-of-fit test. Linear regression

Table 1. General characteristics of the overall population by diabetic status p-value

Overall

No diabetes

Diabetes

Patients, n

856

619

237

Gender (male), n

235

184

0.83

Age (years), mean (±SD)

53.4 (±15.4)

51.0 (±15.5)

50.6 (±13.5)

<0.0001

Systolic BP (mmHg)

125 (±21)

123 (±19)

130 (±23)

<0.0001

Diastolic BP (mmHg)

76 (±13)

75 (±12)

77 (±15)

0.07

Clinical, mean (±SD)

BMI (kg/m )

29.9 (±7.2)

29.3 (±7.1)

31.7 (±7.1)

<0.0001

Waist circumference (cm)

96 (±15)

95 (±15)

102 (±14)

<0.0001

Hip circumference (cm)

109 (±14)

111 (±15)

0.04

Waist-to-hip ratio

0.88 (±0.10)

0.87 (±0.10)

0.92 (±0.08)

<0.0001

HbA1c (%), mean (±SD)

6.3 (±1.5)

5.7 (±0.4)

7.8 (±2.1)

<0.0001

HbA1c (mmol/mol) (±SD)

45.4 (±16.4)

38.8 (±4.4)

61.7 (±23.0)

<0.0001

Fasting blood glucose (mmol/l), mean (±SD)

6.4 (±3.1)

5.1 (±0.7)

9.6 (±4.3)

<0.0001

2-hour plasma glucose (mmol/l), mean (±SD)

7.5 (±3.6)

6.4 (±1.6)

13.4 (±5.3)

<0.0001

TG (mmol/l), mean (±SD)

1.5 (±0.9)

1.4 (±0.9)

1.7 (±0.9)

<0.0001

HDL-C (mmol/l), mean (±SD)

1.3 (±0.4)

1.2 (±0.3)

<0.0001

LDL-C (mmol/l), mean (±SD)

3.6 (±1.0)

3.7 (±1.1)

0.14

TC, mean (±SD)

5.6 (±1.2)

5.5 (±1.2)

5.7 (±1.3)

0.06

Insulin, median (25 - 75th percentile)

7.5 (3.4 - 13.8)

6.9 (3.3 - 12.5)

10.2 (4.4 - 17.6)

<0.0001

2-hour insulin, median (25 - 75th percentile)

37.1 (19.5 - 73.0)

35.1 (19.2 - 63.5)

62.3 (24.3 - 118.7)

<0.0001

Glucose/insulin, median (25 - 75th percentile)

0.74 (0.42 - 1.63)

0.72 (0.41 - 1.51)

0.78 (0.47 - 2.05)

0.10

HOMA-IR, median (25 - 75th percentile)

1.9 (0.8 - 3.8)

1.6 (0.7 - 2.9)

3.6 (1.6 - 7.3)

<0.0001

HOMA-β (%), median (25 - 75th percentile)

72.7 (30.9 - 146.5)

90 (41.8 - 162)

44.5 (13.5 - 81.7)

<0.0001

QUICKI, median (25 - 75th percentile)

0.15 (0.14 - 0.17)

0.15 (0.14 - 0.18)

0.14 (0.12 - 0.15)

<0.0001

FIRI, median (25 - 75th percentile)

1.69 (0.75 - 3.39)

1.4 (0.6 - 2.6)

3.2 (1.4 - 6.6)

<0.0001

1/HOMA-IR, median (25 - 75th percentile)

0.53 (0.26 - 1.20)

0.64 (0.34 - 1.49)

0.28 (0.14 - 0.63)

<0.0001

Laboratory

SD = standard deviation; BP = blood pressure; BMI = body mass index; HbA1c = glycated haemoglobin; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; HOMA-IR = homeostatic model assessment of insulin resistance; HOMA-β = functional β-cells; QUICKI = quantitative insulin-sensitivity check index; FIRI = fasting insulin resistance index.

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except for 2-hour glucose measurements where the effect size appeared to be greater among diabetic v. non-diabetic participants (interaction p=0.19) (Table 2). In logistic regression analyses, IRS1 Gly972Arg was not associated with prevalent diabetes after adjustment for age and sex, and after further adjustment for markers of insulin resistance/sensitivity, and markers of adiposity.

models were used for the analysis of quantitative traits and logistic regression models for dichotomous traits, always assuming additive models for the SNPs. We investigated the additive allelic association of Gly972Arg with each trait, overall and according to diabetes status, and tested for heterogeneity by adding the interaction term of diabetes and Gly972Arg to a model that contained the main effects of diabetes and Gly972Arg. A p-value <0.05 was considered significant. We did not adjust for multiple testing. All analyses were done with R (version 2.12.2).

Discussion

Our study investigated the frequency of the IRS1 Gly972Arg variant in the mixed-ancestry population of SA. The overall prevalence of IRS1 Gly972Arg was 7.9%, with a higher occurrence of the variant found in non-diabetics, and it was not associated with obesity, insulin resistance/sensitivity or T2DM. This suggests that knowledge of the the Gly972Arg variant status may not aid diabetes risk evaluation in this setting, and that it cannot explain the high prevalence of diabetes previously reported in this population. Epidemiological studies on the association between the IRS1 Gly972Arg (rs1801278) SNP and various cardiometabolic traits have reported conflicting results.[2,3,15-19] Although individuals carrying the Gly972Arg SNP have a 25% increased risk of developing diabetes,[15] genome-wide association studies involving subjects of European descent found no association between IRS1 and T2DM.[16,17] Instead, a genetic variant, rs294361, located near IRS1 was associated with T2DM in a large-scale study of French and Danish individuals.[17] Similarly, these associations have not been found[18] in populations with a high prevalence of diabetes such as ours[8] and Pima Indians. [20] Jellema et al.[15] investigated some of these factors, including ethnicity, type of study, diagnostic test used to confirm the presence of diabetes, type of measurement of the polymorphism, prevalence of the polymorphism and age. These authors reported heterogeneity for type of study, diagnostic test used to exclude diabetes in the control subjects, and age of the case subjects as sources of inconsistency across studies.[15] The majority of the studies, including ours, used populationbased designs that did not account for the gene-gene interaction phenomenon, defined as an interaction in which one gene suppresses or enhances the expression of another. For example, the protective effect against insulin resistance of the Ala allele Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene was shown to be enhanced in the

Power calculation

Power calculation was performed with CaTS,[14] assuming a diabetes prevalence of 28%,[8] a Gly972Arg frequency of 19%,[2] a genotype odds ratio of 1.25[15] under an additive model and a nominal p-value of <0.05. Based on the above, our population of 224 diabetic and 619 non-diabetic patients provided a statistical power of 60% for a onestage design.

Results

Clinical characteristics of participants according to diabetes status are summarised in Table 1; 237 (24.7%) participants had T2DM. Compared with non-diabetic participants, those with diabetes had significantly higher adipometric variables (all p≤0.04), systolic BP (p<0.0001) and TGs (p<0.0001), whereas HDL-C levels were significantly lower (p<0.0001). Gly972Arg demonstrated HWE (p>0.05) according to gender and diabetes status. No significant differences in the genotype and allele distributions were observed between the study groups. The frequency distributions, both genotype and allele, did not differ significantly according to diabetes status or gender. The prevalence rate for the heterozygous variant (G>A, rs1801278) was 7.9% (n=68) overall, 6.7% (n=16) in diabetic and 8.4% (n=52) in non-diabetic participants. Only one participant (non-diabetic) carried the homozygous variant (A/A) with a corresponding A allele frequency of 4.1% overall, 3.4% in diabetic and 4.4% in non-diabetic participants. In linear regression analyses, IRS1 Gly972Arg was associated with none of the markers of glycaemia, insulin resistance or insulin sensitivity, both overall and in participants with and without diabetes taken separately, with no evidence of significant statistical interaction by diabetes status (all interaction p≥0.30),

Table 2. Generalised linear regression model of the phenotypic features for the at-risk allele A* Overall

No diabetes

Diabetes

Phenotype

Effects size (95% CI)

p-value

Effects size (95% CI)

p-value

Effects size (95% CI)

p-value

Interaction (p-value)

Fasting glucose

0.05 (-0.56 - 0.62)

0.86

0.12 (-0.07 - 0.32)

0.21

-0.16 (-2.32 - 2.00)

0.88

0.67

2-hour glucose

0.36 (-0.28 - 1.01)

0.27

0.06 (-0.35 - 0.48)

0.77

2.56 (-1.26 - 6.38)

0.19

0.01

HbA1c

0.01 (-0.27 - 0.28)

0.95

0.02 (-0.09 - 0.13)

0.73

-0.02 (-1.09 - 1.03)

0.96

0.88

Fasting insulin

-0.06 (-4.35 - 4.22)

0.98

-0.34 (-2.87 - 2.18)

0.79

0.64 (-14.63 - 15.92)

0.93

0.82

2-hour insulin

5.73 (-11.05 - 22.51)

0.50

2.20 (-14.54 - 18.94)

0.80

23.03 (-33.94 - 80.01)

0.43

0.30

Glucose/insulin

-0.36 (-2.76 - 2.05)

0.77

-0.33 (-2.35 - 1.68)

0.75

-0.30 (-7.78 - 7.18)

0.94

>0.99

HOMA-IR

0.03 (-1.77 - 1.84)

0.97

-0.04 (-0.64 - 0.56)

0.89

0.12 (-6.81 - 7.05)

0.97

0.91

QUICKI

-0.002 (-0.01 - 0.01)

0.70

-0.001 (-0.02 - 0.01)

0.88

-0.006 (-0.03 - 0.01)

0.54

0.73

FIRI

0.03 (-1.59 - 1.65)

0.97

-0.04 (-0.58 - 0.50)

0.89

0.11 (-6.13 - 6.35)

0.97

0.91

CI = confidence interval; HbA1c = glycated haemoglobin; HOMA-IR = homeostatic model assessment of insulin resistance; HOMA-β = functional β-cells; QUICKI = quantitative insulin-sensitivity check index; FIRI = fasting insulin resistance index. *Models are adjusted for age, sex and presence of diabetes.

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presence of the IRS1 Gly972Arg variant.[21] Insulin sensitivity was significantly greater in X/Ala (PPARγ2) + X/Arg (IRS1 Gly972Arg) than in Pro/Pro (PPARγ2) + X/Arg (IRS1 Gly972Arg) carriers.[21] Furthermore, a study that investigated the development of diabetes in mice with three mutations in the insulin receptor, IRS1 and IRS2 reported a higher prevalence (40%) of progression to diabetes in mice with all three mutations compared with mice carrying one mutation (5%).[22]

Study strengths

Our study included extensive data collection on a range of diabetes determinants, and is the first study to investigate the IRS1 Gly972Arg variant in an African population using two independent laboratories to genotype our study population.

Study limitations

The study was limited by the cross-sectional design. The sample size was small, so therefore replication of this analysis in a larger sample size is required to definitively rule out the association between IRS1 Gly972Arg and diabetes. We did not adjust for population stratification, as appropriate markers that can be used to map disease genes or correct for population stratification in the mixed-ancestry population are not yet available. Potential population stratification in unrelated samples may cause spurious positive or negative associations in population-based association studies.[23] Insulin resistance was not based on the glycaemic clamp.

Conclusion

The prevalence of the Gly972Arg variant in the mixed-ancestry population of SA is comparable to that in African Americans (11.6% in control subjects),[24] but was not associated with obesity, insulin resistance/sensitivity or diabetes. The lack of association found between the IRS1 Gly972Arg variant and diabetes in this population study does not exclude its role in the gene-gene and geneenvironment interaction mechanisms underlying the pathogenesis of diabetes. Acknowledgements. We thank the community of Bellville South, Cape Town, SA. This research was supported by grants from the University Research Fund of the Cape Peninsula University of Technology, the South African Medical Research Council, the Harry Crossley Foundation and Stellenbosch University.

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References 1. Rocchi S, Tartare-Deckert S, Mothe I, van Obberghen E. Identification by mutation of the tyrosine residues in the insulin receptor substrate-1 affecting association with the tyrosine phosphatase 2C and phosphatidylinositol 3-kinase. Endocrinology 1995;136(12):5291-5297. [http://dx.doi.org/10.1210/en.136.12.5291] 2. Burguete-Garcia AI, Cruz-Lopez M, Madrid-Marina V, et al. Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: A candidate gene study. Metabolism 2010;59(1):38-45. [http://dx.doi.org/10.1016/j.metabol.2009.07.007] 3. Clausen JO, Hansen T, Bjørbaek C, et al. Insulin resistance: Interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 1995;346:397-402. [http://dx.doi.org/10.1016/S0140-6736(95)92779-4] 4. Sesti G, Federici M, Hribal ML, et al. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 2001;15(12):2099-2111. [http://dx.doi.org/10.1096/fj.01-0009rev] 5. Almind K, Inoue G, Pedersen O, Kahn CR. A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 1996;97(11):2569-2575. [http://dx.doi.org/10.1172/JCI118705] 6. Prudente S, Morini E, Trischitta V. Insulin signaling regulating genes: Effect on T2DM and cardiovascular risk. Nat Rev Endocrinol 2009;5:682-693. [http://dx.doi.org/10.1038/nrendo.2009.215] 7. Federici M, Pandolfi A, de Filippis EA, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 2004;109:399-405. [http://dx.doi. org/10.1161/01.CIR.0000109498.77895.6F] 8. Erasmus RT, Soita DJ, Hassan MS, et al. High prevalence of diabetes mellitus and metabolic syndrome in a South African coloured population: Baseline data of a study in Bellville, Cape Town. S Afr Med J 2012;102(11):841-844. [http://dx.doi.org/10.7196/SAMJ.5670] 9. Zemlin AE, Matsha TE, Hassan MS, Erasmus RT. HbA1c of 6.5% to diagnose diabetes mellitus – does it work for us? – the Bellville South Africa study. PLoS One 2011;6(8):e22558. [http://dx.doi.org/10.1371/journal. pone.0022558] 10. Chalmers J, MacMahon S, Mancia G, et al. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Sub-committee of the World Health Organization. Clin Exp Hypertens 1999;21(5-6):1009-1060. [http://dx.doi.org/10.3109/10641969909061028] 11. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15(7):539-553. [http://dx.doi.org/10.1002/(SICI)1096-9136(199807)15:7%3C539::AIDDIA668%3E3.0.CO;2-S]. 12. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499-502. 13. Monzillo LU, Hamdy O. Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev 2003;61(12):397-412. [http://dx.doi.org/10.1301/nr.2003.dec.397-412] 14. Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006;38:209-213. [http://dx.doi.org/10.1038/ng1706] 15. Jellema A, Zeegers MP, Feskens EJ, Dagnelie PC, Mensink RP. Gly972Arg variant in the insulin receptor substrate-1 gene and association with type 2 diabetes: A meta-analysis of 27 studies. Diabetologia 2003;46(7):990-995. [http://dx.doi.org/10.1007/s00125-003-1126-4] 16. Voight BF, Scott LJ, Steinthorsdottir V, et al. Twelve type 2 diabetes susceptibility loci identified through largescale association analysis. Nat Genet 2010;42:579-589. [http://dx.doi.org/10.1038/ng.609] 17. Rung J, Cauchi S, Albrechtsen A, et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 2009;41:1110-1115. [http://dx.doi.org/10.1038/ng.443] 18. Baier LJ, Hanson RL. Genetic studies of the etiology of type 2 diabetes in Pima Indians: Hunting for pieces to a complicated puzzle. Diabetes 2004;53(5):1181-1186. [http://dx.doi.org/10.2337/diabetes.53.5.1181] 19. Feng X, Tucker KL, Parnell LD, et al. Insulin receptor substrate 1 (IRS1) variants confer risk of diabetes in the Boston Puerto Rican Health Study. Asia Pac J Clin Nutr 2013;22(1):150-159. [http://dx.doi.org/10.6133/ apjcn.2013.22.1.09] 20. Knowler WC, Bennett PH, Hamman RF, Miller M. Diabetes incidence and prevalence in Pima Indians: A 19fold greater incidence than in Rochester, Minnesota. Am J Epidemiol 1978;108(6):497-505. 21. Stumvoll M, Stefan N, Fritsche A, et al. Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity. J Mol Med (Berl) 2002;80(1):3338. [http://dx.doi.org/10.1007/s001090100282] 22. Kido Y, Burks DJ, Withers D, et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest 2000;105(2):199-205. [http://dx.doi.org/10.1172/JCI7917] 23. Deng HW. Population admixture may appear to mask, change or reverse genetic effects of genes underlying complex traits. Genetics 2001;159(3):1319-1323. 24. Lei HH, Coresh J, Shuldiner AR, Boerwinkle E, Brancati FL. Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in AfricanAmericans: The Atherosclerosis Risk in Communities Study. Diabetes 1999;48(9):1868-1872. [http://dx.doi. org/10.2337/diabetes.48.9.1868]

Accepted 17 October 2013.

