SAMJ Vol 107, No 9 (2017) by HMPG

SEPTEMBER 2017

PRINT EDITION

CME Chronic kidney disease CORRESPONDENCE South African student protests, 2015 - 2016: The aftermath IN PRACTICE Ngoma herbal tonic interferes with rapid urine drug screening test Responding to essential medicine stock-outs in the Eastern Cape CASE REPORT Orbital apex syndrome in a 6-year-old RESEARCH Osteosarcoma outcomes Central-line-associated infection in neonatal intensive care Differences in risk perception of noncommunicable diseases in Diepsloot adults

Makes colon cleansing plain sailing...

Sodium Picosulphate Oral Powder for Solution. For bowel cleansing in conjunction with:

Intravenous Pyelograms (IVP) Bowel Evacuation Abdominal X-Ray Examinations Surgery Colonoscopy S0 Each sachet contains: Sodium Picosulphate 10mg, Magnesium Oxide Ph Eur 3.5g, Citric Acid Ph Eur 12.0g, Aspartame 36mg. Reg.No A38/11.5/0389.

SEPTEMBER 2017 PRINT EDITION

FROM THE EDITOR 4

EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

Children of men … B Farham

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR

EDITOR’S CHOICE CORRESPONDENCE

Undergraduate antimicrobial stewardship training for pharmacy students: Creating a foundation for containment of antimicrobial resistance in South Africa Y Khan, S-A Boschmans, J McCartney, R Coetzee

South African student protests, 2015 - 2016: The aftermath viewed through Medical Science Honours students at the University of Cape Town C Dandara, E R Chimusa, A Wonkam

Use of social media by health professionals in South Africa T D Noakes

IZINDABA 14

BOOK REVIEW Textbook of Global Health H Schneider

OBITUARY Ian Wark Simson L Dreyer

Work-based assessment: A critical element of specialist medical training M M Sathekge

GUEST EDITORIAL Chronic kidney disease A M Meyers

ARTICLE Recent important strategies in the management of chronic kidney disease A M Meyers, M Davies

IN PRACTICE

CLINICAL UPDATE Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test M E Mothibe, E Osuch, C P Kahler-Venter ISSUES IN PUBLIC HEALTH How front-line healthcare workers respond to stock-outs of essential medicines in the Eastern Cape Province of South Africa R Hodes, I Price, N Bungane, E Toska, L Cluver MEDICINE AND THE LAW Facilitating access to adolescent sexual and reproductive health services through legislative reform: Lessons from the South African experience A Strode, Z Essack

HEALTHCARE DELIVERY Building capacity for development and implementation of clinical practice guidelines Q Louw, J M Dizon, K Grimmer, M McCaul, T Kredo, T Young

CASE REPORT Orbital apex syndrome after trauma in a 6-year-old – a rare occurrence A Ahmed

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za SALES MANAGER (CAPE TOWN) Azad Yusuf JOURNAL ADVERTISING Reneé Hinze Ladine van Heerden Makhadzi Mulaudzi Charmalin Simpson

MANAGING EDITORS Claudia Naidu Naadia van der Bergh

DTP AND DESIGN Clinton Griffin Travis Arendse

CONTINUING MEDICAL EDUCATION

CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za

PRODUCTION MANAGER Emma Jane Couzens

EDITORIAL 17

HMPG

TECHNICAL EDITORS Emma Buchanan Christelle Cronje Kirsten Morreira Paula van der Bijl

30 days in medicine B Farham

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman, J M Pettifor, W Edridge, R P Abratt, D L Clarke

September 2017, Print edition

ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574 SAMA website: www.samedical.org Journal website: www.samj.org.za

RESEARCH 38

Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria O Ijarotimi, D O Soyoye, O Adekanle, D A Ndububa, B I Umoru, O I Alatise

Osteosarcoma outcomes at a South African tertiary hospital L Lisenda, Z A Linda, F P J Snyman, R D Kyte, M Lukhele

Central-line-associated bloodstream infections in a resource-limited South African neonatal intensive care unit C Geldenhuys, A Dramowski, A Jenkins, A Bekker

Residual allergenicity of amino acid-based and extensively hydrolysed cow’s milk formulas M E Levin, D M Blackhurst, F Kirstein, D Kok, G F van der Watt, A D Marais

A review of antenatal corticosteroid use in premature neonates in a middle-income country* A Laher, D E Ballot, T Ramdin, T Chirwa

White blood cell count and C-reactive protein together remain useful for diagnosis and staging of acute appendicitis in children* S Monsalve, A Ellwanger, S Montedonico

The spectrum and outcome of paediatric traumatic brain injury in KwaZulu-Natal Province, South Africa, has not changed over the last two decades* J J P Buitendag, V Y Kong, J L Bruce, G L Laing, D L Clarke, P Brysiewicz

Concomitant HIV infection in newly diagnosed multiple myeloma patients is hard to recognise and should be tested for routinely in areas of high endemicity* J J B de Groot, M J Webb, J E Raubenheimer, M C Struwig, V J Louw

A third of patients treated at a tertiary-level surgical service could be treated at a secondary-level facility* S van Straten, C Stannard, J Bulabula, K Paul, J Leong, M J Klipin

New-onset diabetes after transplant: Incidence, risk factors and outcome* S C Alagbe, A Voster, R Ramesar, C R Swanepoel

Age-group differences in risk perceptions of non-communicable diseases among adults in Diepsloot township, Johannesburg, South Africa: A cross-sectional study based on the Health Belief Model* Z Kaba, N Khamisa, N Tshuma *Abstract only, full article available online.

ONLINE CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Directory of Open Access Journals (DOAJ) Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions ZAR1 488.00 p.a. Foreign subscriptions ZAR3 408.00 p.a. Single copies ZAR124.00 local, ZAR284.00 foreign Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012 481 2071 Email: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE Health and Medical Publishing Group (Pty) Ltd Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 Tel. 012 481 2069 Email: dianes@hmpg.co.za EDITORIAL OFFICE Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 Tel. 021 532 1281 | Cell. 072 635 9825 Email: publishing@hmpg.co.za Please submit all letters and articles for publication online at http://www.editorialmanager.com/samj © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association Use of editorial material is subject to the Creative Commons Attribution – Non-commercial Works Licence. https://creativecommons.org/licenses/bync/4.0

CAREERS AND CLASSIFIEDS CPD QUESTIONS

Printed by TANDYM PRINT

SEPTEMBER 2017

Background photo: Surgically trained medical technicians and nurses prepare for a caesarean section in the Caia District Hospital operating theatre, Sofala Province, Mozambique | Shaun Swingler

PRINT EDITION

Box photos: A dialysis session (used with the patient’s permission) | National Kidney Foundation of South Africa; Student protest, October 2015 | Jess Davies; Late presentation of osteosarcoma | Laughter Lisenda

September 2017, Print edition

CASE REPORT Orbital apex syndrome in a 6-year-old RESEARCH Osteosarcoma outcomes Central-line-associated infection in neonatal intensive care Differences in risk perception of noncommunicable diseases in Diepsloot adults

Antibiotics A4 Range Ad.pdf

2017/06/26

10:05 AM

Pharma Dynamics actively supports

the fight against antimicrobial resistance.