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The prevalence of hypotension and hypoxaemia in blunt traumatic brain injury in the prehospital setting of Johannesburg, South Africa: A retrospective chart review W Stassen, BTech (EMC), MPhil EM; T Welzel, MB ChB, DipPEC (SA), HDipIntMed (SA), EMDM (Piedmont), MMedSc (Clin Epi) Division of Emergency Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: W Stassen (stassen88@gmail.com) Background. Each year, ~89 000 (180/100 000) new cases of head injury are reported in South Africa (SA), with the majority of patients being in the economically active population. Hypotension and hypoxaemia significantly increase the morbidity and mortality in patients who have suffered a traumatic brain injury (TBI). Cerebral tissue is particularly vulnerable to these secondary insults in the period immediately following a TBI, emphasising the importance of prehospital care in TBI. Objective. To establish the prevalence of prehospital hypotension and hypoxaemia in moderate to severe blunt TBI in greater Johannesburg, Gauteng, SA. Methods. The records of adult patients who sustained a moderate to severe TBI between 1 January and 31 December 2011 were retrospectively reviewed for hypotension (systolic blood pressure <90 mmHg) and hypoxaemia (oxygen saturation <90%) during their prehospital phase of care. These results were subject to descriptive analysis. Results. A total of 299 records were identified, 66 of which met the inclusion criteria. The prevalence of prehospital hypotension and hypoxaemia were 33.3% (n=22) and 37.9% (n=25), respectively, while 21.2% (n=14) of patients suffered double insults of hypotension and hypoxaemia. Hypotension and hypoxaemia were associated with haemorrhage (p=0.011) and chest injuries (p=0.001), respectively. Conclusion. The prevalence of hypotension in this study was similar to that observed in international studies, but the prevalence of hypoxaemia was much higher. There is a need for local guidelines to be developed to inform the quality of TBI care in the context of the developing world. S Afr Med J 2014;104(6):424-427. DOI:10.7196/SAMJ.7494

Traumatic brain injury (TBI) describes any injury of the intracranial structures and cerebral parenchyma that might result from trauma to the head. Included in this definition is the cascade of pathophysiological events that lead to progressive worsening of the initial injury such as intracranial haemorrhage and cerebral oedema.[1] TBI may result in altered brain function and present with confusion, altered consciousness, coma, convulsions and/or focal neurology.[1] According to the National Institute for Occupational Health,[2] each year ~89 000 (180/100 000) new cases of head injury (of any severity) are reported in South Africa (SA). Of these cases, 50% were due to road traffic collisions (bicycle, vehicle or pedestrian), 25% to falls and a further 20% to violence.[2] Hypotension and hypoxaemia have been found to significantly increase mortality in patients who have suffered a TBI.[1,3-7] In one of the largest US-based studies on the effect of hypotension and hypoxaemia on mortality in TBI, the prevalence of hypotension was 34.6% in the period from injury to the end of emergency centre resuscitation.[4] Hypotension was associated with a doubling in mortality from 27% in normotensive patients to 64.8% in their hypotensive counterparts; conversely, favourable outcomes decreased from 51.5% to 19.4%.[4] Another study reported an eight-fold increase in the relative risk of mortality when a patient had ≥2 hypotensive episodes during his/her recovery.[5] Jeremitsky et al.[6] found that patients who died had 50% more hypotensive episodes than survivors, that hypotensive patients had a longer length of hospital stay, and that fewer hypotensive

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patients made it to discharge. Hypotension was also independently associated with mortality after multivariate analysis.[6,7] The effects of hypotension on outcome are particularly pronounced in the acute stages following TBI.[8] A more recent study – the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) study – combined the results of numerous randomised controlled trials (RCTs) conducted among moderate and severe TBIs in a meta-analysis to establish the relationship between hypoxia and hypotension at admission or in the prehospital phase and outcome.[8] Seven studies were included in the meta-analysis and yielded a combined sample size of 6 629 patients. The IMPACT study used proportional odds modelling to show that patients who had hypotensive episodes before or at admission had worse outcomes (odds ratio (OR) 2.7).[8] Most TBIs are followed by an epsiode of apnoea, even if just for a brief period.[10] Numerous studies have revealed the impact that hypoxaemia (partial pressure of oxygen (PaO2) <60 mmHg or oxygen saturation (SpO2) <90%) has on the eventual outcome of patients who have sustained a TBI. Chesnut et al.[4] in their large prospective study found the admission prevalence of hypoxaemia in moderate to severe TBI to be 22.4%. Hypoxaemia was associated with a near doubling in mortality from 27% to 50%.[4] The association between hypotension, hypoxaemia and their duration and mortality was established using multivariate logistic regression. Nearly a quarter (24.6%) of patients suffered hypoxic episodes during transport. Hypoxaemia was associated with a higher incidence of mortality (OR

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2.66), the mortality rate rising to 37% v. 20% among patients without hypoxaemia. Prehospital intubation appeared to have no significant variance on the incidence of hypoxaemia.[9] The association between hypoxaemia and mortality in TBI is not as strong as that between hypotension and mortality, but should the two occur simultaneously, the mortality might be as high as 75%.[6] Cerebral tissue is particularly vulnerable to these secondary insults in the period immediately following a TBI.[10-11] A case can be made for earlier intervention to avoid these insults, indicating the importance of prehospital care in TBI. These findings were corroborated in an Australian study that described an additive dose relationship between hypotension and mortality, i.e. the longer the patient remained hypotensive, the worse the outcome.[6] The effects of hypotension on outcome are particularly pronounced in the acute stages following TBI.[8] This study was primarily aimed at establishing the prevalence of prehospital hypotension and hypoxaemia in patients with moderate to severe blunt TBIs in greater Johannesburg, Gauteng, SA.

Eligible records (n=299) Transfers (n=19)

Eligible records (n=280) Paediatric patients (n=34)

Eligible records (n=246)

Methods

A retrospective, cross-sectional descriptive study was conducted by three methods: (i) an electronic search through a billing database for International Classification of Diseases 10th revision codes that match the description for ‘injuries to the head’ (S00-S09); (ii) an electronic database search through university student patient report forms for any motor vehicle collision, pedestrian-vehicle collision, fall, assault, explosion or sport-related injury; and (iii) a manual search through helicopter patient report forms. Ethical clearance was granted by the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town. All patient records were limited to adult patients (≥18 years) who were seen between 1 January and 31 December 2011 and had a Glasgow Coma Score (GCS) of ≤13/15. All transfers and paediatric patients were excluded from the search. If any essential pieces of data were missing (GCS, blood pressure (BP) or saturation measurements) or if the patient died before emergency medical services (EMS) arrival, the patient record was excluded. Cases were further scrutinised for clinical evidence of blunt TBI and any cases not fitting this criterion were excluded (Fig. 1). A blunt mechanism of trauma was selected, as this is the predominant presentation that paramedics face. The highest immediate gain might therefore be achieved by improving the management practices for this more common presentation over those for any penetrating mechanism of trauma. Demographic characteristics such as age, gender, race, mechanism of injury and concomitant injuries were extracted from each record. The presence of hypoxaemia (defined as SpO2 ≤90%) and/or hypotension (defined as a systolic blood pressure (SBP) ≤90 mmHg) was captured for each record. The initial SpO2 and BP readings were recorded (initial prevalence), including the lowest reading for each (prehospital prevalence). Finally, ancillary data regarding the prehospital treatment that these patients received were recorded. Data were subject to descriptive analysis and the association between hypotension or hypoxaemia and injuries sustained was examined using a χ2 test.

Results

A total of 299 patient records were identified from the initial data search and 66 records matched the inclusion and exclusion criteria (Fig. 1). All records (n=14) included from the second data collection method were void of demographic data and data regarding concomitant injuries and treatment. Table 1 describes the demographics and other data of the sample. The median

425

Incomplete data (n=39)

Eligible records (n=207) GCS >13/15 ( n=136)

Eligible records (n=71) Not blunt TBI (n=3)

Eligible records (n=68) Duplicate (n=1) Patient died on scene (n=1) Eligible records (n=66) Fig. 1. Study flowchart. (GCS = Glasgow Coma Score; TBI = traumatic brain injury.)

GCS was 5/15. The prevalence of hypoxaemia and hypotension is summarised in Fig. 2. The mean (± standard deviation (SD)) initial SBP was 114.2 mmHg (±38.4) and the mean (±SD) lowest SBP was 106.7 mmHg (±34.8). Initial and prehospital hypoxaemia occurred in 37.9% (n=25) of patients. Finally, the mean (±SD) SpO2 was 90.2% (±18.6) and 89.65% (±18.42) initially and at its lowest, respectively. There was a strong association between injuries and hypotension and hypoxaemia. Of patients with hypotension, 86.7% (p=0.011) had injuries that had the potential to cause hypotension and of those

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with hypoxaemia, 42.1% (p=0.001) had a chest injury that could be a likely cause of hypoxaemia. Table 1. Sample description (N=66) n (%) Gender Male

43 (66)

Female

8 (12)

Unspecified

15 (22)

Race Black

33 (51)

White

14 (21)

Indian

1 (2)

Unspecified

18 (27)

Mechanism of injury Road traffic collision

28 (42)

Pedestrian accident

9 (14)

Motorbike accident

5 (8)

Assault

4 (6)

Bicycle accident

4 (6)

Fall

1 (2)

Falling object

1 (2)

Unspecified

14 (21)

Mode of transport Air (helicopter)

45 (68)

Road (ambulance)

7 (11)

Unspecified

14 (21)

Concomitant injury Chest injury

11 (16)

External haemorrhage

18 (27)

Facial fracture

8 (12)

Major fracture

19 (28)

Occult haemorrhage

8 (12)

Isolated head injury

10 (15)

Unspecified

14 (21)

An SBP of <90 mmHg was seen in 27.3% (n=18) of patients at initial presentation, while 33.3% (n=22) had hypotension at some point during their prehospital phase of care. This prevalence is almost identical to that seen by Chesnut et al.,[4] who reported a 34.6% prevalence. This contrasts with a decade-old study from Cape Town that identified a hypotension rate of 8.3%. [12] The Cape Town-based study included patients who were transferred from referring facilities and many patients who did not have prehospital data available. Episodes of hypotension might have already been corrected in the referring facilities or went unrecorded, potentially leading to an underestimation of hypotension. The prevalence of hypotension is more than double (68%) in the study by Manley et al.,[5] but their study period, however, included the first 24 hours following admission, making comparisons difficult. A statistically significant proportion (86.7%; p=0.011) of patients with hypotension had concomitant injuries that had the potential to cause haemorrhage and hypotension. This finding is supported in the literature that suggests hypotension in TBI typically has a haemorrhagic aetiology,[3,13] and that TBI as a sole cause of hypotension is only seen in 8.5%[3] - 13%[13] of patients. It has been suggested that hypotensive patients with TBI should be approached as if they were suffering from haemorrhagic shock.[13] More patients developed hypotension than originally presented with low BPs, raising the question of whether paramedics responded adequately to a decrease in BP. To investigate this, we performed a χ2 test to establish whether a relationship existed between fluid volume and morphine and midazolam dosages administered and hypotension. The mean (range) total fluid volume that the

27.3%; n=18

21.2%; n=25

20 15 10 5 0

Initial hypotension

Prehospital hypotension

Initial hypoxaemia

Prehospital hypoxaemia

Hypoxaemia + hypotension

Fig. 2. Prevalence of hypotension and hypoxaemia.

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patients received in the prehospital period was 919.2 ml (0 - 1 921.1). This fluid therapy had no statistically significant effect on the prevalence of hypotension regardless of the volume infused (p=0.15). As was to be expected, patients who were hypotensive were given more fluid than those who were not, probably in an attempt to correct the hypotension. This difference did not reach statistical significance. Aggressive fluid resuscitation is recommended in patients with isolated TBI to prevent hypotension,[14] but greater caution is necessary when there are potential sites of uncontrolled haemorrhage. [14] The mean fluid volume of this sample is comparable to that administered to TBI patients in an international study (1 056 ml) who had a much lower incidence of hypotension (18%) at these volumes.[15] If the administered fluid volume was adequate, these patients might have benefited from the use of inotropes to improve their BP and cerebral perfusion pressure (CPP). However, the benefit of inotropes may be offset by the risk of hypertension and the potential for developing acute respiratory distress syndrome.[16] The mean (±SD) morphine dose was 8.1 mg (±5.5). The current data showed no association between the morphine dose administered and the prevalence of hypotension (p=0.94). However, a systematic review of RCTs in 2011 found that bolus doses of morphine might be deleterious to outcome by increasing intracranial pressure and decreasing CPP.[17] The mean (±SD) midazolam dose (9.7 mg (±7.2)) was higher than that of morphine. A statistically significant association between the midazolam dose and the prevalence of hypotension (p=0.009) was found, in keeping with international studies.[18] Unfortunately, it was not possible to compare drug doses or infused volumes against body weight, as recorded data was too unreliable.

Hypoxaemia

37.9%; n=25

33.3%; n=22

Patients, %

Hypotension

37.9%; n=25

40 30

Discussion

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The mean (±SD) lowest SpO2 was 89.65% (±18.42). The prevalence of initial and prehospital hypoxaemia was 37.9% (n=25). Interestingly, the prevalence in this Johannesburg-based sample was much higher than that reported in the literature (22.4%),[4] even though 81% of patients were intubated. Of patients with hypoxaemia, 42.1% had a concomitant chest injury that could be responsible for hypoxaemia. As with hypotension, this relationship was statistically significant (p=0.001). Despite the controversies in prehospital intubation, the US Brain Trauma Foundation

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recommends that all patients with a GCS of ≤9/15 who do not have a self-maintained airway, or where pulse oximetry readings remain ≤90%, receive aggressive airway management by the most appropriate practicable means taking into account the skill and level of experience of the prehospital care provider and the milieu of the trauma system in which she/he functions.[11] Locally, there are no published protocols that guide prehospital intubation in the TBI patient and research in this area is lacking. An observational study from the Western Cape did, however, identify an increased mortality in TBI patients who underwent prehospital intubation.[19] Other factors that have been associated with an increase in mortality (injury severity, BP, hypoand hypercapnia, and hypoxaemia)[1,3-12] in this population were not reported on. There was no statistical difference in the prevalence of hypoxaemia in patients who were intubated in the field v. those who were not (p=0.15).

Study limitations

Paramedics may inherently be less willing to record grossly abnormal values and this might lead to reporting bias, underestimating the prevalence of hypotension and hypoxaemia. Often, patients (especially those airlifted) were sedated and intubated on scene and the pre-sedation GCS and pre-intubation saturation levels were not recorded. This falsely lowers the GCS and increases SpO2 levels, which could potentially lead to overestimation of TBI severity and underestimation of the prevalence of hypoxaemia. We retrospectively reviewed charts of cases from 2011, so the data presented might not be entirely contemporaneous. The study was also affected by the inherent limitations of a retrospective design based on data of single local EMS providers, thereby limiting extrapolation to other systems. The relatively small sample size may also affect the ability of this study to reach statistical significance in some measures.

Conclusion

The prevalence of hypotension and hypoxaemia in the greater Johannesburg area is comparable with that observed in international studies. More patients developed hypotension during their prehospital phase of care than had hypotension at initial presentation. Hypotension was associated with midazolam dosage and the presence of injuries that could result in significant haemorrhage. Similarly, hypoxaemia was associated with injuries to the chest and not with field intubation. The current study pointed towards a critical need for educational interventions and the development of a national TBI

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protocol for prehospital care providers that is based on sound clinical evidence and can guide decision-making on the most appropriate interventions in the prehospital setting to optimise outcome. Funding. The research was self-funded by WS.

References 1. Heegaard W, Biros M. Traumatic brain injury. Emerg Med Clin North Am 2007;25(3):655-678. [http:// dx.doi.org/10.1016/j.emc.2007.07.001] 2. National Health Laboratory Service. World Head Injury Awareness Day 2011. http://www.nioh.ac.za/? page=topical&id=13&rid=56 (accessed 9 March 2014). 3. Chesnut RM, Gautille T, Blunt BA, et al. Neurogenic hypotension in patients with severe head injuries. J Trauma 1998;44(6):958-963. [http://dx.doi.org/10.1097/00005373-199806000-00003] 4. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34(2):216-222. [http://dx.doi.org/10.1097/00005373199302000-00006] 5. Manley G, Knudson MM, Morabito D. Hypotension, hypoxia, and head injury: Frequency, duration and consequences. Arch Surg 2001;136(10):1118-1123. [http://dx.doi.org/10.1001/archsurg.136.10.1118] 6. Jeremitsky E, Omert L, Dunham M, et al. Harbingers of poor outcome the day after severe brain injury: Hypothermia, hypoxia and hypoperfusion. J Trauma 2003;54(2):312-319. [http://dx.doi. org/10.1097/01.TA.0000037876.37236.D6] 7. Moppett IK. Traumatic brain injury: Assessment, resuscitation and early management. Br J Anaesth 2007;99(1):18-31. [http://dx.doi.org/10.1093/bja/aem128] 8. McHugh GS, Engel DC, Butcher I, et al. Prognostic value of secondary insults in traumatic brain injury: Results from the IMPACT study. J Neurotrauma 2007;24(2):287-293. [http://dx.doi.org/10.1089/ neu.2006.0031] 9. Chi JH, Knudson M, Vassar MJ, et al. Prehospital hypoxia affects outcome in patients with traumatic brain injury: A prospective multicentre study. J Trauma 2006;61(5):134-141. [http://dx.doi. org/10.1097/01.ta.0000196644.64653.d8] 10. Stiver SI, Manley GT. Prehospital management of traumatic brain injury. Neurosurg Focus 2008;25(4):1-11. [http://dx.doi.org/10.3171/FOC.2008.25.10.E5] 11. Minardi J, Crocco TJ. Management of traumatic brain injury: First link in the chain of survival. Mt Sinai J Med 2009;76(2):138-144. [http://dx.doi.org/10.1002/msj.20105] 12. Reed AR, Welsh DG. Secondary injury in traumatic brain injury patients – a prospective study. S Afr Med J 2002;92(3):221-224. 13. Mahoney E, Biffl W, Harrington D, et al. Isolated brain injury as a cause of hypotension in the blunt trauma patient. J Trauma 2003;55(6):1065-1069. [http://dx.doi.org/10.1097/01. TA.0000100381.89107.93] 14. Roppolo LP, Wigginton JG, Pepe PE. Intravenous fluid resuscitation for the trauma patient. Curr Opin Crit Care 2010;16(4):283-238. [http://dx.doi.org/10.1097/MCC.0b013e32833bf774] 15. Berlot G, La Fata C, Bacer B, et al. Influence of prehospital treatment on the outcome of patients with severe blunt traumatic brain injury: A single-centre study. Eur J Emerg Med 2009;16(6):312-317. [http://dx.doi.org/10.1097/MEJ.0b013e32832d3aa1] 16. Contant CF, Valadka AB, Gopinath SP, Hannay HJ, Robertson CS. Adult respiratory distress syndrome: A complication of induced hypertension after severe head injury. J Neurosurg 2001;95(4):560-568. [http://dx.doi.org/10.3171/jns.2001.95.4.0560] 17. Roberts DJ, Hall RI, Kramer AH, et al. Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trials. Crit Care Med 2011;39(12):2743-2751. [http://dx.doi.org/10.1097/CCM.0b013e318228236f] 18. Choi YF, Wong TW, Lau CC. Midazolam is more likely to cause hypotension than etomidate in emergency department rapid sequence intubation. Emerg Med J 2004;21(6):700-702. [http://dx.doi. org/10.1136/emj.2002.004143] 19. Sobuwa S, Hartzenberg HB, Geduld H, Uys C. Outcomes following prehospital airway management in severe traumatic brain injury. S Afr Med J 2013;103(9):644-646. [http://dx.doi.org/10.7196/ SAMJ.7035]

Accepted 18 November 2013.

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Setting ART initiation targets in response to changing guidelines: The importance of addressing both steadystate and backlog C Martin,1 MB ChB, DipHIVMan, DTM&H; N P Naidoo,1 MPH; W D F Venter,1,2 FCP, MMed, DTM&H, DipHIVMan; A Jaffer,1 MPH; P M Barker,3,4 MB ChB, MRCP, FAAP Wits Reproductive Health and HIV Institute, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa epartment of Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa D 3 Institute for Healthcare Improvement, Cambridge, Massachusetts, USA 4 Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina, USA 1 2

Corresponding author: C Martin (cmartin@wrhi.ac.za)

Background. Target setting is useful in planning, assessing and improving antiretroviral treatment (ART) programmes. In the past 4 years, the ART initiation environment has been transformed due to the change in eligibility criteria (starting ART at a CD4+ count <350 cells/μl v. <200 cells/μl) and the roll-out of nurse-initiated management of ART. Objective. To describe and illustrate the use of a target-setting model for estimating district-based targets in the era of an expanding ART programme and changing CD4+ count thresholds for ART initiation. Method. Using previously described models and data for annual new HIV infections, we estimated both steady-state need for ART initiation and backlog in a North West Province district, accounting for the shift in eligibility. Comparison of actual v. targeted ART initiations was undertaken. The change in CD4+ count threshold adds a once-off group of newly eligible patients to the pool requiring ART – the backlog. The steady-state remains unchanged as it is determined by the annual rate of new HIV infections in previous years. Results. The steady-state need for the district was 639 initiations/month, and the backlog was ~15 388 patients. After the shift in eligibility in September 2011, the steady-state target was exceeded over several months with some backlog addressed. Of the total backlog for this district, 72% remains to be cleared. Conclusion. South Africa has two pools of patients who need ART: the steady-state of HIV-infected patients entering the programme each year, determined by historical infection rates; and the backlog created by the shift in eligibility. The healthcare system needs to build longterm capacity to meet the steady-state need for ART and additional capacity to address the backlog. S Afr Med J 2014;104(6):428-430. DOI:10.7196/SAMJ.7507

Target setting has been useful for both the National Department of Health (NDoH) and supporting partners to plan, assess and improve the current performance of HIV testing and antiretroviral treatment (ART) programmes. Various models for estimating HIV testing and ART initiation need and coverage in South Africa (SA) have been popularised.[1-4] However, less attention has been afforded to models which enable programme managers to effectively understand and plan for the ART need based on the local context, i.e. district and sub-district needs over the long term. In the last 4 years, the ART initiation environment in SA has changed substantially due to policy amendments related to the roll-out of nurse-initiated management of ART,[5] and the change in the recommended CD4+ count threshold for initiation of ART, i.e. a shift from <200 cells/μl to <350 cells/μl.[6] There remains a need for simple, practical tools which can be understood and applied at a local level to enable district planners to accurately plan and evaluate their HIV testing and ART programmes on an ongoing basis. Planning for both the sick and currently well sections of the HIV population in need of ART is imperative to ensure that the appropriate resources, including drugs, are allocated and utilised efficiently and effectively. Furthermore, planning should account

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for current performance relative to national and district-level targets. Leydon et al.[1] proposed a model which uses local target setting in district healthcare facilities, accounting for the backlog of clients needing treatment. We propose that the current ART need in SA can be planned for in terms of an annual ‘steady-state’ that adds new clients each year, and a single pool (‘backlog’) of currently asymptomatic patients who are eligible for treatment by virtue of the change in guidelines from a CD4+ count threshold of <200 cells/μl to <350 cells/μl. The healthcare system response is different for these two categories. Experience in supporting districts has shown that although some districts may meet their annual ‘steady-state’ ART initiation targets, districts have yet to meet the backlog need for ART created by the shift in CD4+ count thresholds.

Objectives

With the district health information system as a source, we used routine observational data from ART programmes in a North West Province (NWP) district[7] to describe and illustrate the use of a target-setting model for estimating district-based targets in the era of an expanding ART programme and changing CD4+ count thresholds for ART initiation.

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Methods

Using two previously described models and tools developed by the Institute for Healthcare Improvement and the Wits Reproductive Health and HIV Institute, we estimated the steady-state and backlog need for ART initiation in a NWP district resulting from the shift in CD4+ count thresholds.[1,2] These were calculated on the basis of a district population of 695 933[8] and antenatal HIV prevalence of 32.4%[9] Ethics approval was obtained from the Human Research Ethics Committee (Medical), University of the Witwatersrand (clearance no. M130206).

Steady-state calculation

The previously published highly active antiretroviral therapy (HAART) calculator is used to determine the steady-state need for ART initiations.[2] This determines the number of incoming clients eligible for ART to be added to the programme each year, based on Actuarial Society of South Africa estimates for new HIV infections in previous years. It is estimated that it will take 5 years from the time of HIV acquisition to the time that an HIV-infected person’s CD4+ cell count falls below 350 cells/μl, making him/ her eligible for ART.[10] We used a simplified model to determine the steady-state for ART initiation prior to the change in CD4+ count thresholds, which assumed that patients with CD4+ counts of <200 cells/μl are started on ART or die. Patients with CD4+ counts of 200 - 350 cells/μl are started on ART, stay alive in the backlog ‘pool’ until they are started on treatment or die. As described by Leydon et al.,[1] the steadystate need for ART initiation is determined by the historical annual infection rates and is not influenced by a change in CD4+ count thresholds. The change in CD4+ count thresholds does create a backlog, i.e. a one-time pool of additional patients with CD4+ counts 200 - 350 cells/µl who require ART. However, once this additional pool of patients has been initiated on ART, the annual requirements of the healthcare system for initiating new patients on treatment returns to a steady-state that is determined by new HIV infections in previous years.[1]

Results

For this NWP district, the steady-state need was calculated at 639 initiations/month (7 669 per year). The backlog need created by the change in CD4+ count threshold was ~15 388 patients. Since September 2011, after the shift in CD4+ count threshold, the steadystate target was exceeded over several months.

Discussion

Practical tools and models that facilitate target setting at a district level enhance the response to the HIV epidemic. SA has two pools

Time of infection before HAART initiation (years), n 2003 500k

2003 2004 2005

2006 2007

6 2008

2009

Time of infection before HAART initiation (years), n 2004 1 2 3 4 5 6 7 500k 2005 1 2 3 4 5 6 500k 2006 1 2 3 4 5 500k

Start HAART 2010 Steady-state 500k

8 7 6

Start HAART 2011 500k

Steady-state Backlog

500k 500k

Steady-state

Time of infection before HAART initiation (years), n Start HAART 2003 2012 1 2 3 4 5 6 Steady-state 500k 500k

Backlog calculation

The change in ART initiation criteria results in a shortened interval from HIV acquisition to ART initiation: from 7 years if the threshold is 200 cells/μl to 5 years if the threshold is 350 cells/μl.[10] In the year that the CD4+ count threshold changes, an additional set of patients needing ART is added to the pool – in this case, an

In those months, the backlog was decreased by the number of patients started on ART in excess of the steady-state target. The model assumes that ART initiations below the targeted steady-state threshold are initiations in patients with CD4+ counts <200 cells/μl and that ART initiations above the steadystate target are initiations in patients with CD4+ counts between 200 cells/μl and 350 cells/μl. In months where initiations fell below the steady-state target, the backlog was not affected. Using these assumptions, the backlog was decreased by 3 335 initiations during months when the steady-state target was exceeded. The backlog was not affected when the initiation rate dropped below the steady-state target, since the great majority of patients treated under these conditions were assumed to have a CD4+ count of <200 cells/ μl. Of the backlog, 72% remained, meaning that in this NWP district, ~12 000 of the projected 15 300 patients remained in the backlog pool awaiting initiation onto ART. Fig. 2 depicts the relationship between actual ART monthly initiations, the steady-state monthly initiation target and backlog (CD4+ count 200 - 350 cells/µl) for the district. Actual ART initiations in the district were compared with targeted steady-state need. In the months where ART initiations exceeded the steadystate target, the backlog was reduced; however, during months where the steady-state target was not met, the backlog remained static.

additional 2 years’ worth of the steady-state need. This is the backlog. The model for calculating SA’s steady-state and backlog is shown in Fig. 1. In this model, the system was at steady-state in 2010 when the CD4+ count threshold was 200 cells/µl. In that year in SA, ~500 000 patients infected in 2003[11] needed treatment. In 2011, the CD4+ count threshold increased to 350 cells/µl, adding the backlog of patients from the 2004 and 2005 cohorts, which each added 500 000 patients to the pool, as well as the new steady-state influx of 500 000 patients from the 2006 cohort. In 2012, if the backlog was eliminated, the steady-state conditions returned with 500 000 added from the 2007 cohort. Using observational data at a district level, the proposed model was then applied to generate estimates of actual ART initiations in the district as compared with the steadystate and backlog targeted ART initiations as determined by the methods outlined above. In doing so, we propose that target setting at a district level incorporates two distinct steps: (i) the steady-state calculation; and (ii) the backlog estimate resulting in a comprehensive and more accurate district ART target.

Fig. 1. A model for calculating South Africa’s steady-state and backlog need for antiretroviral treatment (ART) initiation. Estimated number of new patients requiring ART initiation in 2010 (based on CD4+ count threshold of 200 cells/µl), 2011 (during transition to new threshold of 350 cells/µl) and 2012, assuming that the backlog created by the shift in eligibility is cleared. (HAART = highly active antiretroviral therapy; 500k = 500 000.)

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Steady-state

14 000

will further add to the pool of patients in the backlog. Further, the model assumes that those patients who are lost to follow-up will either die or re-enter the treatment pool at a later date and are therefore not added back into the backlog estimate.

12 000

Conclusion

Backlog (CD4+ 200 - 300 cells/µl) 18 000

1 400

1 000 800

10 000

600

8 000 6 000

400

Backlog target, n

16 000

1 200

4 000 200 Apr 11 Jun 11 Aug 11 Oct 11 Dec 11 Feb 12 Apr 12 Jun 12 Aug 12 Oct 12 Dec 12 Feb 13

Jun 10

Aug 10 Oct 10 Dec 10 Feb 11

2 000 Apr 10

Monthly ART initiations (actual and steady-state), n

Actual ART inititation

Fig. 2. The relationship between backlog and exceeding the steady-state target for the North West Province district. (ART = antiretroviral treatment.)

of HIV patients who need ART. Firstly, as described previously, there is a steady-state rate of HIV-infected patients who should be entering the ART programme each year. This is determined by the annual rate of new HIV infections in previous years. Secondly, a shift in the CD4+ count threshold causes a onetime additional backlog that is quantifiable and can be addressed by a temporary increase in system capacity. When steady-state rates are exceeded, the backlog can be worked down. Using this model, we estimated that in this NWP district the backlog decreased by 27% during the months when initiation rates exceeded the steady-state rate. Understanding the different approaches for steady-state and backlog initiations is needed to appropriately respond to the HIV care and treatment needs in each district. Each requires a different planning response. Translated to SA as a whole, the healthcare system needs to build reliable longterm capacity to initiate and care for the ~500 000 new patients per year generated by infections in past years. This annual number is expected to decrease in future years due to the declining annual infection rate (estimated 320 000 in 2012).[11] But the healthcare system also needs to be able to temporarily increase capacity to address the backlog of an additional one million patients in need of ART (Fig. 1) created by changes in the CD4+ count threshold. In addition, system planners need to build capacity to meet long-term chronic care needs of all of those started on ART each year. The most recent data on ART initiation (~500 000 per year)[12] suggest that SA is only

providing sufficient ART initiation capacity to meet its steady-state needs. The projected additional one million patients who need treatment will undoubtedly place tremendous strain on the already overburdened healthcare system, which will need to add even greater capacity following any further increase in the CD4+ count threshold.

Study limitations

The proposed model is based on assump tions that introduce some limitations to generalisability of the findings. The model is based on estimates regarding population size, antenatal prevalence and ART initiation numbers. The number of new infections has decreased over the past 5 years from a high of 530 000 in 2006 to 320 000 in 2012.[11] This means that the model, based on an average infection rate of 500 000 per year, overestimates the steady-state need for future years. The model is simplistic in terms of its assumptions regarding the average time from HIV infection to ART need depending on CD4+ count thresholds, the consequences of not initiating ART at these thresholds, and the assumed CD4+ counts of individuals who are being initiated on ART when the initiation targets are below or exceed the steady-state targets. The model has not included in the target the estimated 400 000 HIV-infected pregnant women who need to receive antiretrovirals each year for the duration of pregnancy and breastfeeding, since these women are only transiently added to the pool of treated HIV-infected patients under the current NDoH policy. The policy to initiate all tuberculosis patients on ART

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This paper highlights and describes a practical model for setting targets for ART initiation that can be applied at all levels of the healthcare system. It highlights the distinction between the steady-state need for ART initiation, and the backlog need created by changes in CD4+ count thresholds. Any further increase in the CD4+ count threshold with future World Health Organization recommendations would add further patients to the backlog, again with no effect on the steady-state requirements. Despite the limitations of the model, its simplicity allows it to have practical application and to provide a support tool to district planners in terms of the ART programme. Appropriate planning for the ART need, in a changing environment, is imperative to ensuring that targets are met, and that all eligible patients are identified, are able to access care and are initiated on ART. References 1. Leydon NG, Venter F, Webster PD, Moleko W, Osih R, Barker PM. Achieving the HIV and AIDS National Strategic Plan: A practical calculator for local target setting in district health facilities. S Afr Med J 2010;100(7):420-424. 2. Barker PM, Venter F. Setting district-based annual targets for HAART and PMTCT – a first step in planning effective intervention for the HIV/AIDS epidemic. S Afr Med J 2007;97(10):916-917. 3. Adam MA, Johnson LF. Estimation of adult antiretroviral treatment coverage in South Africa. S Afr Med J 2009;99(9):661-667. 4. Johnson LF. Access to antiretroviral treatment in South Africa, 2004 - 2011. Southern African Journal of HIV Medicine 2012;13(1):22-27. 5. National Department of Health. Clinical Guidelines for the Management of HIV & AIDS in Adults and Adolescents 2010. Pretoria: NDoH, 2010. http://www.sahivsoc.org/upload/ documents/Clinical_Guidelines_for_the_Management_of_ HIV_AIDS_in_Adults_Adolescents_2010.pdf (accessed 30 April 2013). 6. The Presidency, Republic of South Africa. Statement on the meeting of the South African National AIDS Council (SANAC). 12 August 2011. http://www.thepresidency.gov.za/pebble. asp?relid=4650 (accessed 30 April 2013). 7. Health Information Systems Programme. http://hisp.org/ (accessed 10 March 2014). 8. Statistics South Africa. South African National Population Census of 2011. https://www.statssa.gov.za/Census2011/ Products/Census_2011_Census_in_brief.pdf (accessed 10 March 2014). 9. National Department of Health. The 2010 National Antenatal Sentinel HIV & Syphilis Prevalence Survey in South Africa. Pretoria: NDoH, 2011. http://www.gov.za/documents/ download.php?f=155559 (accessed 10 March 2014). 10. Pantaleo G, Graziosi C, Fauci AS. The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 1993;328(5):327335. [http://dx.doi.org/10.1056/NEJM199302043280508] 11. Actuarial Society of South Africa AIDS Committee. ASSA2008. http://aids.actuarialsociety.org.za/ASSA2008-Model-3480.htm (accessed 10 June 2013). 12. Pillay Y. Opening plenary. Southern African HIV Clinicians Society Conference. Cape Town, South Africa, 25 - 28 November 2012.

Accepted 24 September 2013.

RESEARCH

Paediatric otitis media at a primary healthcare clinic in South Africa L Biagio,1 MComMPath; D W Swanepoel,1-3 PhD; C Laurent,1,4 MD, PhD; T Lundberg,5 MD epartment of Speech-Language Pathology and Audiology, University of Pretoria, South Africa D Ear Sciences Centre, School of Surgery, University of Western Australia, Nedlands, Australia 3 Ear Science Institute Australia, Subiaco, Australia 4 ENT Unit, Department of Clinical Science, Umeå University, Sweden 5 Family Medicine, Department of Public Health and Clinical Medicine, Umeå University, Sweden 1 2

Corresponding author: L Biagio (leigh.biagio@up.ac.za) Background. No published studies on the prevalence of paediatric otitis media at primary healthcare clinics (PHCs) in South Africa (SA) are available. Objective. To examine the point prevalence of otitis media in a paediatric population in a PHC in Johannesburg, SA, using otomicroscopy. Methods. A sample of 140 children aged 2 - 16 years (mean 6.4; 44.1% females) were recruited from patients attending the PHC. Otomicroscopy was completed for each of the participants’ ears by a specialist otologist using a surgical microscope. Results. Cerumen removal was necessary in 36.0% of participants (23.5% of ears). Otitis media with effusion was the most frequent diagnosis (16.5%). Chronic suppurative otitis media (CSOM) was diagnosed in 6.6% of children and was the most common type of otitis media in participants aged 6 - 15 years. Acute otitis media was only diagnosed in the younger 2 - 5-year age group (1.7%). Otitis media was significantly more prevalent among younger (31.4%) than older children (16.7%). Conclusion. CSOM prevalence, as classified by the World Health Organization, was high. Consequently diagnosis, treatment and subsequent referral protocols may need to be reviewed to prevent CSOM complications. S Afr Med J 2014;104(6):431-435. DOI:10.7196/SAMJ.7534

Otitis media is a pervasive childhood disease posing significant healthcare challenges.[1] Estimates suggest that 80% of children will have at least one episode of acute otitis media (AOM) before 3 years of age.[2] A global incidence study reported an AOM incidence rate of 10.9%.[3] The true incidence of otitis media with effusion (OME) is difficult to estimate as the disorder is by definition asymptomatic. Furthermore, most screening studies determine the presence of middle-ear fluid without differentiating between AOM and OME.[4] An analysis of previous studies estimated the point prevalence of middle-ear effusion on screening as 20.0%.[4] The global incidence of the most severe form of otitis media, chronic suppurative otitis media (CSOM), is 4.8%. CSOM is estimated to contribute to more than half of the global burden of hearing impairment.[5] The burden and population demographics of otitis media differ greatly between developed and developing regions. India and subSaharan Africa (SSA) account for most deaths from complications arising from otitis media.[5] The incidence of AOM in SSA, South Asia and Oceania is two- to eight-fold higher than in the rest of the world,[3] with the aboriginal population demonstrating the highest incidence.[4] SSA has the second-highest incidence of CSOM.[3] The epidemiology of otitis media, and reasons for regional differences in incidence and prevalence are complex, with risk factors involving multiple host-related factors (age, gender, race, allergy, immune competence specifically related to HIV status, malnutrition, craniofacial abnormalities, genetic predisposition) and environmental factors (upper respiratory infection, seasonality, daycare, presence of siblings, tobacco smoke exposure, breastfeeding, socioeconomic status).[1,3,4,6] HIV-positive children are more prone to, and more severely affected by, otitis media than immunocompetent children.[7]

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An estimated 3 million of the 3.3 million children worldwide who are HIV-positive (0 - 14 years of age) live in SSA.[8] Of the SSA countries, South Africa (SA) has the second-highest prevalence of new HIV infections in children.[9] HIV status is therefore likely to be important factor in the epidemiology of otitis media in SA. Despite the diverse risk factors and influences, otitis media is largely preventable, and can be effectively managed through medical and surgical approaches.[6] However, knowledge of the prevalence of otitis media, especially of the most severe form of the disease – CSOM – is important in determining treatment protocols.[6] In a community where CSOM prevalence is low, the disease will generally resolve without treatment or complications.[6] However, early medical intervention is indicated in communities where CSOM prevalence rates are >4.0%, which is considered a high-risk population.[5,6] The World Health Organization (WHO) has classified the prevalence of CSOM in Africa among children and adults as high, estimated to be between 3.0% and 6.0%.[5] Estimates of otitis media in SA, which were included in recent global prevalence studies completed by Acuin[5] and Monasta et al.,[3] are based on only two studies. [10,11] One additional study provided an indication of the prevalence of only OME in SA.[12] Estimates of the point prevalence of otitis media in SA rural populations varied from 6.5% to 18.0%.[11,12] OME was reported most frequently by all studies (paediatric prevalence of 3.8 - 12.0%), with CSOM seen in 0.3 - 6.0% of the paediatric population.[10-12] However, variations in CSOM definition make comparison between studies difficult. Previous SA studies investigating otitis media prevalence selected rural populations, characterised by many of the poor socioeconomic conditions associated with otitis media, but focused on school-aged children[10,11] as opposed to younger preschool children who are more prone to otitis media.[4] Otoscopy, rather than otomicroscopy, was

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used previously to diagnose middle-ear pathology. Otomicroscopy, however, offers greater diagnostic sensitivity and specificity than either otoscopy or pneumatic otoscopy,[13] and is therefore likely to provide a more accurate diagnosis, and classification, of otitis media. No studies on otitis media prevalence have been performed at primary healthcare clinics (PHCs) in SA. The current study therefore employed otomicroscopy to ascertain the point prevalence of otitis media in a paediatric population in an SA PHC.