CMY

Pharma Dynamics antimicrobial portfolio

SOLUTION for

INFUSION

MIXRA256/05/2017

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

FROM THE EDITOR

Children of men ... There is a recurring theme in apocalypse fiction – and I am not talking about famine or war. It is infertility. I have often wondered why, probably because having lived most of my life in the developing world, it is something I have seldom come across. However, recent studies suggest that in the developed world, scenarios such as those painted in Children of Men and The Handmaid’s Tale may well come to pass. A study from the Hebrew University of Jerusalem published recently in Human Reproduction Update[1] shows that sperm counts among men in the developed world have more than halved during the past 40 years and are currently falling by around 1.4% per year. The research drew on 185 studies conducted between 1973 and 2011, involving around 43 000 men. The team found that sperm concentration fell from 99 million per mL in 1973 to 47.1 million per mL in 2011 – a drop of 52.4%. In the same group, the total sperm count dropped by just under 60%. Are people worried about this? Apparently they are, with the World Health Organization describing current knowledge of male infertility as ‘very low’. This was also the stance of the UK Medical Research Council, which has called for those in the field to put projects forward for funding. The situation is complicated by the fact that more and more couples in the developed world delay childbearing into their 30s, when the likelihood of conception is lower anyway.[2] The causes are so far unknown, but just about everything, from cell phones, to smoking, to oral contraceptives contaminating drinking water, has been blamed. But should we really be worried? Not entirely flippantly, I would suggest that this is a good reason for European

countries (and indeed those of the Antipodes) to stop their ‘fortress’ approach to immigration from the developing world. Not only do they have top-heavy, ageing populations, but now their fertility is also declining. These countries need young immigrants – those from the Middle Eastern countries are often highly qualified, able to fill skill gaps in the ageing European populations, while others are all too willing to work in areas that local youngsters decline. So, not only would immigration change the age structure of these populations, but, until the immigrants too are smitten by whatever is dropping fertility, they will provide more fertile populations as well. My previous training in population biology now comes to the fore – this shows all too well that humankind is simply another biological population, subject to the vagaries of our environment. We forget this at our peril! Bridget Farham Editor ugqirha@iafrica.com 1. Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends in sperm count: A systematic review and meta-regression analysis. Hum Reprod Update 2017 (epub 2 August 2017). https://doi. org/10.1093/humupd/dmx022 2. The Guardian. The infertility crisis is beyond doubt: Now scientists must find the cause. https://www. theguardian.com/science/2017/jul/29/infertility-crisis-sperm-counts-halved (accessed 14 August 2017).

S Afr Med J 2017;107(9):721. DOI:10.7196/SAMJ.2017.v107i9.12799

September 2017, Print edition

Most people would see this as a straight line. The rare ones have the ability to turn it into a heartbeat.

Your rarity as a medical professional should be rewarding. At PPS, we value the way you look at the world and thatâ&#x20AC;&#x2122;s why we have graduate financial solutions that are as unique as your skill set. To find out more, contact your PPS-accredited financial adviser or visit pps.co.za

#R AREISREWARDING

Life Insurance

Investments

Financial Planning

Short-Term Insurance

Medical Aid

PPS offers unique financial solutions to select graduate professionals. PPS is an authorised Financial Services Provider.

EDITOR’S CHOICE

CME: Chronic kidney disease

In the USA, the proportion of the population with chronic kidney disease (CKD) reached 15% by 2017. In South Africa (SA), this figure may well be higher. CKD management in the developed world aims at the apex of the triangle, i.e. improvements in dialysis and transplantation, as well as the mid-triangle area, i.e. strategies in slowing the progression to end-stage renal disease. In SA, however, the huge costs of dialysis and transplantation dictate that our CKD management should first and foremost be aimed at prevention and secondly at renoprotection. The review[1] presented in this CME section of SAMJ highlights recent information relating to the use of metformin in the management of diabetes in patients with CKD, the essential and early treatment of CKD acidosis (i.e. estimated glomerular filtration rate ≤59 mL/min.), early dietary therapy, early lowering of serum uric acid and introduction of adequate and ongoing exercise – all aimed at slowing the progression of CKD. In addition, the use of high-dose statins in preventing cyst growth and eventual renal failure in patients with autosomal-dominant polycystic disease is explained.

Age-group differences in risk perceptions of non-communicable diseases among adults in Diepsloot, Johannesburg, SA

Non-communicable diseases (NCDs) in SA occur simultaneously with an ageing HIV-positive population, resulting in premature deaths in persons <70 years of age. Poor risk perception of NCDs results in poor adoption practices of NCD preventive measures. There is a gap in age-related research regarding risk perceptions of NCDs in the SA population. In this study, age-group differences in risk perceptions of NCDs based on the Health Belief Model were investigated. The cross-sectional design used secondary data obtained from Community AIDS Response (CARe), Johannesburg, SA. Data were collected by means of a cross-sectional survey in Extension 2 (Blocks I, J, K and L) of Diepsloot township, Johannesburg.[2] The Pearson χ2 test of independence was used to examine the relationship between age groups and risk perceptions of NCDs. A p-value of <0.05 was considered statistically significant. A total of 2 135 participants were included in the analysis, of whom 71.5% were young adults (18 - 35 years). The mean age of the study participants was 32.1 (standard deviation 9.87) years. Significant associations were found between age groups and risk perceptions of NCDs. More middle-aged adults than young adults and older-aged adults perceived family history (74.00% v. 72.74% v. 62.39%; p=0.045) and smoking (83.80% v. 77.20% v. 74.31%, p=0.004) as risk factors that would increase their risk of NCDs. A higher proportion of olderaged adults than young adults and middle-aged adults perceived effects on life and family (89.91% v. 77.39% v. 75.40%; p=0.004) as risks of NCD morbidities. More middle-aged adults than young adults and older-aged adults perceived the usefulness of not smoking (84.60% v. 81.06% v. 74.31%; p=0.028) as an effective NCD preventive measure. More young adults than middle-aged and older-aged adults considered health check-ups as a time-consuming process to prevent risks of NCDs (59.31% v. 58.00% v. 41.28%; p=0.001). Young adults had poorer risk perceptions of NCDs than middleaged and older-aged adults in Diepsloot township, resulting in poor practice of NCD preventive measures among young adults in the area. This may be due to misunderstanding of the concept of invulnerability, possibly resulting from the limited access and exposure to NCD-related information among young adults compared with middle-aged and older-aged groups. This highlights the need to

expand public health education programmes to increase outreach to the young adult population and increase accessibility to information relating to NCD risks, and encourage adoption of NCD preventive measures.

Central-line-associated bloodstream infections in a resource-limited SA neonatal intensive care unit

The rate of central-line-associated bloodstream infection (CLABSI) in SA public sector neonatal intensive care units (NICUs) is unknown. Tygerberg Children’s Hospital (TCH), Cape Town, introduced a neonatal CLABSI surveillance and prevention programme in August 2012. In this study,[3] the authors describe CLABSI events and identify risk factors for development of CLABSI in a resource-limited NICU using a retrospective case-control study of prospectively collected NICU CLABSI events matched to four randomly selected controls, sampled from the NICU registry between 9 August 2012 and 31 July 2014. Clinical data and laboratory records were reviewed to identify possible risk factors, using stepwise forward logistic regression analysis. A total of 706 central lines were inserted in 530 neonates during the study period. Nineteen CLABSI events were identified, with a CLABSI rate of 5.9/1 000 line days. CLABSI patients were of lower gestational age (28 v. 34 weeks; p=0.003) and lower median birth weight (1 170 g v. 1 975 g; p=0.014) than without CLABSI, had longer catheter dwell times (>4 days) (odds ratio (OR) 5.1 (95% confidence interval (CI) 1.0 - 25.4); p=0.04) and were more likely to have had surgery during their NICU stay (OR 3.5 (95% CI 1.26 - 10); p=0.01). Significant risk factors for CLABSI were length of stay >30 days (OR 20.7 (95% CI 2.1 - 203.2); p=0.009) and central-line insertion in the operating theatre (OR 8.1 (95% CI 1.2 - 54.7); p=0.03). Gramnegative pathogens predominated (12/22, 54%), with most isolates (10/12, 83%) exhibiting multidrug resistance. The TCH NICU CLABSI rate is similar to that reported from resource-limited settings, but exceeds that of high-income countries. Prolonged NICU stay and central-line insertion in the operating theatre were important risk factors for CLABSI development. Intensified neonatal staff training regarding CLABSI maintenance bundle elements and hand hygiene are key to reducing CLABSI rates.

Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria

Duodenal ulcer is the most common peptic ulcer disease worldwide. In the past, sub-Saharan Africa has been described as an area of mixed prevalence for peptic ulcer disease, but recent reports have disputed this. Changes in the prevalence of duodenal ulcer have been reported, with various reasons given for these. The change in endoscopic prevalence of duodenal ulcer at Obafemi Awolowo University Teaching Hospital (OAUTH), Ile-Ife, Nigeria, between January 2000 and December 2010 is described.[4] This was a retrospective, descriptive study of patients who underwent upper gastrointestinal endoscopy in the endoscopy unit of OAUTH between January 2000 and December 2010. The data were obtained from the endoscopy register, demographic indices, presenting symptoms and post-endoscopic diagnoses being retrieved for each patient. The study period was divided into the years 2000 - 2004 and 2005 2010, the frequencies of duodenal ulcer and other post-endoscopic diagnoses being compared between these two time periods to see whether there were changes. Over the study period, 292 patients (15.8%) were diagnosed with duodenal ulcer, second only to 471 (26.2%) with acute gastritis. The

September 2017, Print edition

WORLD FORUM EDITOR’S CHOICE FOR MEDICINE prevalence of duodenal ulcer for 2000 - 2004 was 22.9% (n=211 patients), compared with 9.2% (n=81) for 2005 2010 (p<0.001). There was a significant decline in the endoscopic prevalence of duodenal ulcer over the decade.

Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test

The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. The cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) was investigated using a qualitative rapid urinalysis assay.[5] The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused falsenegative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests.

13 – 16 NOVEMBER 2017 DÜSSELDORF GERMANY www.medica-tradefair.com

The world of medicine at a glance: • Electromedical equipment/ Medical technology • Laboratory technology/Diagnostics • Physiotherapy/ Orthopedic technology • Commodities and consumer goods • Information and communication technology If you want to see it all, know it all and experience it all, come to the largest world forum for medicine in Düsseldorf!

BE PART OF THE NO.1!

BF 1. Meyers AM, Davies M. Recent important strategies in the management of chronic kidney disease. S Afr Med J 2017;107(9):730-733. https://doi.org/10.7196/ SAMJ.2017.v107i9.12366 2. Kaba Z, Khamisa N, Tshuma N. Age-group differences in risk perceptions of noncommunicable diseases among adults in Diepsloot township, Johannesburg, South Africa: A cross-sectional study based on the Health Belief Model. S Afr Med J 2017;107(9):797-804. https://doi.org/10.7196/SAMJ.2017.v107i9.12168 3. Ijarotimi O, Soyoye DO, Adekanle O, Ndububa DA, Umoru BI, Alatise OI. Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria. S Afr Med J 2017;107(9):750-753. https://doi.org/10.7196/SAMJ.2017.v107i9.12342 4. Geldenhuys C, Dramowski A, Jenkins A, Bekker A. Central-line-associated bloodstream infections in a resource-limited South African neonatal intensive care unit. S Afr Med J 2017;107(9):758-762. https://doi.org/10.7196/SAMJ.2017. v107i9.12124 5. Mothibe ME, Osuch E, Kahler-Venter CP. Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test. S Afr Med J 2017;107(9):734-737. https:// doi.org/10.7196/SAMJ.2017.v107i9.12197

Southern African - German Chamber of Commerce and Industry 47 Oxford Road _ Forest Town 2193 JOHANNESBURG P.O. Box 87078 _ Houghton 2041 Tel. +27 (0)11 486 2775 _ Fax +27 (0)86 675 2175 tradefairs@germanchamber.co.za _ www.germanchamber.co.za

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

CORRESPONDENCE

Undergraduate antimicrobial stewardship training for pharmacy students: Creating a foundation for containment of antimicrobial resistance in South Africa

Y Khan, S-A Boschmans, J McCartney Department of Pharmacy, Faculty of Health Sciences, Nelson Mandela University, Port Elizabeth, South Africa khanyasmine07@gmail.com

To the Editor: The inappropriate and excessive use of antimicrobial agents has cultivated the development and progression of antimicrobial resistance worldwide, which has been recognised as a threat to global health and safety.[1] In response to this alarming growth in antimicrobial resistance, antimicrobial stewardship initiatives, which aim to improve the judicious use of antimicrobial agents, have gained global support.[2] The Antimicrobial Resistance Strategy Framework in South Africa (SA) recognises the education of healthcare professionals as a strategy for containment of antimicrobial resistance in SA.[3] Prescribers and pharmacists serve as the ‘nucleus’ of antimicrobial stewardship teams.[4] Pharmacists play a crucial role in the surveillance of and feedback on antimicrobial stewardship practices when evaluating and dispensing prescriptions.[5] It is, therefore, essential that both medical and pharmacy students receive adequate undergraduate antimicrobial stewardship training, so as to ensure the effective implementation of antimicrobial stewardship in practice. The guest editorial by Brink, Schoeman and Muttingh[6] published in the May 2017 issue of the SAMJ correctly emphasised a current barrier to the implementation of antimicrobial stewardship in SA: a lack of undergraduate antimicrobial stewardship training for prescribers. The editorial commented on the results of an SA study that revealed the apparent gaps in the antimicrobial stewardship knowledge of participating final-year medical students.[7] Similarly, a national survey was conducted in 2016 that focused on the knowledge and perceptions of antimicrobial stewardship concepts among final-year pharmacy students in SA.[8] The results of the study revealed that although the majority (95.8%) of students felt that the implementation of antimicrobial stewardship programmes is essential, only 71.9% were familiar with stewardship programmes in SA, and 96.5% of participants stated that they would like more education on antimicrobial stewardship.[8] At the 37th annual general meeting of the Academy of Pharmaceutical Sciences of SA, held in July 2016, it was emphasised that steps need to be taken to ensure adequate undergraduate antimicrobial stewardship training for pharmacy students in SA. In response to the national call for undergraduate antimicrobial stewardship training for pharmacy students, a study is now being undertaken to develop a proposed minimum curriculum content suitable for implementation in undergraduate pharmacy degree programmes in SA. This study has the support of the SA National Department of Health. The study aims to ensure that the proposed curriculum content is in line with international and national antimicrobial stewardship recommendations, while simultaneously incorporating the expertise of antimicrobial stewardship professionals in SA. The methodology involves a series of phases, including a desktop review; consultation with academic pharmacists from SA universities; and consultation with experts in the field of antimicrobial stewardship in SA (including infectious disease specialists, clinical microbiologists and antimicrobial stewardship pharmacists). The results obtained from the study phases will be collated to develop a well-informed and practical curriculum, capable of ensuring that graduating pharmacists are well equipped to execute their antimicrobial stewardship roles. The researchers invite any interested persons to contact the author if they would like to be involved in the study.

R Coetzee School of Pharmacy, Faculty of Natural Science, University of the Western Cape, Bellville, South Africa 1. Barlett JG. A call to arms: The imperative for antimicrobial stewardship. Clin Infect Dis 2011;53(1):S4S7. https:// doi.org/10.1093/cid/cir362 2. World Health Organization. WHO Global Strategy for Containment of Antimicrobial Resistance. Geneva: WHO, 2001. http://www.who.int/drugresistance/WHO_Global_Strategy.htm/en/ (accessed 20 May 2017). 3. National Department of Health, South Africa. Antimicrobial resistance national strategy framework 2014 - 2024. Pretoria: Government Printer, 2014. 4. Mendelson M. Role of antibiotic stewardship in extending the age of modern medicine. S Afr Med J 2015;105(5):414-419. https:// doi.org/10.7196/SAMJ.9635 5. MacDougall C, Polk R. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev 2005;18(4):638-656. https://doi.org/10.1128/cmr.18.4.638-656.2005 6. Brink A, Schoeman J, Muttingh G. Undergraduate antibiotic stewardship training: Are we leaving our future prescribers ‘flapping in the wind? S Afr Med J 2017;107(5):357-358. https://doi.org/10.7196/ SAMJ.2017.v107i5.12496 7. Wasserman S, Potgieter S, Shoul E, et al. South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers? S Afr Med J 2017;107(5):405-410. https://doi.org/10.7196/SAMJ.2017.v107i5.12370 8. Burger M, Fourie J, Loots D, et al. Knowledge and perceptions of antimicrobial stewardship concepts among final year pharmacy students in pharmacy schools across South Africa. S Afr J Infect Dis 2016;31(3):84-90. https://doi.org/10.1080/23120053.2016.1192808

S Afr Med J 2017;107(9):722. DOI:10.7196/SAMJ.2017.v107i9.12649

South African student protests, 2015 2016: The aftermath viewed through Medical Science Honours students at the University of Cape Town

To the Editor: The student protests of 2015 - 2016, under the banner #FeesMustFall, swept across South Africa (SA) like a veldt fire.[1] Several new initiatives have now become possible, thanks to the energy, vision and leadership of the students. For example, at the University of Cape Town (UCT), an agreement was reached between the university Executive and protesting students to, among other things, establish an Institutional Reconciliation and Truth Commission (IRTC). At national level, the SA government launched the Fees Commission, which is yet to finalise its work. Several students were detained, some without trial, for at least 4 months. Most affected universities failed to complete their programmes, with the UCT Faculty of Health Sciences opting for a ‘mini-semester’ in January 2017 to facilitate the completion of academic work remaining from the year 2016.[1] Other universities proceeded with examinations in guarded venues during the final days of the protests, while still others seem to have used marks students had achieved up to the beginning of the protests as the final marks reflected on certificates.[1] Now, only 6 - 18 months later, some academic effects of the 2015 - 2016 student protests are already manifesting. Reflecting on the UCT Honours in human genetics programme, we have a microcosm of students who have come through different universities and been affected differently. Our rigorous selection process for the honours programme depends on academic achievement; therefore, the different decisions taken by universities in completing their programmes are now manifesting in class. We acknowledge that student protest action brought a new impetus to examining issues affecting higher education and education in general. But we retrospectively question the usefulness of some of the results of examinations written soon after the protests, as students were exhausted, stressed and had not completed some of their course content. On reflection, all the students we recruited this year had

September 2017, Print edition

CORRESPONDENCE

‘very good marks’, but, practically, we are faced with students finding it more difficult than previous cohorts of recruited students to cope with the same honours course. There are many possible reasons for this, but there are several clues to support the idea that some students may not have completed their courses, as their universities opted to use available coursework marks as final results. Preliminary assessment results in our programme have seen one student deregister, and as many as 20% struggling and needing assistance to avoid a high likelihood of failure, contrasting with a history of a 100% pass rate for the past 10 years. It is possible that the issues we are facing in UCT’s human genetics honours programme are shared by other disciplines across many universities nationwide. This reflection should by no means be used to stigmatise the protests by students, whose grievances are legitimate and are supported by ourselves and especially by many faculty members. The #FeesMustFall movement has made compelling arguments regarding the need for renewed energy to transform education.[2,3] This reflection paper is intended as a call for proactive measures from all stakeholders in education to address present and future challenges in a way that minimises negative effects on students’ academic performances. It cannot be that every time we need to confront or redress vestiges of apartheid or socioeconomic ills, we wait for students to put their lives and careers on the line, similarly to the students and youths of 1976.[4] As a society, it is important that issues raised by our students receive our full attention and that we create clear, transparent roadmaps on remedial action. C Dandara, E R Chimusa, A Wonkam Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa, and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa collet.dandara@uct.ac.za 1. Davids N. On extending the truncated parameters of transformation in higher education in South Africa into a language of democratic engagement and justice. Transform Higher Edu 2016;1(1):7. https://doi.org/10.4102/the.v1i1.7 2. Heleta S. Decolonisation of higher education: Dismantling epistemic violence and Eurocentrism in South Africa. Transform Higher Edu 2016;1(1):8. https://doi.org/10.4102/the.v1i1.9 3. Du Preez P, Simmonds S, Verhoef AH. Rethinking and researching transformation in higher education: A meta-study of South African trends. Transform Higher Edu 2016;1(1):7. https://doi. org/10.4102/the.v1i1.2 4. Bunting I. The higher education landscape under apartheid. In: Cloete N, Maassen P, Fehnel R, Moja T, Perold H, Gibbon T (eds.). Transformation in Higher Education: Global Pressures and Local Realities in South Africa. Dordrecht: Kluwer Academic Publishers, 2004:35-52. https://doi.org/10.1007/1-40204006-7_3

S Afr Med J 2017;107(9):723. DOI:10.7196/SAMJ.2017.v107i9.12714

Use of social media by health professionals in South Africa

To the Editor: The article by Dr Kubheka[1] contains an important error. I did not advise a ‘breast-feeding mother … to wean her child on a low-carbohydrate and high-fat diet’. I gave generic nutritional information to a (presumed) mother who asked a generic ‘we’ question on behalf of ‘moms’ and ‘babies’. In the course of the 26-day multimillion-rand Health Professions Council of South Africa (HPCSA) hearing into my professional conduct, it was never established that the woman was in fact a mother, or that she was herself breastfeeding. Nor did she lay the complaint (of unprofessional conduct) against me, but this is perhaps beside the point. What is more important is that the HPCSA based their charge against me on the presumption that by answering a single tweet, whether or not that tweet sought generic information or specific medical advice, I (and therefore all medical practitioners doing the same in the future) had intentionally entered a doctor-patient