Methods

Study population

Witkoppen Health and Welfare Centre (WHWC) is a PHC that provides services to the Diepsloot community north of Johannesburg, SA. Diepsloot is a densely populated settlement consisting of government-subsidised housing, brick houses built by landowners, and shacks fashioned from scrap metal, wood, plastic and cardboard. [14] Estimates suggest that >90% of the >150 000 population is unemployed, with many families lacking access to basic services such as running water, sewage and rubbish removal. WHWC serves as a specialist centre for HIV and tuberculosis (TB) treatment. In 2012, the clinic had 95 521 patient visits. Of the children (<14 years) who attended the clinic in 2012, and whose caregivers consented, 4.0% tested positive for HIV. A consecutive sample of 140 children aged 2 - 16 years (range 2 15.8; mean (± standard deviation (SD)) 6.4 (±3.5); 44.1% females) were recruited from registered patients of WHWC. The participants were recruited from the entire paediatric population attending the clinic for any purpose, whether for a routine clinic appointment or for chronic or acute treatment. Caregivers were required to provide written consent after being informed (verbally and in writing) of the study objectives and methods. Although the typical annual paediatric HIV prevalence among patients of WHWC who consented to HIV testing was known, HIV status for the individual study participants was not recorded because ethical clearance did not allow for this. Caregivers and children were interviewed immediately prior to otomicroscopy to obtain biographical information and history of earache, ear discharge or hearing loss during the 2 weeks prior to participation in the study. The investigation was conducted following approval from the Research Ethics Committee of the Faculty of Humanities, University of Pretoria.

Data collection

Otomicroscopy was completed for each ear of the participants by a specialist otologist using a Leica M525 F40 surgical microscope. Observations regarding ear canal obstruction, presence of secretion, tympanic membrane patency, translucency and position, as well as the concluding diagnosis were documented. On-site data collection continued over the course of 2 weeks. The diagnosis and classification of the types of otitis media were based on: (i) clinical data of otalgia and otomicroscopic findings of opacity and bulging of the intact tympanic membrane for AOM;[15] (ii) a wet, swollen and contourless eardrum for perforated AOM; (iii) evidence of seromucoid effusion in the middle ear (completely filled or air-fluid level or bubbles), with an intact tympanic membrane without symptoms of acute infection for OME;[15] and (iv) evidence of a perforation or cholesteatoma with or without purulent discharge for CSOM.[5]

Data analysis

Otomicroscopic examinations could be completed for 136 participants (272 ears) (four participants failed to co-operate during otomicroscopy). Descriptive statistics were used to determine the frequency with which the caregivers reported otological symptoms, the presence of cerumen,

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and otological status of otitis media for the age groups 2 - 5 years and 6 - 15 years. The two age groups were delineated to represent preschool children (aged 2 - 5 years) and children attending school (aged 6 15 years). Descriptive statistics on otological status were presented for participants and ears, respectively. A participant was classified as ‘normal’ when an otological diagnosis of ‘normal’ was made on otomicroscopy in both ears. When a diagnosis could not be made by otomicroscopy due to partial or complete obstruction of the external ear canal, the ear was classified as ‘undetermined’. If a participant had ‘undetermined’ status in one or both ears, the participant was classified as ‘undetermined’. Descriptive statistics on otological status were also completed excluding cases where a diagnosis could not be made in one or both ears. Comparisons of otological status (for data including and excluding ‘undetermined’ ears) between age groups, gender, and left and right ears were made using Pearson’s χ2 tests with p<0.05 considered to be significant.

Results

Table 1 summarises the symptoms and complaints of otological disorders for the 2 weeks prior to evaluation, as disclosed by the participants’ caregivers. Caregivers indicated that 7.4% of participants presented with earache, 5.2% with discharge and 6.6% with possible hearing loss. Earache and discharge for participants aged 2 - 5 years were reported almost twice as often as for participants aged 6 - 15 years. Cerumen removal was necessary for 36.0% of participants (23.5% of ears) to obtain a clear view of the tympanic membrane for otomicroscopic diagnosis. Cerumen was removed manually in this study and was halted in the event of any discomfort. Cerumen removal was required for 39.5% of 2 - 5-year-old participants (23.7% of ears), and for 31.7% of participants aged 6 - 15 years (23.3% of ears). Cleaning was not possible for a greater number of participants aged 2 - 5 years (14.5% of participants) than those aged 6 - 15 years (10.0% of participants). Table 2 summarises the participants and ears with no, partial and complete obstruction of the tympanic membrane by cerumen (after manual cerumen removal as far as was possible without causing discomfort) at the time of otomicroscopic diagnosis of middle-ear status. The otological status was reported for both ears and participants (Table 3). Cerumen could not be removed, and otomicroscopic diagnosis of middle-ear status could consequently not be made, in one or both ears of 12.9% of participants. A diagnosis could not be made in either ear of three participants. Table 4 summarises the otological status for the paediatric sample but excludes ears where a diagnosis could not be made due to partial or complete cerumen obstruction. Diagnosis by otomicroscopic examination revealed that otitis media was significantly more prevalent for the younger (31.4%) v. the older participants (16.7%; p=0.034; χ2 test). OME was the most frequently diagnosed pathology for participants aged 2 - 5 years (23.9%), while CSOM was most commonly diagnosed for those aged 6 - 15 years (9.3%). AOM was only diagnosed in the younger participants (3.0%). Table 1. Caregiver report of symptoms of otological disorder over 2 weeks prior to otomicroscopy (N=136) Age (yrs), % 2-5

6 - 15

Total, %

Earache

9.2

5.0

7.4

Hearing loss

2.6

11.7

6.6

Discharge

6.6

3.3

5.2

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Otitis media was equally distributed between right and left ears. More male participants (29.2%) than female participants (18.5%) presented with otitis media, but the difference was not statistically significant (p>0.05; χ2 test).

Discussion

Establishing regional otitis media prevalence rates is important when determining treatment protocols.[6] The point prevalence of OME in Table 2. Obstruction of the tympanic membrane during otomicroscopic examination Age (yrs), % 2-5

6 - 15

Total, %

136

None

30.3

46.7

37.5

Partial

44.7

23.3

35.3

Complete

0.0

1.7

0.7

Partial and complete

9.2

10.0

9.6

Partial

13.2

11.6

12.5

Complete

2.6

6.7

4.4

152

120

272

None

38.8

55.8

46.3

Partial

55.9

34.2

46.3

Complete

5.3

10.0

7.4

Subjects Total, n Bilateral obstruction

Unilateral obstruction

Ears Total, n Obstruction

the current study population (excluding undetermined participants) was 16.5%, which is the highest in current reports from SA.[10-12] It is also higher than the non-aboriginal OME prevalence in the AsiaPacific region (1.14 - 13.8%),[16] but still considerably lower than bilateral OME prevalence for aboriginal children (31.0%), who have the highest OME prevalence rate in the world.[16] A higher prevalence of OME for male participants was found in the current study, although it was not statistically significant (p>0.05; χ2 test). Previous research on gender differences have reported divergent findings with some demonstrating a statistically significant higher prevalence in male children, while others found no gender differences.[2,4] Our study findings support that of Teele et al.,[2] who found that OME was associated with male children. Although HIV status was not assessed in participants enrolled in our study, WHWC reported a new HIV prevalence rate of 4.0% among children aged ≤14 years in 2012. This is higher than the SA HIV prevalence rate of 2.4% for babies tested at 6 weeks of age (reported between March 2012 and February 2013).[17] Individuals with HIV are known to be more prone to, and more severely affected by, otitis media than seronegative children.[18] Positive HIV status may therefore have contributed to the OME point prevalence measured, and to that of the more severe form of otitis media, namely CSOM. In our study, the prevalence of CSOM for the total paediatric sample (excluding undetermined participants) was 6.6%, which is classified by the WHO as high,[5] and is similar to previous estimates of CSOM prevalence in SSA.[5] The CSOM prevalence of 9.3% measured among 6 - 15-year-olds in the current study would be rated as the highest prevalence according to the WHO classification system. [5] The higher CSOM prevalence for older children was anticipated as the pathology and sequelae develop from long-term, chronic middle-ear inflammation. Differences in the terminology and definitions used in previous studies make comparisons problematic. Perforations of the tympanic membrane can be associated with either AOM or CSOM. Prescott and Kibel[11] did not report CSOM, but described the prevalence of perforated tympanic membranes in their study (6.0% of participants), which was comparable

Table 3. Otological status as diagnosed by otomicroscopy Age (yrs), % All, %

2-5

6 - 15

Male, %

Female, %

Left, %

Right, %

Total, n

136

Normal

66.9

60.5

75.0

61.4

72.1

Otitis media

20.6

27.7

11.7

25.3

16.4

AOM

1.5

2.6

0.0

1.3

1.6

CSOM

5.1

4.0

6.7

4.9

OME

14.0

21.1

5.0

17.3

9.9

12.5

11.8

13.3

11.5

Participants

Undetermined Ears Total, n

272

152

120

150

122

136

Normal

75.8

71.1

81.6

72.0

81.4

75.7

Otitis media

16.5

21.0

10.9

19.3

11.8

17.7

15.5

AOM

0.7

1.3

0.0

0.7

0.8

1.5

0.0

CSOM

4.8

3.3

6.7

5.3

4.2

4.4

5.2

OME

11.0

16.4

4.2

13.3

6.8

11.8

10.3

7.7

7.9

7.5

8.7

6.8

6.6

8.8

Undetermined

AOM = acute otitis media; CSOM = chronic suppurative otitis media; OME = otitis media with effusion.

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Table 4. Otological status as diagnosed by otomicroscopy excluding participants and ears where a diagnosis could not be made Age (yrs), % All, %

2-5

6 - 15

Male, %

Female, %

Left, %

Right, %

Total, n

121

Normal

75.2

68.6

83.3

70.8

81.5

Otitis media

24.8

31.4

16.7

29.2

18.5

Participants

AOM

1.7

3.0

0.0

1.5

1.8

CSOM

6.6

4.5

9.3

7.7

5.6

OME

16.5

23.9

7.4

20.0

11.1

Total, n

251

140

111

137

110

127

124

Normal

82.1

77.1

88.3

78.8

87.3

81.1

83.1

Otitis media

17.9

22.9

11.7

21.2

12.7

18.9

16.9

AOM

0.8

1.4

0.0

0.7

0.9

1.6

0.0

Ears

CSOM

5.2

3.6

7.2

5.9

4.5

4.7

5.6

OME

11.9

17.9

4.5

14.6

7.3

12.6

11.3

AOM = acute otitis media; CSOM = chronic suppurative otitis media; OME = otitis media with effusion.

with the CSOM prevalence of the total sample of our study (6.6% of participants). The CSOM prevalence in primary-school children reported in our study and that of Prescott and Kibel[11] is considerably higher than in previous SA studies.[10,12] Formal healthcare institutions, albeit at different levels (primary v. tertiary) of healthcare, were sampled in our study and in that of Prescott and Kibel,[11] which may explain the higher CSOM prevalence than the school populations targeted by Halama et al.[10] and Nel et al.[12] In a recent study on the otological, audiological and bacteriological findings in children with CSOM in an SA tertiary hospital, HIV infection was present in 54.6% of participants with CSOM.[19] As WHWC is a specialist HIV centre, the HIV rate among participants may have contributed to a higher CSOM prevalence than the findings of Halama et al.[10] and Nel et al.[12] From the sample of 272 ears, only two ears (0.8%) were identified with AOM (1.7% of participants, excluding those where a diagnosis could not be made). As may be expected, given that AOM prevalence decreases with age, the two participants diagnosed with AOM fell within the 2 - 5-year age group.[2] Previous SA studies did not distinguish between active AOM, OME and ‘previous evidence’ of AOM.[10-12] A study performed by Swart et al.[20] on 2 430 5 - 8-yearold children in rural Swaziland reported a lower point prevalence of AOM (0.007%).[20] The lower prevalence of AOM reported by Swart et al.[20] compared with our study (1.7%) may be due to their exclusion of children <5 years of age. A recent study by Chadha et al.[21] of 15 718 children in India reported an AOM point prevalence rate of 0.65%. This is also lower than was found in our study, but children <5 years of age were again excluded from Chadha et al.’s study. Timing of data collection and possible seasonal influences on AOM as a complication of chronic allergic rhinitis may also have played a role in the AOM point prevalence measured.[1,22] However, the expression of allergic rhinitis in SA is mainly that of a persistent disease, especially inland where grass pollens are present for significant periods of time.[22] What was noteworthy was that caregivers of 7.4% of the participants reported that their children complained of earache within 2 weeks of the assessment. This suggests that caregivers may not seek medical opinion in response to episodic otalgia, but rather adhere to fixed clinic visit schedules. Additionally, the rapid spontaneous recovery rate for AOM (80%

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within 2 - 3 days)[23] means that a point prevalence study such as ours is likely to underestimate the actual occurrence of AOM.[3] Although not the most common finding on otomicroscopy, the presence of complete occlusion of the ear canal due to impacted cerumen was higher (14.7% unilateral and bilateral complete obstruction from cerumen) than in the studies by Chadha et al.[21] and Swart et al.[20] (7.93% and 7.5%, respectively). The rate of cerumen impaction was, however, similar to a previous finding for a sample of SA school children, where impacted cerumen was reported in 14% of paediatric participants.[11] The CSOM point prevalence measured in our study has implications for treatment protocols. In low-risk populations, OME and AOM are conditions that mostly resolve without treatment or complications. [6] Although beyond the scope of the current research, intervention paradigms may have to be reassessed in the light of the categorisation of the high CSOM prevalence in the paediatric population sampled according to WHO criteria.[5] Many of the risk factors to which high rates of CSOM are attributed could be identified in the population sampled, including short-term breastfeeding, overcrowding, poor hygiene, poor nutrition, and exposure to tobacco, wood and charcoal smoke.[4] Caregivers need to be informed of the high prevalence of complications of otitis media among children in the community, and the impact of hearing impairment caused by CSOM, and should be encouraged to seek medical advice for any symptoms of ear disease. Other measures that may reduce the burden of otitis media include routine otological screening of school children and increased referral [21] of children with recurrent ear disease for specialist opinion. Further research using strict CSOM diagnostic criteria is required to determine whether the prevalence rates measured in our study are typical of the experience of PHCs in underserved communities in SA.

Study limitations

Our study included a smaller sample of participants than previous similar otitis media prevalence studies.[10-12] With larger participant numbers, stratification of the sample across age groups would be possible. Future studies on the prevalence of OME in a paediatric sample at primary healthcare levels in SA would be improved by careful documentation of additional disease and treatment regimens, especially those related to HIV and TB status.

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Conclusion

No studies on otitis media prevalence have been performed previously at primary healthcare level in paediatric populations in SA. Otitis media was significantly more prevalent among younger (31.4%) than older children (16.7%). We found an OME point prevalence of 16.5% for children aged between 2 and 16 years with a CSOM prevalence of 6.6%, which is classified by the WHO as high.[5] The lack of timely medical intervention, together with the presence of environmental risk factors for otitis media, may explain the high rate of CSOM identified. With CSOM prevalence rates at a PHC being this high, the diagnosis, treatment and subsequent referral protocols may need to be reviewed to prevent complications. References 1. Daly KA, Hoffman HJ, Kvaerner KJ, et al. Epidemiology, natural history, and risk factors: Panel report from the Ninth International Research Conference on Otitis Media. Int J Pediatr Otorhinolaryngol 2010;74(3):231-240. [http://dx.doi.org/10.1016/j.ijporl.2009.09.006] 2. Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: A prospective, cohort study. J Infect Dis 1989;160(1):83-94. [http://dx.doi.org/10.1093/ infdis/160.1.83] 3. Monasta L, Ronfani L, Marchetti F, et al. Burden of disease caused by otitis media: Systematic review and global estimates. PloS One 2012;7(4):1-12. [http://dx.doi.org/10.1371/journal.pone.0036226] 4. Casselbrant ML, Mandel EM. Epidemiology. In: Rosenfeld RM, Bluestone CD, eds. Evidence-based Otitis Media. 2nd ed. Chicago: BC Decker, 2003:147-162. 5. Acuin J. Chronic Suppurative Otitis Media: Burden of Illness and Management Options. Geneva: WHO, 2004. http://www.who.int/pbd/deafness/activities/hearing_care/otitis_media.pdf (accessed 17 January 2011). 6. Morris PS, Leach AJ. Acute and chronic otitis media. Pediatr Clin North Am 2009;56(6):1383-1399. [http:// dx.doi.org/10.1016/j.pcl.2009.09.007] 7. Miziara ID, Weber R, Araújo Filho BC, Pinheiro Neto CD. Otitis media in Brazilian human immunodeficiency virus infected children undergoing antiretroviral therapy. J Laryngol Otol 2007;121(11):1048-1054. [http:// dx.doi.org/10.1017/S0022215107006093] 8. United Nations Children’s Fund. Towards an AIDS-free Generation: Children and AIDS: Sixth Stocktaking Report, 2013. New York: UNICEF, 2013. http://www.unaids.org/en/media/unaids/contentassets/documents/ unaidspublication/2013/20131129_stocktaking_report_children_aids_en.pdf (accessed 7 January 2013).