relationship with the person posting the tweet. Kubheka’s article specifically distinguishes between ‘generic’ and ‘direct medical’ advice. Hence her assertion that ‘it is advisable that professionals share generic information online, and avoid responding with direct medical advice to individuals’. This distinction is the difference between responding to an ‘I’ or a ‘we’ question, and the question I answered was a ‘we’ question seeking generic medical information. The HPCSA’s Professional Conduct Committee judging my case concluded that answering a tweet does not, by itself, initiate a doctorpatient relationship. My legal team argued inter alia that both parties must first agree before there is a doctor-patient relationship, as had clearly not happened in this case. Any doctor willfully attempting to enter a doctor-patient relationship on Twitter must very likely act unprofessionally, since there is a high probability that the act of ‘treating’ a patient on Twitter will involve supersession. This is because patients resorting to Twitter are not actually seeking medical care, so they have no reason to address any requests to their personal caregivers. This is why Kubheka’s advice that ‘any medical discussion professionals enter into on social platforms be accompanied by the advice that patients must consult their practitioners’ quite misses the point. Twitter is an information-sharing platform that cannot be equated with what happens in the doctor’s consulting room. Importantly, persons access Twitter to seek information that will help to guide their decision on what medical care they might seek from the medical profession in the future. They understand that Twitter is not a medium for the provision of medical care. Logically, persons seeking information on Twitter do so for reasons either of (no) cost and convenience, or specifically because they have not been able to source that information elsewhere. Had they already been satisfied with information received from caregivers, they would not have resorted to Twitter. This is a fact of life that legislation or guidelines, however framed, will never eradicate. The second reason why it is not possible to provide ethical medical care via Twitter is that any registered medical practitioner wishing to do so must request the patient to provide personal medical information. Exposing such information publicly on a social media platform could constitute a breach of medical ethics. Kubheka’s warning here is important: ‘Crucially, information shared online is in the public domain and has relative permanence.’ One conclusion might be that the existing regulations for professional behavior by medical professionals adequately prescribe the boundaries of ethical conduct on Twitter. What became very apparent during my HPCSA ‘hearing’ was the widespread ignorance within the profession of exactly how the general public use Twitter, specifically (but also other forms of social media), to access medical advice and information. There are four relevant points here: Firstly, as I have described, patients do not seek medical care on Twitter, and so they will not consult their personal physicians using this medium. Rather, they seek the opinions of those doctors, scientists and lay persons whose hobbies include spending time sharing such information. Few clinicians with busy medical practices will have sufficient leisure time to also be active on Twitter. Secondly, the vast majority of medical questions on Twitter that I encounter do not seek specific medical advice, such as in asking ‘Should I take a statin drug if my blood cholesterol is elevated?’ Much more likely are questions of clarification, for example, ‘What medical benefits can a patient expect if she uses a statin?’ Experienced medical hobbyists

September 2017, Print edition

ETHICS FOR ALL 2017

PORT ELIZABETH JOHANNESBURG DURBAN CAPE TOWN

Join renowned speakers from around the world as we take an in-depth look at the risks facing doctors today. Ethics for All gives you the insight and expertise to navigate ethical dilemmas with confidence. This year’s events will examine a range of themes including breaking bad news to patients, behavioural ethics in healthcare, and the rising cost of indemnity.

PORT ELIZABETH

JOHANNESBURG

DURBAN

CAPE TOWN Wednesday 18 October 2017 17.30 – 21.30 Cape Town International Convention Centre

THURSDAY

OCTOBER

SATURDAY

OCTOBER

SUNDAY

OCTOBER

WEDNESDAY

OCTOBER

Thursday 12 October 2017 17.30 – 21.30 Boardwalk Hotel Saturday 14 October 2017 08.30 – 13.00 The Wanderers Sunday 15 October 2017 08.30 – 13.00 Southern Sun Elangeni & Maharani Hotel

The Medical Protection Society Limited (“MPS”) is a company limited by guarantee registered in England with company number 36142 at Level 19, The Shard, 32 London Bridge Street, London, SE1 9SG. MPS is not an insurance company. All the benefits of membership of MPS are discretionary as set out in the Memorandum and Articles of Association. MPS® and Medical Protection® are registered trademarks.

6519 Setting the Record Straight (SAMA Insider).indd 1

6519:07/17

medicalprotection.org/ethicsforall

14/07/2017 12:38

CORRESPONDENCE

providing information on Twitter would, as Kubheka suggests, likely avoid answering the first question directly. Rather, they would more probably provide information about the risks and benefits of these drugs. So apprised, the patient is better able to make an informed decision about what form of medical therapy is likely to be best. When patients do seek medical care, they do so explicitly by asking for a medical appointment, indicating that they wish to establish a conventional doctor-patient relationship following the conventional channels. Thirdly, Twitter is almost instantly self-correcting. Incorrect advice posted on Twitter will almost immediately be challenged by those whose experience or expertise suggests the information in a tweet to be incorrect. This is a key value of this very public medium of information sharing. My HPCSA case provided an excellent example of this. Within minutes of my disputed tweet going live, two dietitians had expressed the opinion that my advice was wrong, and had offered alternative options. The person who had posted the original tweet now had a range of options to consider, as is the desirable outcome in this public form of information sharing.

Fourthly, the use of social media has democratised the delivery of medical information, a critical point to which medical professionals will need to adapt if they wish to attract and retain social-mediasavvy patients. Importantly, social media publicises in a very open way those therapeutic interventions that either do or do not work. Essentially, there is no place for failed therapies or charlatan activities to hide on social media. Naturally, this is challenging for those taught to believe that registered medical practitioners are the sole source of credible medical information and advice, provided only as part of a conventional doctor-patient consultation. T D Noakes Retired. The Noakes Foundation, Bergvliet, Cape Town, South Africa Noakes@iafrica.com @ProfTimNoakes 1. Kubheka B. Ethical and legal perspectives on use of social media by health professionals in South Africa. S Afr Med J 2017;107(5):386-389. https://doi.org/10.7196/SAMJ.2017.v107i5.12047

S Afr Med J 2017;107(9):724. DOI:10.7196/SAMJ.2017.v107i9.12709

September 2017, Print edition

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

IZINDABA

30 days in medicine Increasing emergence of drugresistant gonorrhoea

New data from 77 countries show that gonorrhoea is becoming increasingly resistant to treatment, and high-income countries in particular are reporting infections that are impossible to treat. New data from the World Health Organization global gonococcal antimicrobial surveillance programme, which monitors trends in drug-resistant gonorrhea, were published in PloS Medicine. Nearly all countries (97%) that report data found strains resistant to ciprofloxacin and 81% of countries reported increasing resistance to azithromycin. Even more worrying, 66% of countries reported the emergence of strains resistant to the current last-resort treatment, extended-spectrum cephalosporins (ESCs), oral cefixime or injectable ceftriaxone. In addition, three countries – Japan, France and Spain – reported gonorrhoea superbugs. Although most verified treatment failures are from high-income countries, this is probably a reflection of surveillance levels in resource-poor countries and may not reflect the true burden of ESC treatment failure. Wi T, Lahra MM, Ndowa F, et al. Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action. PLoS Med 2017;358:e1002344. https://doi.org/10.1371/journal. pmed.1002344

Reduced radiotherapy effective in treatment of early breast cancer

Radiotherapy targeted to the original tumour site or a lower dose to the whole breast is associated with similiar low rates of local tumour recurrence as standard radiotherapy to the whole breast and fewer longterm adverse effects in women treated for early breast cancer, according to a large randomised trial in the UK, published recently in The Lancet. The study randomised 2 016 women who had undergone breastconserving surgery for early breast cancer to three radiotherapy treatment groups: standard 40 Gy whole-breast radiotherapy, a reduced regimen of 36 Gy to the whole breast, and 40 Gy to the tumour site only. Radiotherapy was given in 15 daily fractions. After a median follow-up of just over 6 years, local relapse occurred in 9 patients (1%) given whole breast radiotherapy, in 3 (<1%) of those treated with reduced-dose radiotherapy and in 6 (1%) of those given radiotherapy to the tumour site only.