9. Joint United Nations Programme on HIV/AIDS. Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. Geneva: UNAIDS, 2013. http://www.unaids.org/en/media/unaids/contentassets/documents/ epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf (accessed 17 December 2012). 10. Halama A, Voogt GR, Musgrave GM, van der Merwe CA. Prevalence of otitis media in a Venda village. S Afr Med J 1987;71(9):577-579. 11. Prescott CAJ, Kibel MA. Ear and hearing disorders in rural grade 2 (Sub B) schoolchildren in the western Cape. S Afr Med J 1991;79(2):90-93. 12. Nel M, Odendaal W, Hurter M, Meyer S, van der Merwe A. [Die voorkoms en aard van gehoorprobleme en middeloorpatologiee by ’n groep swart stedelike kinders in graad I]. S Afr J Commun Disord 1988;35:25-29. 13. Lee D-H, Yeo S. Clinical diagnostic accuracy of otitis media with effusion in children, and significance of myringotomy: Diagnostic or therapeutic? J Korean Med Sci 2004;19(5):739-743. [http://dx.doi.org/10.3346/ jkms.2004.19.5.739] 14. Carruthers J. Dainfern and Diepsloot: Environmental justice and environmental history in Johannesburg, South Africa. Environ Justice 2008;1(3):121-126. [http://dx.doi.org/10.1089/env.2008.0526] 15. Bluestone CD, Gates GA, Klein JO, et al. Definitions, terminology, and classification of otitis media. Ann Otol Rhinol Laryngol 2002;111:8-18. 16. Mahadevan M, Navarro-Locsin G, Tan HKK, et al. A review of the burden of disease due to otitis media in the Asia-Pacific. Int J Pediatr Otorhinolaryngol 2012;76(5):623-635. [http://dx.doi.org/ 10.1016/j. ijporl.2012.02.031] 17. Gauteng Department of Health. Annual report 2012/13. Pretoria: Gauteng DoH, 2013. http://www. gautengonline.gov.za/Publications%20and%20Reports/FINAL%20Annual%20Report%20OOP.pdf (accessed 21 December 2013). 18. Shapiro NL, Novelli V. Otitis media in children with vertically-acquired HIV infection: The Great Ormond Street Hospital experience. Int J Pediatr Otorhinolaryngol 1998;45(1):69-75. [http://dx.doi.org/10.1016/S01655876(98)00089-5 ] 19. Tiedt NJ, Butler IRT, Hallbauer UM, et al. Paediatric chronic suppurative otitis media in the Free State Province: Clinical and audiological features. S Afr Med J 2013;103(7):467-470. [http://dx.doi.org/10.7196/SAMJ.6636] 20. Swart SM, Lemmer R, Parbhoo JN, Prescott CA. A survey of ear and hearing disorders amongst a representative sample of grade 1 schoolchildren in Swaziland. Int J Pediatr Otorhinolaryngol 1995;32(1):23-34. [http://dx.doi. org/10.1016/0165-5876(94)01109-B] 21. Chadha SK, Sayal A, Malhotra V, Agarwal AK. Prevalence of preventable ear disorders in over 15 000 schoolchildren in northern India. J Laryngol Otol 2013;127(1):28-32. [http://dx.doi.org/ 10.1017/ S0022215112002691] 22. Green RJ. Allergic rhinitis in South African children: There is something new in the air. S Afr Fam Pract 2005;47(6):28-31. 23. Rosenfeld RM, Kay D. Natural history of untreated otitis media. Laryngoscope 2003;113(10):1645-1657. [http://dx.doi.org/10.1097/00005537-200310000-00004]

Accepted 17 January 2014.

Tick-box admission forms improve the quality of documentation of surgical emergencies, but have limited impact on clinical behaviour G L Laing, MB ChB, FCS (SA), Cert Trauma Surgery (SA); J L Bruce, FCS (SA); D L Clarke, FCS (SA), MMedSci, MBA, MPhil Pietermaritzburg Metropolitan Trauma Service, KwaZulu-Natal, South Africa, and Department of General Surgery, Nelson Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Corresponding author: D L Clarke (damianclar@gmail.com) Introduction. We used modern error theory to develop a tick-box admission form for emergency surgical patients. The tick boxes were designed to actively direct care down appropriate clinical algorithms by encouraging staff to make decisions based on recorded clinical data. Objective. To audit the effect of these tick-box forms on the quality of documentation and the resuscitation process. Methods. We designed and implemented a standardised tick-box admission form, and audited its impact by comparing 100 emergency surgical admissions before the intervention with 100 thereafter. We assessed the quality of the documentation in both groups and analysed the effect of use of the tick-box admission form and the decision nodes on the clinical behaviour of the admitting clinicians. Results. The introduction of standardised tick-box admission forms dramatically improved the quality of documentation of acute surgical admissions. However, the impact of the decision nodes on clinical behaviour was less obvious. We demonstrated a tendency to cognitive dissonance in that, even though clinicians recorded abnormal physiological data, they did not consistently interpret this information correctly. Conclusions. Although the use of tick-box admission forms improves the quality of documentation, the impact on clinical behaviour is less certain. Quality improvement is a multifactorial endeavour, and without a pervasive culture of patient safety, tick-boxes alone may well be ineffective. S Afr Med J 2014;104(6):435-438. DOI:10.7196/SAMJ.7673

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Human error is a significant problem in complex human organisations such as the aviation and nuclear power industries, and in modern trauma systems. However, the aviation and nuclear power industries have used insights provided by modern error theory to develop enviable safety records. To date, the healthcare system has not achieved a comparable record.[1-3] The challenge to healthcare managers and clinicians is to use modern error theory to improve the quality of healthcare systems. Modern error theory provides insights into the evolution of error in healthcare systems by recognising that it is predominantly the system, rather than the individual, that fails. While individuals may make mistakes, it is the system that allows human error to affect patient care. A robust system directs care along certain desired pathways. If care does not follow the appropriate pathway, a robust system will autoregulate to redirect care down an appropriate pathway. If a system is not robust, it is possible for an individual to override it and violate protocols. Violations remain a significant cause of human error in healthcare systems. A study from the University of Pittsburgh demonstrated a correlation between inadequate documentation of prehospital care and mortality.[4] The authors reviewed all emergency medical service records for 2002 and 2003 in King County, Washington, USA. Multivariate analysis demonstrated that failure to record one or more physiological parameters at the scene of the injury predicted an increased risk of death.[4] The authors concluded that inadequate record keeping reflected poor care. They rejected the hypothesis that the severity of the pathology treated by the prehospital staff meant that poor documentation merely reflected lack of time to make appropriate notes, and concluded that poor documentation is a proxy marker for poor care. We have previously audited the quality of documentation of trauma patients in our institutions and found it to be inadequate.[5,6]

Objective

We set out to address this deficit, and in light of the modern understanding of human error, sought to implement a standardised tick-box style admission form that would fulfil the dual role of improving the admission documentation of surgical patients and creating decision nodes to actively direct care down appropriate clinical algorithms (Appendix 1, available in the online version of this article).[7,8] By way of example, after making the admitting clinician document basic physiological data, a ‘yes’ or ‘no’ tick-box asking a clinical question such as ‘is shock present?’ or ‘does the patient require active rewarming?’ was included. This was intended to force a clinical decision and prompt an appropriate clinical response.

Methods

The study assessed the impact of the tick-box admission forms on patient safety by reviewing the quality of the data recorded and the impact of the forms on patient care. Before implementation of this intervention, all admission assessments were performed without any preprinted standardised rubric and it was our impression that the general quality of admission documentation was below an acceptable standard. We audited 100 consecutive admissions before the introduction of this intervention. The issue of establishing an adequate benchmark for quality of documentation was discussed among senior departmental colleagues. We collectively came to a consensus that the following 29 criteria should be present in the assessment of any emergency surgical admission: admitting doctor’s first and last name; patient’s name and

surname; a clear definition of the acute surgical pathology; time and date of clinical assessment; clarification of any significant previous medical history; clarification of any significant previous surgical history; clarification of any known allergies; clarification of any significant social history; pulse rate; blood pressure; respiratory rate; saturation of oxygen in haemoglobin (PaO2); core body temperature; findings on examination of the central nervous system; findings on examination of the cardiovascular system and lungs; findings on abdominal examination; use of adjuncts during resuscitation; the type(s) of resuscitation fluids utilised; the volume of resuscitation fluids utilised; urine output volumes following resuscitation; require ment for antimicrobials; requirement for analgesia; laboratory investigations utilised; interpretation of laboratory investigation results; imaging investigations utilised; interpretation of imaging investigation results; communication with senior surgical staff; definitive clinical assessment; and definitive management plan. The tick-box clerking form was designed by the authors. It was presented to all members of the surgical department using Microsoft PowerPoint with digital projection, together with hard copies of the form. The presentation involved a lecture on error theory and the importance of standardisation of accurate documentation (for the purposes of quality improvement), followed by a thorough orientation in the use of the form. This document was then implemented as departmental policy for the admission of all surgical patients. Medical doctors were the only staff permitted to admit surgical patients, with the demand that the tick-box form be completed following initial patient examination and stabilisation. No other ancillary staff member was involved in the exercise of using the form. All surgical patients admitted to the Department of General Surgery at Grey’s Hospital, Pietermaritzburg, KwaZulu-Natal, South Africa, were included in the study. We categorised the admission process into the following discrete steps based on current approaches to the acute management of trauma and sepsis: resuscitation (airway, breathing, circulation, core temperature, and neurological deficit), response to resuscitation (urine output), drugs used (antibiotics and analgesia), and need for added special investigations. The ten decision nodes illustrated in Table 1 were incorporated into the clerking sheet. The study assessed the impact of this tick-box admission form on both the quality of the admission documentation and the clinical behaviour of the admitting clinician. One month after implementation of the system, 100 tick-box admission forms were audited and compared with the previous method of admission in respect of quality. The authors performed the audit. We assessed the impact of the decision nodes on clinical behaviour by classifying responses as either compliant (tick-box was selected) or not compliant (tick-box was not selected). Thereafter, we analysed whether the compliant nodes were accurately or inaccurately selected using the following classification: • compliant + accurate (pathology present and appropriately recognised) • compliant + inaccurate (pathology present without recognition or intervention).

Results

Use of the tick-box admission form resulted in a significant improvement in the quality of recorded data (unpaired Student’s t-test; p=0.0006). Table 2 compares the quality of the data recorded before and after the intervention, and illustrates improved data entry for all parameters. How this affected clinical care is less

Appendix A is available online at http://dx.doi.org/10.7196/SAMJ.7673

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Table 1. Decision nodes Process

Clinical data

Decision node

Resuscitation

Airway

Is an emergency airway required?

Resuscitation

Arterial oxygen saturation (SaO2)

Is supplemental oxygen required?

Resuscitation

Blood pressure and pulse

Is shock present?

Resuscitation

Core body temperature

Is active rewarming of patient required?

Response to resuscitation

Urine output

Is urine output normal or low?

Drugs

Indication for antimicrobials

Are antibiotics required?

Drugs

Pain

Is analgesia required?

Investigations

Arterial blood gas

Is the arterial blood gas normal or abnormal?

Investigations

Full blood count

Is full blood count normal or abnormal?

Investigations

Urea and electrolytes

Are urea and electrolytes normal or abnormal?

certain; Table 3 summarises the analysis of the decision nodes. Compliance was good for status of the airway, the need for supplemental oxygen and the haemodynamic status of the patients. It was poor in terms of assessing adequacy of urine output, the need for antibiotics and analgesia, and the need for review of blood results. However, despite compliance with completion of decision nodes, the interpretation of basic clinical data was not consistently correct. Six patients in this cohort were shocked on presentation: in one case the data were not recorded, and in four cases the data were recorded but the doctor failed to recognise the pathological condition. Similarly, in three patients with a core body temperature <35oC, the clinician did not recognise that active rewarming was indicated. No patients who required antibiotics were administered the appropriate drug, and 14 who required analgesia were not given it, despite the decision node

Table 2. Quality of the data recorded before and after the intervention Resuscitation process

Clinical data

A (pre-intervention, N=100), n

B (post-intervention, N=100), n

Resuscitation

Respiratory rate

Resuscitation

Oxygen saturation

Resuscitation

Temperature

Resuscitation

CNS examination

Resuscitation

Type of fluid

Resuscitation

Volume of fluid

End-point of resuscitation

Urine output

Drugs

Antibiotics

Drugs

Analgesia

Investigations

ABG

Investigations

Urea and electrolytes

Investigations

Full blood count

A = documented clinical variables pre-intervention; B = documented clinical variables post-intervention; CNS = central nervous system; ABG = arterial blood gas. Studentâ&#x20AC;&#x2122;s t-test (unpaired) comparing categories A and B: p<0.001.

Table 3. Summary of analysis of the decision nodes Resuscitation process

Decision node

A (compliant, total), N

B (compliant, accurate), n

C (compliant, inaccurate), n

Resuscitation

Emergency airway

Resuscitation

Oxygen required

Resuscitation

Shock present

Resuscitation

Active rewarming required

End-point of resuscitation

Interpretation of urine output

Drugs

Antibiotics administered

Drugs

Analgesics administered

Investigations

ABG

Investigations

Urea and electrolytes

Investigations

Full blood count

A = compliance completing decision nodes; B = compliant and accurate; C = compliant and inaccurate; ABG = arterial blood gas. Studentâ&#x20AC;&#x2122;s t-test (unpaired) comparing categories B and C: p<0.0001.

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that actively asked whether or not analgesia was indicated. Nodes relating to the quantification of urine output, the administration of antibiotics and analgesics and the interpretation of laboratory results were particularly poorly completed. Fig. 1 shows examples of this cognitive dissonance: the admitting clinicians have recorded low systolic blood pressures and low core body temperature, but have incorrectly selected the ‘shock not present’ and the ‘no need for active rewarming’ tick-boxes, respectively. Compliance with documentation of special investigation results was poor: in 19 cases, abnormal urea and electrolyte results were incorrectly interpreted, and in eight cases abnormal full blood count results were not recognised.

Discussion

Preprinted tick-box forms have been shown to improve communication between units and hospitals, and checklists have been shown to improve safety in the operating room.[7-10] This research has been adopted from the aviation industry, where checklist use is routine and has been successful in promoting safety and reducing error.[9,10] Checklists fulfil a number of functions. They force staff to record specific data, which then fosters interpretation of and reaction to data results. They also promote teamwork and co-operation. However, checklists need to be implemented within a broader culture of patient safety if they are to be effective. Our experience supports this contention, as while our tick-box admission forms improved documentation, they did not necessarily improve quality of care, our audit revealing persistent violations of safe practice. Documentation pertaining to the resuscitation process was well recorded, with the exception of the record of core body temperature. The monitoring of urine output as a guide to resuscitative efforts was poorly captured, as was the need for appropriate drugs. This is a significant failing, as delayed initiation of antibiotics predicts increased morbidity from sepsis. The timeous review of blood results was particularly poorly performed; once again this was a significant omission, as delayed recognition of acute kidney injury translates into increased morbidity. In addition to these limitations in the data capture process, the interpretation of data was problematic. This misinterpretation of physiological data may be a result of cognitive dissonance, which is the psychological discomfort a person experiences when attempting to reconcile conflicting views of reality simultaneously.[1,2,11] A view of reality is referred to as cognition. The theory states that people are driven to eliminate a feeling of dissonance by eliminating an existing cognition. In other words, an individual may be biased towards a certain decision, even though the evidence favours an alternative decision. We have previously described the problem of cognitive dissonance in trauma care.[3] This study demonstrates that clinicians can fail to interpret abnormal clinical data. The examples cited in Fig. 1 illustrate the phenomenon of cognitive dissonance. The major limitation of our tick-box admission forms is that it is a paper-based system. It is possible for clinicians to override (omit) the decision nodes, as there is no mechanical lockout system that forces them to comply. A mechanical lockout system is a generic errorreduction strategy that prevents the next step in a process, unless certain preceding tasks have been completed.[1-3] The most common example of such a system is an online purchase system. It is designed to prohibit completion if certain mandatory data are not entered. The

438

Fig. 1. Examples of cognitive dissonance.

purchaser is forced to either comply by entering mandatory data or abandon the process completely. We have shown that this pattern is difficult to achieve with a paper-based system, as it cannot overcome the problem of non-compliance and cognitive dissonance. Our research group’s next intended step is to translate the current tick-box admission form into an electronic format. This could theoretically be designed with a mechanical lockout system and function as a clinical decision support system. Such systems include electronic prompts to promote compliance and direction of medical care down appropriate clinical pathways.