The 5-year estimated cumulative incidence of local relapse was 1.1% (95% confidence interval (CI) 0.5 - 2.3) in the whole-breast radiotherapy group, 0.2% (95% CI 0.02 - 1.2%) in the reduceddose group, and 0.5% (95% CI 0.2 - 1.4%) in the partial-breast radiotherapy group. Clinical, photographic and patient assessments showed similar rates of adverse effects after reduced-dose or partial-breast radiotherapy, with changes in breast appearance and breast hardness being significantly lower than with whole-breast radiotherapy. Coles CE, Griffin CL, Kirby AM, et al. Partial breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5 year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017 (epub 2 August 2017). https://doi.org/10.1016/S01406736(17)31145-5

Labile blood pressure associated with higher risk of dementia

Labile blood pressure may raise the risk of dementia, according to research published in Circulation. In the study, more than 1 600 Japanese adults without dementia, with an average age of 71 years, were asked to measure their blood pressure at home for a month. More than half the study participants were women. Participants measured their blood pressure three times in the morning before eating breakfast or taking medication. Participants included normotensives and hypertensives, 40% of whom were taking medication for hypertension. Researchers reviewed the blood pressure readings, conducted cognitive testing to uncover early dementia, and reviewed records for occurrence of stroke. In 5 years of follow-up, 134 participants developed Alzheimer’s disease and 47 developed vascular dementia. Those with the highest variability in systolic blood pressure were more than twice as likely to develop any type of dementia or Alzheimer’s disease, and nearly three times as likely to develop vascular dementia. Oishi E, Ohara T, Sakata S, et al. Day-to-day blood pressure variability and risk of dementia in a general Japanese elderly population. Circulation 2017;136(6):516-525. https://doi.org/10.1161/ CIRCULATIONAHA.116.025667

B Farham Editor ugqirha@iafrica.com

BOOK REVIEW Textbook of Global Health

By A-E Birn, Y Pillay and T H Holtz. 4th ed. New York: Oxford University Press, 2017. ISBN: 9780199392285 Coinciding with a renewed focus on health needs and disease in the global south, the Millennium Development Goal era saw the emergence and widespread use of the term ‘global health’. The term has been associated with greatly increased funding flows and the mobilisation of a panoply of individual and institutional actors under the banner of global health. But what exactly does ‘global health’ mean? Definitional debates have

abounded, centred particularly in northern academic public health institutions, where departments and programmes in global health have become the norm. In 2008, Stuckler and McKee[1] suggested that global health is in fact a malleable metaphor, describing and legitimising a wide variety of practices, rather than a single concept. Therefore, for some, global health is really another name for international health, which itself was a recasting of tropical medicine (and colonial medicine before that). For others, it is about the agenda of global security in the face of new threats such as the Ebola or Zika viruses, or the architecture of global players (whether the

September 2017, Print edition

SAMF

Guidance

ribing

on Presc

and ry Tract Alimentaism ol b Meta g -Formin nd Blood Blood a s Organ stem scular Sy Cardiova logicals

Dermato

d stem an rinary Sy Genitou mones Sex Hor al Hormon Systemictions ra a p re P r ctives fo Anti-Infe Generalic Use em st Sy nd plastic a gents Antineo omodulating A Immun em Syst skeletal Musculo System Nervous Central ducts sitic Pro Antipara em tory Syst

iation, ical Assoc an Med lishing Group, 40 ic fr A th 0 b The Sou nd Medical Pu ge, Pretoria 0 Health a 9, Lynnwood Rid 7478 X-XX-X PO Box 8-1-XXXXX ISBN 97

Respira

Sensory

Organs

Media Contrast

F M SA

frican South A nes Medici ry Formula

frican South A ormulary es F Medicin

ines n Medic ritten w th Africa The Sou researched and Clinical n of ry is Formula rs of the Divisio ersity of niv be by mem cology of the U tion with Pharma n, in collabora als. n w Cape To care professio health ican outh Afr by the S e formulary d e sh li b th Pu on, rmacists, Associati Medical at doctors, pha concerned d rs e e im th a is e and o -effectiv dentists nurses, e safe and cost ines. ic th d h e it m w ing of prescrib

12th n Editio

n Edity oiftCaipeoTown’se h t 2 1ve of the Univers mcology and th ,

itiati roup l Phara A joint in ision of Clinica al Publishing G on. Div ociati Medic ss d A n l a a h ic d Healt ican Me outh Afr for the S rs e sh li b pu

oning

t of Pois

Treatmen

The REFERENCE MEDICAL REFERENCE ESSENTIAL MEDICAL The ESSENTIAL for professional! healthcare professional! every healthcare for every

The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the University of Cape Town’s Division of Clinical Pharmacologyyand the Health and Medical Publishing Group, University of Cape Town’s Division of Clinical Pharmacolog and the Health and Medical Publishing Group, publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines. 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

Go to www.samf12.org to download the order form or contact

Smith DianeSmith Please direct all order queries to:Diane Medical and Health Health and Medical Group Publishing Publishing Group

2069 4812069 012481 Tel:012 Tel: dianes@hmpg.co.za Email:dianes@hmpg.co.za Email: order dispatchofoforder postedonondispatch invoicetotobebeposted Taxinvoice Tax

IZINDABA

World Health Organization (WHO) or the Bill and Melinda Gates Foundation) seeking to influence health developments across the globe.[2] In the context of these multiple meanings, the Textbook of Global Health is a highly welcome and significant arrival. Written from a refreshingly critical ‘political economy’ perspective that is often absent in discourse on global health, it provides the most coherent and systematic framing of the field currently available to scholars and practitioners. Reflecting shifts in thinking and terminology, the textbook is an update of the 2009 3rd edition, which was entitled Textbook of International Health. A full chapter is devoted to outlining the continuities and differences between international and global health, while another provides an overview of current global health actors and activities. As with previous editions, the textbook properly locates contemporary global health in a longer history of changing world orders, stretching back to colonialism, and the rise of agencies such as the WHO post-World War II. Within this clear overarching framework, the book then addresses all the major themes of global health: global patterns of disease, equity and social determinants of health, globalisation, trade and health, the rise of humanitarianism, climate change, health systems and health financing. It concludes with chapters on ‘building healthy societies’ and social-justice approaches to global health, inviting

readers to consider ‘how the world order might be reimagined and rearranged’. It is a weighty tome of 712 pages, and each of the themes is dealt with expertly and thoroughly. From a pedagogical point of view, the chapters are laid out sequentially as a course on global health, and include key questions and lessons. While such courses are, in reality, unusual in South Africa (SA) or the region, individual chapters will be very useful for general public health programmes and for courses on globalisation and health. One of the three co-authors is Dr Yogan Pillay, deputy director-general in the National Department of Health, and the approaches and content of the textbook will resonate with many in SA. I highly recommend the Textbook of Global Health as an incredible resource for educators, researchers and practitioners concerned with situating their work in a wider global reality. Helen Schneider School of Public Health, University of the Western Cape, South Africa hschneider@uwc.ac.za 1. Stuckler D, McKee M. Five metaphors about global-health policy. Lancet 2008;372(9633):95-96. https://doi.org/10.1016/S0140-6736(08)61013-2 2. Sheikh K, Schneider H, Agyepong IA, Lehmann U, Gilson L. Boundary-spanning: Reflections on the principles and practice of global health. BMJ Glob Health 2016;1:e000058. https://doi.org/10.1136/ bmjgh-2016-000058

OBITUARY Ian Wark Simson (1 July 1930 - 25 May 2017)

Prof. Ian Simson passed away unexpectedly on 25 May 2017 at his home in Howick, KwaZulu-Natal, at the age of 86 years. Ian was born in Johannesburg on 1 July 1930. After matriculating at Hilton College, Natal, in 1947, he returned to Johannesburg to study at the University of the Witwatersrand, where he obtained the MB BCh degree in 1953 followed by an MD in 1961. Later he was also awarded Fellowship of the Royal College of Pathology (London).