Conclusion

Our tick-box admission forms improved the quality of documentation, but revealed a significant incidence of violations of safe practice. Improving clinical care in our environment is a complex endeavour that requires a multifaceted approach with numerous interventions. A single isolated intervention is unlikely to be successful. Fostering a pervasive culture of patient safety is essential if tick-box admission forms are to be effective in the promotion thereof. References 1. Reason J. Understanding adverse events: Human factors. Qual Health Care 1995;4(2):80-89. [http://dx.doi. org/10.1136/qshc.4.2.80] 2. Reason J. Human error: Models and management. BMJ 2000;320(7237):768-770. [http://dx.doi. org/10.1136/bmj.320.7237.768] 3. Clarke DL, Gouveia J, Thomson SR, Muckart DJ. Applying modern error theory to the problem of missed injuries in trauma. World J Surg 2008;32(6):1176-1182. [http://dx.doi.org/10.1007/s00268-008-9543-7] 4. Laudermilch DJ, Schiff MA, Nathens AB, Rosengart MR. Lack of emergency medical services documentation is associated with poor patient outcomes: A validation of audit filters for pre-hospital care. J Am Coll Surg 2010;210(2):220-227. [http://dx.doi.org/10.1016/j.jamcollsurg.2009.10.008] 5. Alexander T, Fuller G, Hargovan P, Clarke DL, Muckart DJ, Thomson SR. An audit of the quality of care of traumatic brain injury at a busy regional hospital in South Africa. S Afr J Surg 2009;47(4):120-126. 6. Stewart WW, Farina Z, Clarke DL, Thomson SR. Variations in levels of care within a hospital provided to acute trauma patients. S Afr J Surg 2011;49(4):194-198. 7. Goodyear HM, Lloyd BW. Can admission notes be improved by using preprinted assessment sheets? Qual Health Care 1995;4(3):190-193. [http://dx.doi.org/10.1136/qshc.4.3.190] 8. Fisher RB, Dearden CH. Improving the care of patients with major trauma in the accident and emergency department. BMJ 1990;300(6739):1560-1563. [http://dx.doi.org/10.1136/bmj.300.6739.1560] 9. Weiser TG, Haynes AB, Dziekan G, Berry WR, Lipsitz SR, Gawande AA; Safe Surgery Saves Lives Investigators and Study Group. Effect of a 19 item surgical safety checklist during urgent operations in a global patient population. Ann Surg 2010;251(5):976-980. [http://dx.doi.org/10.1097/SLA.0b013e3181d970e3] 10. Haynes AB, Weiser TG, Berry WR, et al.; Safe Surgery Saves Lives Study Group. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009;360(5):491-499. [http://dx.doi. org/10.1056/NEJMsa0810119] 11. Clark L. Decision-making during gambling: An integration of cognitive and psychobiological approaches. Philos Trans R Soc Lond B Biol Sci 2010;365(1538):319-330. [http://dx.doi.org/10.1098/rstb.2009.0147]

Accepted 3 April 2014.

June 2014, Vol. 104, No. 6

GUEST EDITORIAL

Sexual health in the South African context Sexual health is a major area of relevance to global public health. The World Health Organization (WHO) has stipulated that every person has the right to sexual health.[1] The United Nations Educational, Scientific and Cultural Organization (UNESCO) has identified sexual rights and sexual health education and training as a global priority.[2] There is also growing interest in human rights and lesbian, gay, bisexual, transgender and intersex (LGBTI) issues internationally. However, there are few centres of excellence for sexual health in lowand middle-income countries, where the vast majority of the world’s population live, and there is a real need to establish such resources. Recently, the clinical utility and operational criteria of sexual disorders have received some attention in the literature owing to the recent revision of the Diagnostic and Statistical Manual of Mental Disorders to version 5 (DSM-5) and the ongoing revision of the International Classification of Diseases and Related Health Problems to version 11 (ICD-11). Locally, for example, a recent WHO-funded meeting in South Africa explored the clinical utility of proposed revisions to the ICD-11. In August 2013, a team of 20 South African sexual health experts from across health science disciplines met with human rights legal experts and sexual health activists to engage in the first multidisciplinary sexual health collaborative meeting of its kind in South Africa. Its aim was to gain stakeholder input in the development of research protocols for evaluating the clinical utility of ICD-11 revisions in the areas of sexual dysfunction (F52) and gender identity disorders (F64) within the South African context. While considerable expertise in the area of sexual health was identified during this meeting, concerns about limitations in education and training also emerged. The integrated multidisciplinary model prescribed by UNESCO’s sexual health curriculum, in accordance with WHO guidelines, teaches healthcare providers to conduct a robust sexual history with patients presenting with sexual health complaints.[3] This sexual history allows the healthcare provider to: (i) confirm the patient’s diagnosis; (ii) evaluate the impact of the distress on the patient’s overall health; and (iii) set management goals. When used in combination with a medical history focused particularly on cardiovascular, neurological, urogenital, hormonal and psychological systems, the sexual history provides indicators of aetiology, while establishing comorbid medical conditions and their potential role in sexual dysfunction. A thorough assessment helps with early detection, diagnosis and treatment. Currently, few South African clinicians receive the necessary training to address sexual dysfunction comprehensively, and there are no accredited South African training programmes in this area. Some of those wishing to specialise in sexual medicine have obtained qualifications abroad. These limited educational opportunities are mirrored in the limited current, original research in the area of sexual health in South Africa.[4] This gap in training and continued professional development in the area of sexual health has implications for clinician confidence when assessing and treating sexual problems in patients in general and in sexual minority groups such as LGBTI patients in particular. The intention of this editorial and the related CME series is to help generate renewed interest in the area of sexual health and provide

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practical information to family practitioners on a variety of topics related to sexual health and function. Interested readers wishing to apply a framework for clinical assessment and treatment of patients presenting with sexual dysfunctions are referred to Ramlachan and Campbell’s[5] review of an integrative, multidisciplinary treatment approach. Boa[6] provides a comprehensive review of female sexual dysfunctions and treatment options, while Ramlachan and Campbell[7] review the epidemiology, clinical assessment and treatment options for male sexual dysfunctions. Campbell and Stein[8] discuss an approach to hypersexual disorder, highlighting the family practitioner’s role in patient care, and Wilson et al.[9] outline the role of the Groote Schuur Transgender Unit in providing healthcare for South African transgender patients. Geffen’s[10] review of the relationship between sexual functioning and age completes this CME series. Megan M Campbell Counselling Psychologist and Postdoctoral Research Fellow, Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa mm.campbell@uct.ac.za

Dan J Stein Professor and Head, Department of Psychiatry and Mental Health, University of Cape Town, and Director, MRC Unit on Anxiety and Stress Disorders, Cape Town, South Africa dan.stein@uct.ac.za 1. Cottingham J, Kismodi E, Hilber AM, et al. Using human rights for sexual and reproductive health: Improving legal and regulatory frameworks. Bull World Health Organ 2010;88(7):551-555. [http:// dx.doi.org/10.2471/BLT.09.063412] 2. United Nations Educational, Scientific and Cultural Organization. The International Technical Guidance on Sexuality Education: An evidence-informed approach for schools, teachers and health educators. Paris: UNESCO, 2009. 3. Montorsi F, Adaikan G, Becher E, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2010;7(11):3572-3588. [http://dx.doi.org/10.1111/j.1743-6109.2010.02062.x] 4. Campbell MM, Stein DJ. Sexual dysfunction: A systematic review of South African research. S Afr Med J 2014;104(6):440-444. [http://dx.doi.org/10.7196/SAMJ.7827] 5. Ramlachan P, Campbell MM. An integrative treatment model for patients with sexual dysfunctions. S Afr Med J 2014;104(6):445. [http://dx.doi.org/10.7196/SAMJ.8374] 6. Boa R. Female sexual dysfunction. S Afr Med J 2014;104(6):446. [http://dx.doi.org/10.7196/SAMJ.8373] 7. Ramlachan P, Campbell MM. Male sexual dysfunction. S Afr Med J 2014;104(6):447. [http://dx.doi. org/10.7196/SAMJ.8376] 8. Campbell MM, Stein DJ. Hypersexual disorder in general practice. S Afr Med J 2014;104(6):448. [http://dx.doi.org/10.7196/SAMJ.8409] 9. Wilson D, Marais A, de Villiers A, Addinall R, Campbell M. Transgender issues in South Africa, with particular reference to the Groote Schuur Hospital Transgender Unit. S Afr Med J 2014;104(6):449. [http://dx.doi.org/10.7196/SAMJ.8392] 10. Geffen L. Sexual function and ageing. S Afr Med J 2014;104(6):450. [http://dx.doi.org/10.7196/ SAMJ.8396]

S Afr Med J 2014;104(6):439. DOI:10.7196/SAMJ.8391

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REVIEW

Sexual dysfunction: A systematic review of South African research M M Campbell, PhD; D J Stein, FRCPC, PhD Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: M M Campbell (mm.campbell@uct.ac.za) Background. The World Health Organization is in the process of revising the International Classification of Diseases and Related Health Problems (ICD). Sexual dysfunction disorders (F52) have been identified as having poor clinical utility. South Africa (SA) has been selected as one of five low- and middle-income countries in which studies will be developed to assess the clinical utility of the proposed ICD-11 revisions for sexual dysfunction disorders. Objective. To identify scientific research generated in SA on sexual dysfunction disorders to guide these studies. Methods. A systematic review of SA research on sexual dysfunction disorders published in peer-reviewed journals. Results. Despite the high prevalence of ejaculatory and erectile dysfunctions, only five SA articles have addressed male sexual dysfunction since 1970. Lack of sexual interest and inability to reach orgasm are the most commonly reported complaints for women, yet only four SA articles have been published on the topic of female sexual dysfunction. Diabetes mellitus, cardiovascular disease, genitourinary disease and psychiatric or psychological disorders are common comorbid conditions associated with sexual dysfunction in both sexes, but only nine articles address sexual dysfunction as the main topic with respect to comorbid conditions. Conclusion. Despite growing awareness of the importance of sexual health, SA-based scientific research on sexual dysfunction is limited. Further work is needed to inform recommendations for ICD-11 revisions drawn from the SA context. S Afr Med J 2014;104(6):440-444. DOI:10.7196/SAMJ.7827

Sexual health is essential to an individual’s general health, affecting quality of life and psychosocial and emotional wellbeing; however, sexual problems are estimated to affect 40 - 45% of women and 20 - 30% of men, with the prevalence increasing as individuals grow older.[1] A global study of sexual attitudes and behaviours, targeting an adult population aged 40 - 80 years across 29 countries, identified early ejaculation and difficulty in achieving and maintaining an erection as the problems most commonly reported by men, affecting 24% and 17%, respectively.[2] Lack of sexual interest and inability to reach orgasm were the most commonly reported complaints for women, affecting 32% and 25%, respectively.[2] Diabetes mellitus, cardiovascular disease, genitourinary disease, psychiatric or psychological disorders, and poor general health have been identified as common comorbid conditions associated with sexual dysfunction in both sexes.[1] However, despite the high prevalence of sexual problems and comorbidity with commonly presenting diseases and disorders, <20% of people experiencing

sexual difficulties seek assistance from healthcare providers and only 9% report being asked about their sexual health by their healthcare practitioner.[1] The International Classification of Diseases and Related Health Problems (ICD) is in the process of being revised by the World Health Organization (WHO), with publication of the ICD-11 planned for 2017. The WHO has identified improved clinical utility as a key goal during this revision process, with an emphasis on improving the usefulness of revised classifications for patient case conceptualisation, communication, and decision-making with respect to treatment and case management.[3] An essential element of the ICD revision process has been formative and evaluative field-testing. Formative field-testing provided feedback about the basic structure and content of the ICD and included a global survey of the opinions of 4 887 psychiatrists.[4] Results of this survey indicated that psychiatrists considered the sexual dysfunction (F52) disorders of the ICD-10 as having low ease of use and poor goodness of fit, suggesting the need for considerable revision in the ICD-11 to improve clinical utility.

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Sexual dysfunction is currently defined by the ICD-10 as ‘various ways in which an individual is unable to participate in a sexual relationship as he or she would wish. There may be lack of interest, lack of enjoyment, failure of the physiological responses necessary for effective sexual interaction, or inability to control or experience orgasm’.[5] Sexual dysfunction disorders include sexual desire disorders, orgasmic dysfunction and sexual pain disorders in both sexes, as well as sexual arousal disorders in women and erectile dysfunction (ED) in men. Through an extensive review process, the WHO-appointed Working Group on the Classification of Sexual Disorders and Sexual Health has compiled suggested revisions for this category that are now ready for evaluative field-testing. However, in accordance with the recommendations made by the International Advisory Group for the Revision of the ICD-10 Mental and Behavioural Disorders,[3] all revisions must also be considered for cultural sensitivity, relevance and appropriateness. As a result, South Africa (SA) has been selected as one of five low- and middle-income countries in which country-based field studies will be developed to assess the clinical utility of the proposed ICD-11 revisions for sexual disorders and sexual health, including sexual dysfunctions. In developing these studies, it is important to consider the scientific research on sexual dysfunction generated by SA clinicians drawing from SA population samples.

Methods

Original research articles published in English on the topic of sexual dysfunction were systematically identified using PubMed, Science Direct and EBSCOhost (including Academic Search Premier, AfricaWide Information, eBook Collection), Health Source: Nursing/ Academic Edition, MasterFILE premier, MEDLINE, PsycARTICLES, PsycINFO and SocINDEX databases. Search terms included: ‘sexual dysfunct*’ and ‘South Afric*’. Seventeen original research articles met the search criteria.

Results

Of the 17 articles included in this review, eight were published in international journals that included general medical journals (n=1), specialist medical journals (n=6) and non-medical journals (n=1).[6-13] Nine were published in SA journals, eight in general medical journals (the South African Medical Journal (SAMJ) (n=6) and South African Family Practice (SAFP) (n=2)) and one in a specialist medical journal (the South African Journal of Psychiatry (SAJP)).[14-22] The first article was published in the SAMJ in 1976, while the most recent publication appeared in SAFP in 2013. These articles are summarised in Table 1.

Description of the studies

Male sexual dysfunction was first addressed in a case series that investigated the use of clomipramine in the treatment of retrograde ejaculation following diabetic neuropathy and damage to the bladder neck.[14] Treatment was effective in 2/3 of cases.

Next a case report documented the treatment of hypogonadotrophic hypogonadism as a result of haemochromatosis, with oral testosterone.[9] Over 15 years later, the substitution of phentolamine with chlorpromazine as an alpha-blocker in vasoactive cocktails for intracavernous injection therapy to treat ED was investigated.[15] Results indicated that 96% (n=364) of patients were satisfied with the new treatment, with no significant side-effects reported. More recently, the prevalence of anxiety and depressive symptoms in 100 men presenting for the treatment of ED was investigated using observational analysis and psychometric measures.[16] ED was severe in 57 men, moderate in 36 and mild in 7, while 60 reported premature ejaculation. Of the total sample, 41 patients were hypertensive, while 42 met the criteria for a psychiatric disorder, 33 reported depressive symptoms and 21 met the criteria for an anxiety disorder. Men suffering from ED were likely to also suffer from a psychiatric disorder and/or an accompanying general medical condition, with the probability increasing with severity of ED. Most recently the prevalence of ED in a sample of 803 men attending a primary healthcare clinic in Durban, KwaZulu-Natal, was investigated.[17] Results indicated that 64.9% (n=621) of the sample had ED, severe in 30.4% (n=244) of cases, moderate in 19.9% (n=160), and mild in 14.6% (n=117). ED increased with age, was associated with diabetes, hypertension, cardiovascular disease and depression, and was inversely correlated with economic status. The first SA article addressing female sexual dysfunction investigated the efficacy of a psychoeducation intervention programme for patients presenting with female orgasmic disorder at a family planning clinic.[18] The three-stage intervention began with a history-taking session. Based on this information the patient was given a diagnosis of primary (having never experienced orgasm) or secondary (currently unable to experience orgasm) frigidity. For primary frigidity, masturbation and fantasy were recommended, while education about clitoral stimulation and different sexual positions was provided for patients with secondary frigidity. Reading material was also recommended to the couple. The second stage of intervention involved a follow-up session with the husband to elicit a medical and social history and to provide psychoeducation about the positive impact romance, dating and couple-time could have on the sexual relationship. The third and final stage involved a follow-up session with the female patient to assess whether she had achieved orgasm as a result of the intervention and to address any remaining problems. Thirty-four couples participated in the study, and 18 female patients (53%) reported successful orgasm at termination of the intervention, 8 (24%) reported significant sexual arousal without orgasm, and 8 (24%) reported little or no arousal. Ten years later, a case study was published on the successful treatment of a female patient (aged 25 years) presenting with vaginismus without physical cause.[19] A psychoeducational intervention focused on reducing the female patient’s anxiety about

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AJIM

Khedun et al.[11] (1995)

Robins et al.[12] (1997)

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M/F

ICP

SAJP

SAFP

Dalvie et al.[13] (2004)

Jespersen et al.[7] (2004)

Pankhurst et al.[16] (2005)

Uebel and Schmidt[15] (2007)

Alexander et al.[8] (2011)

Lockhat et al.[17] (2013)

Analysis of structured questionnaire relating to sexual history

Analysis of structured interviews relating to sexual as well as family and relationship histories

Case report

Case series

Case presentation

Cross-over design with psychometric measures (Feiger Sexual Function/Satisfaction Questionnaire)

Case report

Interviews, blood and semen sample analysis

803 (M, age 18 - 99 years, excluding neurological disorders)

129 (W)

364 (M)

100 (M)

12 patients with depression (F, 5 assigned granisetron, 7 controls)

Questionnaire (International Index of Erectile Function-15)

Event log of sexual activity, and psychometric measures (Sexual Function Questionnaire, Sexual Quality of Life Questionnaire, a global efficacy question, Sexual Distress Question)

Questionnaire and follow-up interview following self-administration of vasoactive cocktail at home

Observational analysis and psychometric measures (International Index of Erectile Function, 17-item Hamilton Rating Scale for Depression, Mini International Neuropsychiatric Interview)

Randomised, double-blind, placebo-controlled trial with psychometric measures (Feiger Sexual Function/Satisfaction Questionnaire and Arizona Sexual Experience Scale)

60 (M, malaria vector-control Cross-sectional study using interviews, physical workers) examinations and semen analysis

1 (M, age 42 years)

35 (M/F patients with depression)

1 (M, age 25 years)

97 (M, working at a lead battery acid factory)

66 (M, 39 hypertensive treated Blood sample analysis with hydrochlorothiazide compared with 27 controls)

40 (couples with infertility issues)

1 (F, age 25 years)

3 (M, age 27 - 31 years)

Method

Results

Overall prevalence of ED was estimated at 64.9% â&#x20AC;&#x201C; 14.6% reported mild, 19.9% moderate and 30.4% severe ED. ED increased with age and was associated with economic status and comorbid conditions

No significant treatment effect of oral sildenafil for the treatment of female sexual arousal disorder as a result of spinal cord injury

No significant difference between phentolamine and chlorpromazine, or side-effects reported

42% of patients with erectile dysfunction met criteria for a comorbid psychiatric disorder, 33% reported depressive symptoms, 21% met criteria for an anxiety disorder

No statistically significant difference between patients treated with granisetron and placebo

Few significant associations between DDT exposure and semen count, fertility and sexual functioning

A case of hypersexual disorder and preoccupation with internet pornography

While granisetron showed a significant effect, sumatriptan showed no significant impact on sexual functioning

Hypogonadotrophic hypogonadism (as a result of haemochromatosis) treated with oral testosterone

Lead exposure was associated with increased risk of abnormal sperm morphology

Hydrochlorothiazide depleted serum zinc levels. Low serum zinc levels were associated with sexual dysfunction

Increased sexual dysfunction during the fertile period reported by 50% female v. 30% male patients

Major psychosexual factors: lack of sex education (81% M, 56% F), premarital sex (71% M, 56% F) and infertility (27% M, 43% F)

Successful psychoeducational intervention for vaginismus

Normal ejaculation and conception in 2/3 of cases of retrograde ejaculation treated with clomipramine

Three-stage psychosocial intervention using orgasm 18 (53%) achieved orgasm, 8 (24%) significant sexual arousal without as the outcome to indicate effectiveness orgasm, 8 (24%) little or no arousal

SA = South African; SAMJ = South African Medical Journal; CAJM = Central African Journal of Medicine; AJIM = American Journal of Industrial Medicine; BJU = British Journal of Urology; ICP = International Clinical Psychopharmacology; AJP = American Journal of Psychiatry; ER = Environmental Research; SAJP = South African Journal of Psychiatry; SAFP = South African Family Practice; SC = Spinal Cord; M = male; F = female.