Ian did his clinical training as intern and senior houseman at Baragwanath, Johannesburg and Coronation hospitals. Following in his father’s footsteps, he started his career as a junior pathologist at the South African Institute for Medical Research. In 1958 he moved to the University of Pretoria, where he spent his professional career as a pathologist in the Institute of Pathology until his retirement. When the head of the Department of Anatomical Pathology, Prof. James Barnetson, retired in 1970, Ian was appointed as head, a position that he held with distinction for the next 25 years. Ian was a dedicated pathologist who served the profession in many ways. He was an excellent diagnostic pathologist and teacher and a renowned researcher, and served many committees, registries and societies. He was president of the South African Society of Pathologists, president of the South African Division of the International Academy of Pathology, chairman of the National Cancer Registry and chairman of the Asbestos Tumour Reference Panel, to mention just a few. As a teacher, Ian will be remembered for his excellent and inspiring lectures and

September 2017, Print edition

his strict but fair evaluation of candidates in exams. An extraordinary observer and legendary morphologist, he was respected for his clinical insights and his correlation of clinical and pathological findings. He had an extremely wide interest in all aspects of pathology, but a very special interest in liver pathology. This was reflected in several chapters that he wrote in wellknown books on liver pathology, and also in books on tropical pathology. He had at least 72 publications to his credit, but will be remembered best for those in the field of liver pathology. Ian was a keen golfer and photographer, and loved fly fishing. He is survived by his wife Pam, children Michael, Peter and Fiona, and eight grandchildren. His legacy will live on among his students, colleagues and friends.

Leonora Dreyer Emeritus professor and former head, Department of Anatomical Pathology, University of Pretoria, South Africa leonora.dreyer@gmail.com

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

EDITORIAL

Work-based assessment: A critical element of specialist medical training In the recent Transactions, the Colleges of Medicine of South Africa (CMSA) states that work-based assessment (WBA) should be an essential part of an assessment system, alongside the national professional examination.[1] One of the main reasons for highlighting this topic is the fact that assessment enables our profession to demonstrate our accountability, and our commitment to reflecting professional practice standards, sustaining competence, improving performance and engaging in continuous quality improvement.[1,2] To this effect, most examiners would like WBA to be mandatory, because it would be a means of informing the supervisor’s report for MMed and Fellowship degrees, as well as an opportunity to oblige the registrars to receive feedback, and to reflect and develop. A registrar would have to demonstrate important skills such as professionalism and decision-making under compulsory supervision in real life. In some of our training platforms this valuable tool to promote active learning is already in place, and yet in some departments or institutions it is absent. Perhaps this inhomogeneous practice could explain the finger-pointing game about the examination standards and failure rate. Compulsory WBA could be used to identify, wherever possible, areas of practice where further learning should be focused. WBA should be able to support and contribute to summative assessment strategies that define successful achievement of curricular objectives, competence to entry into practice and continued competence in practice.[2] However, as stated in the CMSA message, colleagues have raised serious concerns about the utility of WBA for high-stakes summative assessment purposes, indicating that assessment tasks in the real world are unpredictable and inherently unstandardised, and therefore will not be equivalent across different hospitals and universities. This could pose a serious threat to the reliability and validity of assessment. There are also serious concerns about the subjectivity of assessments.[1] To address these challenges, the modernised approach to WBA makes a distinction between formative assessment (i.e. assessment for learning) and summative assessment (i.e. assessment of learning), and includes both measures. Furthermore, recent work has shown that the combination of several WBA tools, such as the mini-clinical-evaluation exercise, case-based discussion, objective structured assessments of technical skills and multisource feedback, in a portfolio, is a feasible and reliable method for high-stakes exams.[3,4] Of note is the fact that the new categorisation of WBA tools used by the Royal College of Obstetricians and Gynaecologists divides the WBA into formative encounters, referred to as ‘supervised learning events’, and summative encounters, referred to as ‘assessments of performance’ (Fig. 1).[1,3] With this approach, patients, registrars and examiners are all beneficiaries, as the formative WBA focuses on the provision of structured, mandatory feedback, while encouraging reflective practice by the registrar, and the summative WBA constitutes assessments of observed performance, which allow registrars to demonstrate competence. The summative encounters of the WBA, referred to as ‘assessments of performance’, will consider a model that consists of both local and external examiners, which will improve on validity, and therefore allow inclusion in the high-stakes exam. Therefore, the model could help to remove potential bias, as the assessments will be conducted in consultation with the CMSA and SA Committee of Medical Deans (SACOMD). In part, this will also address the fact that universities have to fulfil the mandate to conduct the assessment for the MMed, in addition to the compulsory high-stakes national professional examination (singleexit examination) that is run by the CMSA. Furthermore, since the formative encounters of WBA aim to identify the registrar’s areas of strength and development, and the summative encounters of WBA

Formative assessments (SLEs) Assessment for learning • Formal quality feedback • Reflective practice Part of this e-portfolio for discussion at educational supervisor meetings, and will not be accessed by CMSA

Summative assessments (AoPs)

CbD Mini-CEX OSATS MSF

Assessment of learning OSATS

• Part of the summative process • Measures of competence Part of this e-portfolio for contribution to the high-stakes exams, and will be accessed by CMSA

AoPs = assessments of performance; CbD = case-based discussion; Mini-CEX = mini-clinical-evaluation exercise; MSF = multisource feedback; OSATS = objective structured assessments of technical skills; SLEs = supervised learning events Adapted by author from Parry-Smith W, Mahmud A, Landau A, Hayes K. Workplace-based assessment: A new approach to existing tools. Obstertrician Gynaecol 2014;16:281-285

Fig. 1. Shows proposed modified WBA tools that divide the WBA into formative encounters, referred to as ‘Supervised Learning Events’ (or SLES), and summative encounters; referred to as ‘assessments of performance’ (or AoPs).