M/F

AJP

M/F

Stein et al.[10] (2001)

ICP

M/F

CAJM

Hurwitz[22] (1989)

Berk et al.[6] (2000)

M/F

SAMJ

Van Zyl[20,21] (1987)

M/F infertility 514 (couples with infertility issues)

SAMJ

Krige[19] (1985)

BJU

SAMJ

Eppel and Berzin[14] (1984)

Stopforth et al.[9] (1999)

M infertility

SAMJ

Michaelides[18] (1976)

34 (married couples)

Dysfunction

Journal

SAMJ

Authors (year)

Sample size, n

Table 1. Original research articles published in SA medical journals drawing on SA samples

CONTINUING MEDICAL EDUCATION

sexual penetration and gentle desensitisation through relaxation exercises, education about her genitalia, practising the use of her pubococcygeal muscles to gain a sense of control over her body, and practising penetration of her vagina with her fingers, then her husband’s fingers and finally with his penis, culminating in intercourse. The joint willingness of the patient and her husband to commit to the therapy process was identified as a significant factor in the successful treatment outcome. More recently, a pharmacotherapy trial investigated the use of granisetron to treat sexual dysfunction associated with antidepressant use in female patients diagnosed with depression.[7] Sexual functioning was assessed at baseline, day 7 and day 14 using psychometric measures. Results indicated no significant treatment effect. Most recently, a pharmacotherapy trial investigated the use of oral sildenafil for the treatment of female sexual arousal disorder as a result of spinal cord injury in a sample of 52 women (North America n=23, Europe n=23, Australia n=4, South Africa n=2).[8] Sexual functioning was monitored using an activity log and psychometric measures. Participants were assessed at baseline and during the 12-week treatment period. Results indicated no significant treatment effect.[8] Studies that considered both male and female sexual dysfunction included an investigation into the psychosexual factors impacting on sexual dysfunction and their related link with infertility in a sample of 514 couples.[20,21] Structured interviews generated information about the patients’ sexual history, family background and relationship history. Analysis of responses revealed that a lack of sex education (81% of men and 56% of women), negative premarital sex experiences (70.5% of men and 56% of women) and infertility (27% of men and 43% of women) were the most significant psychosexual problems affecting couples presenting with infertility problems, while reduced sexual interest (lack of interest in having sex more than once a week) was reported by 68.7% of men and dyspareunia was reported by 50% of women. The study concluded that inadequate sex education and negative premarital sexual and masturbation experiences were the most significant contributors to unhelpful attitudes about sexual behaviour. The high prevalence of psychosexual problems in this SA sample highlighted the need for improved sex education for patients and improved training of medical students in sex counselling. Shortly afterwards, a study aimed to investigate the sexual functioning of couples with primary infertility. The study investigated the influence on sexual functioning of being instructed to have sexual intercourse over the fertile period of the menstrual cycle. [22] Couples answered questions relating to frequency of intercourse and orgasm, desire and arousal, libido, pain and sexual satisfaction, assessed on a self-rating Likert scale, across fertile and non-fertile phases of the cycle. Results indicated that 50% of female patients, as opposed to only 30% of male patients, reported increased sexual

dysfunction during this fertile period, with loss of libido being the most commonly reported symptom in both sexes. More recently, a pharmacotherapy cross-over trial investigated the use of granisetron 1 mg and sumatriptan 100 mg to treat sexual dysfunction associated with serotonergic antidepressant use in male and female patients diagnosed with depression.[6] The trial included 35 patients who administered the medications 1 hour before intercourse. Sexual functioning was assessed using psychometric measures. Despite a high dropout rate, granisetron demonstrated a significant effect on sexual functioning while sumatriptan showed no significant effect. Additional studies have included investigations of the impact of zinc,[11] lead[12] and DDT[13] on sexual functioning. Hydrochlorothiazide used for the treatment of hypertension in a sample of 39 middleaged men significantly decreased serum zinc levels. These low serum zinc levels were associated with sexual dysfunction in the sample.[11] Lead exposure was associated with an increased risk of abnormal sperm morphology in a sample of 97 lead-exposed workers from an hSA lead battery acid factory, but did not demonstrate a significant relationship with sperm count or infertility.[12] No strong evidence for an association between DDT exposure and semen count, fertility and sexual functioning was found in a sample of 60 malaria vectorcontrol workers in Limpopo Province.[13] One final contribution to the SA sexual dysfunction literature is a case presentation of a 42-year-old man presenting with a history of depression, hypersexuality and preoccupation with internet pornography, which was used to propose diagnostic criteria for hypersexual disorder.[10]

Discussion

Despite the high prevalence of ejaculatory and erectile dysfunctions reported in the international literature,[2] only five SA articles[9,14-17] have addressed the topic of male sexual dysfunction since 1970, with an exclusive focus on ED. Lack of sexual interest and inability to reach orgasm are the most commonly reported complaints for women,[2] yet only four SA articles[7,8,18,19] have been published on the topic of female sexual dysfunction. Diabetes mellitus, cardiovascular disease, genitourinary disease and psychiatric or psychological disorders are common comorbid conditions associated with sexual dysfunction in both sexes;[1] however, only nine articles address sexual dysfunction as the main topic with respect to comorbid conditions. SA research to date has focused on sexual dysfunction and diabetes,[14] haemochromatosis,[9] infertility,[20-22] spinal cord injury[8] and psychiatric conditions.[6,7,16,20,21] Limitations of this review include that it is based only on articles published in English in peer-reviewed journals that have been electronically indexed. Nevertheless, it probably covers the most rigorous research that has been conducted in this area.

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Conclusion

References

Acknowledgements. Prof. Stein is supported by the Medical Research Council of South Africa. We thank Dr Geoffrey Reed for his inputs during the review of this manuscript.

Accepted 7 January 2014.

SA-based scientific research on sexual dysfunction is limited and outdated, impeding credible recommendations for ICD-11 revisions drawn from the SA context. Yet SA is uniquely positioned to make a valuable contribution towards the field of sexual health. First, given its focus on human rights, SA is well placed to recognise sexual health as an important component of health. Recognition of the rights and needs of the lesbian, gay, bisexual, transgender and intersex communities in the low- and middle-income world is a key issue that continues to receive little attention in the literature. Second, sexual dysfunction demonstrates high comorbidity with HIV infection, and sub-Saharan Africa continues to experience a very high prevalence of HIV infections, with 1/20 individuals infected, accounting for 69% of people living with HIV globally.[23] Yet the impact of HIV/AIDS and other sexually transmitted infections on sexual dysfunction in the SA context remains an unexplored area, as does the influence of interpersonal violence and intimate partner violence on sexual health and functioning. Domestic violence has been identified as a considerable contributor to the burden of disease in SA, and high rates of sexual and domestic violence significantly contribute to the increased vulnerability of SA women to sexually transmitted diseases and HIV infection.[24] However, limited SA research is currently available to guide clinicians on interventions that address both biomedical and psychosocial aspects of patients’ sexual dysfunction. The WHO-funded SA studies will provide an opportunity to generate preliminary research in this neglected area, and hopefully provide an impetus towards future research. Clinicians who wish to participate in these studies can register on the WHO Global Practice Network for sexual health practitioners (http://kuclas.qualtrics.com/SE/?SID=SV_a4SlSQUBNKvVtLn).

1. Lewis R, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors of sexual dysfunction. J Sex Med 2004;1(1):35-39. [http://dx.doi.org/10.1111/j.1743-6109.2004.10106.x] 2. Moreira E, Brock G, Glasser D, et al. Help-seeking behaviour for sexual problems: The Global Study of Sexual Attitudes and Behaviors. Int J Clin Pract 2005;59(1):6-16. [http://dx.doi.org/10.1111/j.1742-1241.2005.00382.x] 3. International Advisory Group for the Revision of ICD-10 Mental and Behavioural Disorders. A conceptual framework for the revision of the ICD-10 classification of mental and behavioural disorders. World Psychiatry 2011;10(2):86-92. 4. Reed G, Correia J, Esparza P, Saxena S, Maj M. The WPA-WHO global survey of psychiatrists’ attitudes towards mental disorders classification. World Psychiatry 2011;10(2):118-131. 5. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: WHO, 1993. http://www.who.int/classifications/icd/en/GRNBOOK.pdf (accessed 24 March 2014). 6. Berk M, Stein DJ, Potgieter A, et al. Serotonergic targets in the treatment of antidepressant induced sexual dysfunction: a pilot study of granisetron and sumatriptan. Int Clin Psychopharmacol 2000;15(5):291-295. [http://dx.doi.org/10.1097/00004850-200015050-00006] 7. Jespersen S, Berk M, Van Wyk C, et al. A pilot randomized, double-blind, placebo-controlled study of granisetron in the treatment of sexual dysfunction in women associated with antidepressant use. Int Clin Psychopharmacol 2004;19(3):161-164. [http://dx.doi.org/10.1097/00004850-200405000-00007] 8. Alexander MS, Rosen RC, Steinberg S, Symonds T, Haughie S, Hultling C. Sildenafil in women with sexual arousal disorder following spinal cord injury. Spinal Cord 2011;49(2):273-279. [http://dx.doi.org/10.1038/ sc.2010.107] 9. Stopforth HB, Heyns CF, De Kock MLS, Sandler M. Ejaculatory failure and hypogonadotrophic hypogonadism caused by haemochromatosis. BJU Int 1999;83(6):728. [http://dx.doi.org/10.1046/j.1464-410x.1999.00064.x] 10. Stein D, Black DW, Shapira NA, Spitzer RL. Hypersexual disorder and preoccupation with internet pornography. Am J Psychiatry 2001;158(10):1590-1594. [http://dx.doi.org/10.1176/appi.ajp.158.10.1590] 11. Khedun SM, Naicker T, Maharaj B. Zinc, hydrochlorothiazide and sexual dysfunction. Cent Afr J Med 1995;41(10):312-315. 12. Robins TG, Bornman MS, Ehrlich RI, et al. Semen quality and fertility of men employed in a South African lead acid battery plant. Am J Ind Med 1997;32(4):369-376. [http://dx.doi.org/10.1002/(SICI)10970274(199710)32:4%3C369::AID-AJIM8%3E3.0.CO;2-P] 13. Dalvie MA, Myers JE, Thompson ML, et al. The long-term effects of DDT exposure on semen, fertility, and sexual function of malaria vector-control workers in Limpopo Province, South Africa. Environ Res 2004;96(1):1-8. [http://dx.doi.org/10.1016/j.envres.2003.09.002] 14. Eppel S, Berzin M. Pregnancy following treatment of retrograde ejaculation with clomipramine hydrochloride. S Afr Med J 1984;66(23):889-891. 15. Uebel R, Schmidt, A. The substitution of phentolamine with an equal amount of chlorpromazine as an alpha-blocker in vasoactive cocktails used for intracavernous injection therapy for the treatment of erectile dysfunction. S Afr Fam Pract 2007;49(1):14. 16. Pankhurst K, Joubert G, Pretorius, P. Prevalence of anxiety and depressive symptoms in men with erectile dysfunction. South African Journal of Psychiatry 2008;11(2):57-62. 17. Lockhat Y, Ross A, Ramlachan P, Rangiah C. The prevalence of erectile dysfunction at a primary healthcare clinic in Durban, KwaZulu Natal. S Afr Fam Pract 2013;55(3):289-293. 18. Michaelides B. Treatment of frigidity in general practice. S Afr Med J 1976;50(34):1337-1339. [http://dx.doi. org/10.1097/00006254-197703000-00021] 19. Krige P. Vaginismus: A case report. S Afr Med J 1985;67(26):1057-1059. 20. Van Zyl J. Sex and infertility: Part I. Prevalence of psychosexual problems and subjacent factors. S Afr Med J 1987;72(7):482-484. 21. Van Zyl J. Sex and infertility: Part II. Influence of psychogenic factors and psychosexual problems. S Afr Med J 1987;72(7):485-487. 22. Hurwitz, M. Sexual dysfunction associated with infertility. A comparison of sexual function during the fertile and the non-fertile phase of the menstrual cycle. S Afr Med J 1989;76(2):58-61. 23. UNAIDS. Global Report: UNAIDS Report on the Global AIDS Epidemic 2012. Geneva: World Health Organization, 2012. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/ gr2012/20121120_UNAIDS_Global_Report_2012_with_annexes_en.pdf (accessed 24 March 2104). 24. Dunkle K, Jewkes R. Effective HIV prevention requires gender-transformative work with men. Sex Transm Infect 2007;83(3):173-174. [http://dx.doi.org/10.1136/sti.2007.024950]

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An integrative treatment model for patients with sexual dysfunctions P Ramlachan,1 MB ChB, MHlthSc, FECSM; M M Campbell,2 PhD 1 2

ewkwa Medical Centre, Durban, South Africa N Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: P Ramlachan (drprithy@newkwa.co.za)

Approximately one-third of men will suffer from some form of sexual dysfunction (SD) in their lifetime. A South African survey showed that only 10% of doctors talk to their patients about sex. A multidisciplinary and integrative approach to SD is a new global aim. The International Consultation of Sexual Medicine-5 (ICSM-5) diagnostic and treatment algorithm leads family practitioners through a stepwise progression in the assessment of SD.

fasting plasma glucose should be measured in all patients. All men with ED should have serum testosterone measured.

Step 1: Basic evaluation

Step 3: Patient and partner sexual education

The initial evaluation covers the patient’s sexual, medical and psychosocial history, including a focused physical examination and laboratory testing. Sexual history. A structured interviewing process should include enquiry about the patient’s (i) sexual activity; (ii) sexual orientation; (iii) sexual practices; (iv) sexual experiences; (v) sexual cycle; (vi) fertility needs; and (vii) symptoms, duration and severity of the SD. Medical history. The medical history should establish whether the SD is a stand-alone medical condition or a symptom of another disease. Enquiring about a history of the following will assist in determining aetiology: (i) medical conditions such as cardiovascular disease, diabetes, hypogonadism, lower urinary tract symptoms, neurological disease, etc.; (ii) lifestyle factors such as smoking and alcohol use; (iii) psychological factors and other psychiatric conditions; and (iv) concomitant medication use. Psychosocial history. The psychosocial history should elicit the patient’s personal understanding about sexuality and sexual practices. It should establish how the SD is impacting on the patient’s interpersonal relationships, attitudes about sex and attitudes towards treatment. Laboratory tests. The choice of investigations depends on the individual circumstances of the patient. Erectile dysfunction (ED), for example, is an independent marker for cardiovascular risk and can be the presenting feature of diabetes; therefore serum lipids and

Step 2: The need for specialised treatment

Specialised tests and referrals are usually indicated in lifelong or primary SD, in the occurence of specific anatomical or endocrine factors or in the case of complicated psychiatric or interpersonal problems.

This educational process can assist with improved subjective wellbeing by equipping the patient with knowledge and techniques to manage their sexual health and sexual functioning.

Step 4: Treatment options

An integrative model emphasises a patient-centred approach towards sexual health that includes counselling and lifestyle modification, psychological therapies, medical interventions (pharmocology and devices) and surgery.

Step 5: Evaluating the patient’s sexual well-being post treatment

Following treatment, the family practitioner evaluates the patient’s sexual well-being in relation to treatment outcomes, the patientpartner relationship and the patient’s reported life satisfaction or quality of life post treatment.

Conclusion

The ICSM-5 stepwise diagnostic and treatment algorithm will assist clinicians in conducting a basic evaluation, history taking, considering the need for specialist care, conducting patient sexual education, talking through and considering available treatment options, and evaluating the patient’s sexual well-being after treatment. Please see the online version of this article for greater detail. S Afr Med J 2014;104(6):445. DOI:10.7196/SAMJ.8374

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ARTICLE SUMMARY

Female sexual dysfunction R Boa, MB BCh, FECSM Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: R Boa (ros@drboa.co.za)

Patients want to discuss concerns about their sexual health, but these discussions can be difficult to initiate. Most patients wait for their healthcare provider to enquire about their sexual health. Female sexual problems are highly prevalent, affecting up to 43% of women and their quality of life and interpersonal relationships. Addressing sexual health issues with patients can enhance medical practice and improve patient well-being.

Talking about sexual issues

Healthcare providers may feel uncomfortable discussing sexual health issues because of lack of training and skills, and embarrassment. Doctors often underestimate the impact of sexual complaints on a patient’s health. Sexual health questions should be part of a normal review of systems.

Clinical assessment Detailed history

Use open-ended questions to allow the patient to speak freely. Is the problem lifelong or acquired, situational or generalised? Are there problems with desire, arousal, orgasm, pain or a combination of these? Remember drugs and other medical conditions.

Psychometric measures

The Brief Sexual Symptom Checklist for Women, a self-reporting tool, asks four questions regarding a patient’s satisfaction, sexual problem/s and whether she wishes to address these issues. More detailed screening tools may be used, but should not be substituted for a thorough sexual, medical and psychosocial history.

Examination

An examination is mandatory if there is lack of sexual interest due to endocrine changes, a combination of dysfunctions or sexual pain. An ultrasound scan or a laparoscopic examination may be required if an abnormality is suspected.

Laboratory testing

Testing for glucose, haemoglobin level, thyroid, prolactin and reproductive hormones (luteinising hormone and follicle-stimulating hormone) to rule out metabolic or pituitary dysfunction may be

required. Oestrogen or androgen deficiencies are usually detected by history and examination.

Definitions

Female sexual interest/arousal disorder

Female sexual interest/arousal disorder is defined as the lack of, or significantly reduced, sexual interest/arousal. Treatment should focus on providing specific information regarding desire and variations with age, relationship duration, lifestyle changes or the female sexual response cycle. Pharmacotherapy is limited. Topical or systemic oestrogen may improve vaginal atrophy causing decreased lubrication.

Female orgasmic disorder

Female orgasmic disorder is defined as the presence of either of the following symptoms experienced on almost all or all occasions (75 100%) of sexual activity: marked delay, marked infrequency, or absence of orgasm; or markedly reduced intensity of orgasmic sensations. Treatment recommendations include a combination of cognitive behavioural techniques, directed masturbation training and anxiety reduction techniques, with mindfulness and yoga practice as possible adjuncts.

Genitopelvic pain/penetration disorder

This disorder is defined as persistent or recurrent difficulties with one or more of the following: vaginal penetration during intercourse; marked vulvovaginal or pelvic pain during vaginal intercourse or penetration attempts; marked fear of or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of vaginal penetration; marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration.

Conclusion

Female sexual problems are highly prevalent. Patients want to discuss concerns about their sexual health with their healthcare provider. An integrative approach is required, with attention to the biological, psychological, relational and contextual contributors to the sexual problem. Female sexual dysfunctions include interest/ arousal, orgasmic and genitopelvic pain/penetration disorders. S Afr Med J 2014;104(6):446. DOI:10.7196/SAMJ.8373

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ARTICLE SUMMARY

Male sexual dysfunction P Ramlachan,1 MB ChB, MHlthSc, FECSM; M M Campbell,2 PhD 1 2

ewkwa Medical Centre, Durban, South Africa N Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: P Ramlachan (drprithy@newkwa.co.za)

Approximately 31% of men will suffer from a sexual dysfunction in their lifetime. This review provides an approach to managing common causes of male sexual dysfunction, in accordance with the International Society of Sexual Medicine (ISSM) guidelines.

Erectile dysfunction (ED)

ED is defined as a man’s recurrent inability to attain or maintain penile erection sufficient for satisfactory sexual activity. Up to 50% of men with ED also experience premature ejaculation (PE). Detailed history taking assists in refining the diagnosis. The physical examination (i) assists in corroborating aspects of the medical history; (ii) reveals unsuspected physical findings; (iii) assists in identifying specific aetiologies or comorbidities; and (iv) creates an opportunity for education and reassurance about sexual anatomy, appearance and function. The primary goal of treatment is to enable the individual to enjoy a satisfactory sexual experience by (i) identifying and treating any curable causes of ED; (ii) initiating lifestyle/risk factor modification; and (iii) providing education and counselling. Treatment includes medical treatment (oral agents, local therapies and vacuum constriction devices) and psychotherapies. All patients with ED should have their testosterone levels evaluated before treatment begins.

ED and coronary artery disease

ED and coronary artery disease share the same risk factors. Men with ED should have their coronary artery disease risk assessed and treated. The association between depression, ischaemic heart disease and cardiovascular mortality has been well documented. Therefore, irrespective of whether ED is a symptom or a cause of depression, a patient with cardiac disease who is depressed is more likely to have ED.

ejaculatory latency time, sense of ejaculatory control, level of sexual dissatisfaction, distress, and frequency of sexual activity are key elements during assessment. All symptomatic therapies for PE aim to reduce excitation.

Orgasmic dysfunction (OD)

OD is the inability to achieve an orgasm or markedly diminished intensity of an orgasm. It can also be the marked delay of orgasm during any kind of sexual stimulation. Assessment begins by reviewing the conditions under which the man is able to ejaculate. If orgasmic attainment had been possible previously, the life events and circumstances temporarily related to orgasmic cessation are reviewed. Patient education regarding existing factors that can exacerbate OD is an important first step. Treatment with pharmaceuticals has met with limited success.

Male hypoactive sexual desire disorder (HSDD)

HSDD is defined as persistently or recurrently deficient (or absent) sexual/erotic thoughts or fantasies and desire for sexual activity. This may be the result of common medical conditions, social and interpersonal factors or pharmacological agents. Treatment should focus initially on targeting and treating sexual difficulties. Next, the clinician should assess the patient-partner relationship and teach sexual communication and erotic skills.

Conclusion

In male sexual dysfunction it is necessary to consider a broad range of biopsychosocial factors before attempting to decide on the medical treatment. Please see the online version of this article for greater detail.

Premature ejaculation

The prevalence of PE is estimated at 24.9%. Details about the patient’s ejaculatory response, subjective assessment of his intravaginal

S Afr Med J 2014;104(6):447. DOI:10.7196/SAMJ.8376

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Hypersexual disorder in general practice M M Campbell, PhD; D J Stein, FRCPC, PhD Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: M M Campbell (mm.campbell@uct.ac.za)

During the most recent revision of the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-5), hypersexual disorder was proposed as a new diagnostic category. Hypersexual disorder was defined by the DSM-5 sexual disorders working group as ‘a sexual desire disorder characterized by increased frequency and intensity of sexually motivated fantasies, arousal, urges, and enacted behavior in association with an impulsivity component’ resulting in clinically significant personal distress or social, occupational or other impairment and not due to the physiological effect of an exogenous substance. The submission was ultimately rejected, but in the process a number of useful reviews relating to the assessment and treatment of hypersexual disorder were undertaken. This condition has also been termed compulsive sexual disorder, sexual addiction and non-paraphilic sexual disorder, reflecting different approaches to conceptualising its aetiology.

Epidemiology

Research has provided evidence of a population characterised by increased frequency of sexual behaviours. Within this population, there is a group in which such behaviour leads to distress and impairment. Patients who experience increased frequency and intensity of sexual behaviour, with accompanying distress and impaired life functioning, may seek medical treatment.

Differential diagnosis

In making the diagnosis of hypersexual disorder, it is important firstly to differentiate the disorder from normal sexual behaviour. Secondly, it is important to ensure that the diagnosis is not due to another underlying psychiatric or general medical disorder.

Assessment

The clinical assessment includes a thorough clinical interview to elicit information about the history of the presenting problem, the patient’s sexual, medical, psychiatric, substance-use, mental health

and psychosocial history, with a particular focus on comorbid anxiety and depression. Additional information from family members and intimate partners may provide valuable collateral information. Importantly, patients with this disorder may present with comorbid psychiatric conditions, including anxiety and mood disorders, substance-use disorders, attention deficit hyperactivity disorder, personality disorders and paraphilias.

Treatment

Psychopharmacology. Two double-blind, placebo-controlled trials have shown a decrease in hypersexual disorder symptoms with the use of antidepressant medication (desipramine and clomipramine). There are also case series reporting the potential benefits of selective serotonin re-uptake inhibitors, psychostimulants and triptorelin in hypersexual disorder. Psychotherapy. While different psychotherapy modalities have been proposed for the treatment of hypersexual disorder, there are few data from controlled trials to demonstrate the efficacy of these approaches.

Conclusion

There is growing recognition of hypersexual disorder in the literature and while some empirical research is available, more is needed. Family practitioners are very likely to encounter patients with hypersexual disorder, although this may not be the presenting complaint. Hypersexual disorder is associated with HIV infection and sexually transmitted infections because of the high-risk sexual practices patients with this disorder engage in. Sexual health screenings form one essential part of the healthcare of these patients. Please see the online version of this article for greater detail. Acknowledgement. Prof. D J Stein is supported by the Medical Research Council of South Africa. S Afr Med J 2014;104(6):448. DOI:10.7196/SAMJ.8409

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Transgender issues in South Africa, with particular reference to the Groote Schuur Hospital Transgender Unit D Wilson,1 MB ChB, FCPsych (SA); A Marais,1 PhD; A de Villiers,2 MB ChB; R Addinall,3 MSocSc; M M Campbell,1 PhD; The Transgender Unit Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa The Transgender Unit, Groote Schuur Hospital, Cape Town, South Africa 3 Department of Social Development, Faculty of Humanities, University of Cape Town, South Africa 1 2

Corresponding author: D Wilson (d.wilson@uct.ac.za)

There has been ongoing and critical debate around the diagnostic classification and terminology of disorders related to transgender identity. This has resulted in constant shifts in placement and renaming of these diagnoses in various editions of the International Classification of Diseases and Related Health Problems (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). Successively termed transsexualism, gender identity disorder and now gender dysphoria (GD), a defining criterion is the person’s discontent with their assigned gender.

Diagnostic considerations

In both the ICD-11 and DSM-5 revision processes, the challenge has been to find a balance between providing diagnostic categories that facilitate access to healthcare and medical insurance for the transgender community, while protecting these individuals from the potential stigmatisation that may arise in being diagnosed with a mental disorder in order to receive treatment.

Healthcare options Clinical assessment

The initial evaluation and diagnosis are made by a mental healthcare professional, who assesses the individual’s gender concerns in accordance with standard criteria. Differential diagnoses are excluded, eligibility for therapy is considered and capacity to give informed consent is confirmed. After evaluation, information is provided regarding transition options and possible medical interventions. Any co-existing mental health concerns are addressed and the patient is then prepared and referred for hormone therapy and/or surgery.

Sexual reassignment surgery

Best practice recommendations, clinical experience over five decades, and expert professional consensus have consolidated gender reassignment therapy as part of the management of GD. Surgery consists of ablative/reconstructive procedures to the primary or secondary sexual anatomy.

Psychotherapy

Psychosocial support and psychotherapy are also valuable interventions that assist in supporting the individual’s right to autonomy and self-identification. The mental health practitioner’s role is primarily evaluative and supportive.

The Transgender Unit

In 2009, the multidisciplinary Transgender Unit was formed at Groote Schuur Hospital, Cape Town, South Africa. Since 2009, the Unit has assisted 102 patients.

Challenges

The greatest challenges currently facing the Transgender Unit are limited funding and resources, limited professional training and the effect of so few facilities on patients, particularly in rural areas.

Conclusions and recommendations

With new standards of care enabling devolvement of endocrine management to primary or secondary healthcare settings, the Transgender Unit is already putting in place a supportive framework and guidelines to enable general practitioners to offer patients transition therapy.

Endocrine/hormone therapy

Endocrine therapy may now be managed by a competent general practitioner.

S Afr Med J 2014;104(6):449. DOI:10.7196/SAMJ.8392

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Sexual function and ageing L Geffen, MB ChB, FCFP (SA) Institute of Ageing, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: L Geffen (lgeffen@gmail.com)

Older persons engaging in regular consensual sex have shown improved well-being in both physical and psychological health. Engaging in intercourse has been correlated with improved intimate relationships, improved cardiovascular health and lower rates of depression. As people age, changes in physical and mental health, relationship status and societal pressures contribute to sexual function. In South Africa, life expectancy at birth has increased from 52.1 years in 2003 to 59.6 years in 2013, and as of 2011, 8% of the South African population is over the age of 60 years. As society ages, the healthy life-years lived increase.

Sexual behaviour

The National Social Life, Health, and Aging Project (NSHAP) in the USA showed that sexual activity declined with age and was lower among women than men. Of the sexually active men and women aged 75 - 85 years, 54% reported having sex at least 2 - 3 times per month. The majority of older adults were engaged in an intimate relationship and regarded sexuality as an important part of life.

Health and sexual behaviour

The NSHAP showed that poorer health was significantly associated with being less sexually active. The most commonly reported reason for sexual inactivity was the male partner’s physical health. Men and women with diabetes were less likely to be sexually active. The UK National Survey of Sexual Attitudes and Lifestyles (Natsal-3) reported that men and women with a longstanding illness, ≥2 chronic conditions, a BMI >35 kg/m2 or having difficulty ascending stairs due to a health problem were significantly less likely to report sexual activities than those without these issues.

Relationship status and impact on sexual behaviour

The NSHAP demonstrated that women were less likely than men to be in an intimate relationship at any given age, and this difference

increased with age. Of women not in an intimate relationship, 4% reported being in a sexual relationship in the prior 12 months, as opposed to 22% of men.

Problems specific to women

Vaginal atrophy, loss of elasticity, introital stenosis and dyspareunia are often associated with postmenopausal changes. Vaginal dryness has been associated with a previously fractured hip or pelvis, a hip replacement, depressive symptoms, being postmenopausal, and having backache or bone disease for >3 months in the past year. In postmenopausal older women, vulvovaginal atrophy is a progressive problem that is unlikely to resolve without treatment.

Problems specific to men

Andropause is a term that describes changes in men as they age. There is no internationally accepted clinically defined entity, and unlike menopausal women, men can continue to reproduce until the end of their lives. While levels of testosterone do decline as men age, these are of a physiological nature rather than of complete androgen failure. The known prevalence of the latter is 0.5%.

Doctor-patient relationship

It is estimated that only 38% of men and 22% of women over 50 years of age discuss sex with a doctor. It is possible that poor communication between doctor and patient is due to the unwillingness of both parties to initiate the discussion, confounded by age and sex differences. Attitudes about sexuality, especially as people grow older, may also inhibit discussions.

Conclusion

Sexual activity and problems associated with sex are common among older persons. It is important that healthcare professionals become knowledgeable about the sexual practices of their older patients. S Afr Med J 2014;104(6):450. DOI:10.7196/SAMJ.8396

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EMERGENCY PHYSICIAN International SOS (www.internationalsos.com) is the world’s leading medical and travel security services company. We care for clients across the globe, from more than 700 locations in 76 countries. Our expertise is unique: more than 10,000 employees are led by 1,200 physicians and 200 security specialists. Teams work night and day to protect our members. International SOS Medical Services work with global organizations in assessing the health risks and safety of their onsite employees working in some of the most remote and difficult operational environments throughout the world. Each remote site clinic provides both primary and emergency health care to the client’s onsite population THE ROLE: The Emergency Physician’s primary function is to assess, diagnose and treat patients at a General Practice and Emergency Medicine level, providing clinical and professional direction to the Medical Officers on site. This role requires significant full time experience in Emergency Medicine with previous experience of having worked in remote locations or in culturally different locales. DATES: We are currently seeking expressions of interest for ongoing rotational roles commencing in June and July. We also have an ongoing need for future commencement dates to fulfill our rotational requirements. REQUIREMENTS: Experience Emergency Medicine doctors Fellowship of Emergency Medicine in country of registration highly desirable Bachelor of Medicine, Bachelor of Surgery (MBBS) or equivalent Current registration in your country of residence ACLS mandatory, ATLS is desirable. PALs mandatory for some roles BENEFITS: Permanent rotational roles are available to work a fixed pattern of 4 weeks on/4 weeks off or 6 weeks on/6 weeks off paid on and off duty. We also have locum roles available. In return we offer competitive expatriate salary package/benefits including rotational work travel and onsite accommodation and a rewarding and international career within our global organization.

Working for PathCare always produces excellent results!!

Pathologist PathCare Laboratories have a position available for a Haematology Pathologist in N1 City, Cape Town. You will share all duties, including bone marrow biopsies throughout the northern suburbs and surrounding areas (Paarl, Worcester, Stellenbosch, Somerset West). 5 Years post pathology qualification experience, bilingual in English and Afrikaans. If you believe you would thrive in a multi-disciplinary private laboratory, and have similar goals and values to our own, we encourage you to contact us for this position. Requirements: ▪ M.Med or FC Pathology (SA) ▪ Current registration with the HPCSA as a Pathologist ▪ 5 Years post pathology qualification experience ▪ Relevant working experience ▪ Excellent communication and interpersonal skills ▪ Ability to maintain confidentiality and impartiality.

To apply, please email lindyb@pathcare.co.za Closing date: 16 June 2014. www.pathcare.co.za

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CPD

JUNE 2014

Effective in 2014, the CPD programme for SAMJ will be administered by Medical Practice Consulting: CPD questionnaires must be completed online at www.mpconsulting.co.za

True (A) or false (B): Limited access to and availability of eye-care services in urban South Africa (SA) 1. In line with the World Health Organization’s Vision 2020 recom mending that all schoolchildren have a simple vision-screening examination, all provinces of SA offer such screening through a school health National Vision Screening Programme. Identification of a common founder couple for 40 SA Afrikaner families with Parkinson’s disease (PD) 2. PD is a debilitating neurodegenerative condition arising as a result of the progressive loss of dopaminergic neurons in the brainstem. 3. Clinical features include resting tremor, rigidity, bradykinesia, postural instability and responsiveness to levodopa. No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry SA population 4. The mixed-ancestry population of SA has one of the highest prevalences of type 2 diabetes mellitus in Africa. 5. Studies in the Pima Indian population, with as high a prevalence of diabetes as SA’s mixed-ancestry population, have found that there is a strong association with the Gly972Arg variant of the insulin receptor substrate. Hypotension and hypoxaemia in blunt traumatic brain injury 6. Of some 90 000 new cases of head injury reported in SA annually, 50% are due to road traffic collisions (bicycle, vehicle or pedestrian), 25% to falls and a further 25% to violence. 7. Most traumatic brain injuries are followed by an epsiode of apnoea, even if just for a brief period, with hypoxaemia linked to a near-doubling in mortality from 27% to 50%. Paediatric otitis media at a primary healthcare clinic 8. Sub-Saharan Africa has the second highest incidence of chronic suppurative otitis media (CSOM) in the world. 9. Children with HIV are known to be more prone to, and more severely affected by, otitis media than seronegative children.

10. R isk factors that contribute to high rates of CSOM include prolonged breastfeeding, poor hygiene, and exposure to tobacco, wood and charcoal smoke. Sexual dysfunction: A systematic review of South African research 11. Lack of sexual interest and inability to reach orgasm were the most commonly reported complaints for women, affecting 32% and 25%, respectively. 12. Diabetes mellitus, cardiovascular disease, genitourinary disease, psychiatric or psychological disorders, and poor general health have been identified as common comorbid conditions associated with sexual dysfunction in both sexes. An integrative treatment model for sexual dysfunctions 13. The ICSM-5 stepwise diagnostic and treatment algorithm leads family practitioners through a four-step progression in the assessment of sexual dysfunction. 14. All men presenting with erectile dysfunction should have their serum testosterone levels measured on a blood sample. Female sexual dysfunction 15. Female sexual concerns are highly prevalent and distressing. 16. Deficiencies of oestrogen or androgen are usually detected by history and examination. Male sexual dysfunction 17. Up to 50% of men with erectile dysfunction also experience pre mature ejaculation. 18. Erectile dysfunction and coronary artery disease share the same risk factors. Sexual function and ageing 19. Older persons engaging in regular consensual sex have shown improved physical and psychological health. 20. The most commonly reported reason for sexual inactivity was the male partner’s physical health.

CPD questions include articles from CME. The full versions of each article can be found on the SAMJ website (http://www.samj.org.za)

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB001/007/01/2014 (Clinical)

June 2014, Vol. 104, No. 6

For further product information contact PHARMA DYNAMICS : P O Box 30958 Tokai 7966 • Tel 021 707 7000 Fax 021 701 5898 • www.pharmadynamics.co.za • Customer Care Line 0860-PHARMA (742 762)

JUNE 2014

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