aim to determine fitness to progress, this will help to address the issues of standards and failure rates. Of importance is that WBA will be able to assess the ‘does’ level in Millar’s prism of clinical competence, and therefore demonstrate mastery.[5,6] Fortunately, the modified approach still emboldening the philosophy which underpins WBA is the assessment of several domains by multiple assessors over a period of time, with feedback built into each encounter.[7] Excitingly, WBA is an opportunity to develop skills of self-awareness for registrars, as well as a tool to identify and monitor struggling registrars. Clearly the development of such an assessment system must consider and overcome a number of implementation barriers, including assessment fatigue.[8] Therefore, in order for WBA to be successful, the CMSA should ensure that WBA is relevant to professional practice, and provides feedback to promote personal or collective reflection on competence or performance. Additionally, the proposed meaningful partnership between the CMSA and SACOMD should make participation in WBA a mandatory programme requirement that is linked to progression through training, as well as an accreditation standard for training platforms.[2] WBA tools, when combined in a registrar’s e-portfolio to create a central and integrating concept whose purpose is both formative (educational) and summative (high stakes), are a means of planning and implementing lifelong learning to enhance performance, improve quality of care and enhance the effectiveness of our health systems.[1-3] M M Sathekge The Colleges of Medicine of South Africa, Cape Town, South Africa; Department of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, South Africa; and Steve Biko Academic Hospital, Pretoria, South Africa mike.sathekge@up.ac.za 1. Sathekge M. Time to review the contribution of work-based assessment in our high-stakes exams. Transactions 2017;61(1):4-5. https://www.cmsa.co.za/view_document_list.aspx?Keyword=Transactions (accessed 5 June 2017). 2. Watters DA, Campbell G, Crebbin W, Hickey K, Stokes ML. Work-based assessment: A practical guide. Melbourne: Tripartite Alliance (RACP, RACS, RACPSC), 2014. https://www.surgeons.org/ media/20786937/bkt_tripartite_wba__march_7__2_.pdf (accessed 4 May 2017). 3. Parry-Smith W, Mahmud A, Landau A, Hayes K. Workplace-based assessment: A new approach to existing tools. Obstetrician Gynaecol 2014;16:281-285. https://doi.org/10.1111/tog.12133 4. Govaerts M, van der Vleuten C. Validity in the work-based assessment: Expanding our horizons. Med Educ 2013;47(12):1164-1174. https://doi.org/10.1111/medu.12289 5. Miller GE. The assessment of clinical skills/competence/performance. Acad Med 1990;65(Suppl 9):S63-S67. 6. Norcini J, Burch V. Workplace-based assessment as an educational tool: AMEE Guide No. 31. Med Teach 2007;29(9):855-871. https://doi.org/10.1080/01421590701775453 7. Nair BR, Hensley MJ, Parvathy MS, et al. A systematic approach to workplace-based assessment for international medical graduates. Med J Aust 2012;196(6):399-402. https://doi.org/10.5694/mja11.10709 8. Van der Vleuten CP, Schuwirth LW, Scheele F, et al. The assessment of professional competence: building blocks for theory development. Best Pract Res Clin Obstet Gynaecol 2010;24(6):703-719. https://doi. org/10.1016/j.bpobgyn.2010.04.001

S Afr Med J 2017;107(9):728. DOI:10.7196/SAMJ.2017.v107i9.12655

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CME

GUEST EDITORIAL

Chronic kidney disease In the USA, the proportion of the population with chronic kidney disease (CKD) reached 15% by 2017.[1] In South Africa (SA), this figure may well be higher. CKD management in the developed world aims at the apex of the triangle, e.g. improvements in dialysis and transplantation, as well as the mid-triangle area, i.e. strategies in slowing the progression to end-stage renal disease. In SA, however, the huge costs of dialysis and transplantation dictate that our CKD management should first and foremost be aimed at prevention and, secondly, at renoprotection. The review presented in the CME section of SAMJ[2] highlights recent information relating to the use of metformin in the management of diabetes in patients with CKD, the essential and early treatment of CKD acidosis (i.e. estimated glomerular filtration rate (eGFR) ≤59 mL/min), early dietary therapy, early lowering of serum uric acid and the introduction of adequate and ongoing exercise – all aimed at slowing the progression of CKD. Furthermore, the use of high-dose statins in preventing cyst growth and eventual renal failure in patients with autosomal-dominant polycystic disease is explained. One development not mentioned in the review, is the pivotal importance of vitamin D metabolism and secondary hyperparathyroidism (sHPT) in renoprotection. Effective treatment of sHPT significantly reduces the risk of myocardial infarction, stroke and heart failure; therefore, correct management is essential. This is discussed in an article by Friedl and Zitt[3] on vitamin D prohormone in the treatment of sHPT in patients with CKD. Early in CKD (stage 2), the osteocyte begins to produce increased levels of fibroblast growth factor 23 (FGF23), and by CKD stages 3a and 3b the levels are >1 000 times increased. With every decrement of the GFR, phosphate retention would tend to occur, but is offset by an even higher secretion of FGF23. Given the inexorable fall in GFR, sooner or later the serum phosphate will be permanently increased. A reduction in dietary phosphate ingestion is mandatory for all patients with CKD stage 3 and onwards. Sunlight converts epidermal vitamin D2 into inactive vitamin D3 (calciferol), which is stored in the liver. However, large quantities are also stored in adipose tissue of obese persons. Low levels of circulating vitamin D3 are commonly found in CKD stage 3a onwards, especially in overweight patients. FGF23 inhibition of the reabsorption of tubular phosphate results in intermittent hypophosphataemia, which occurs early on in CKD. Moreover, the increased FGF23 markedly inhibits the action of the proximal tubular 1α-hydroxylase enzyme responsible

for the conversion of calciferol to calcitriol (1,25(OH)2D3). Low levels of active vitamin D3 result in a marked decrease in the absorption of dietary calcium, resulting in intermittent hypocalcaemia and sHPT. Prevention of sHPT should start early, when the eGFR is ≤60 mL/min. Early administration of calcitriol has resulted in accelerated coronary and carotid artery calcification. However, the administration of relatively large doses of calciferol (20 000 - 30 000 IU weekly) on a permanent basis is safe, and will not lead to hypercalcaemia or metastatic vascular calcification. The extent to which this strategy is effective in preventing sHPT is still a matter of debate, but does form part of the most recent recommendations.[4] Calcitriol in a dose of 0.25 µg/day should be introduced only when the eGFR has decreased to <20 mL/min. Finally, it is in the hands of our general practitioners and primary healthcare workers to diagnose CKD early and to either introduce adequate therapy or to refer early. Future government support for a prevention programme is also absolutely essential, but is currently not provided for. A M Meyers National Kidney Foundation of South Africa, Johannesburg; School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Faculty Practice Centre, Donald Gordon Medical Centre, Johannesburg; and Renal Dialysis Unit, Klerksdorp Hospital, South Africa nkfsa@mweb.co.za 1. Henriques C. New CDC infographic shows 1 in 7 Americans now have chronic kidney disease. https://ckdnews/2017/06/07/chronic-kidney-diseases-now-affects-1in-7-us-adults-according-to-cdcinfopraphic/ (accessed 8 August 2017). 2. Meyers AM, Davies M. Recent important strategies in the management of chronic kidney diseases. S Afr Med J 2017;107(9):730-733. https://doi.org/10.7196/SAMJ.2017.v107i9.12366 3. Friedl C, Zitt E. Vitamin D prohormone in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Int J Nephrol Renovasc Dis 2017;10:109-122. https://doi.org/10.2147/IJNRD. S97637 4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;(Suppl 3):1-150. https://doi.org/10.1038/kisup.2012.76

S Afr Med J 2017;107(9):729. DOI:10.7196/SAMJ.2017.v107i9.12785

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CME

Recent important strategies in the management of chronic kidney disease A M Meyers,1 MB BCh, FCP (SA), FRCP (Lond), Cert Nephrology (SA) Phys; M Davies,2 MB BCh, FCP (SA), Cert Nephrology (SA) Phys National Kidney Foundation of South Africa, Johannesburg; School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Faculty Practice Centre, Donald Gordon Medical Centre, Johannesburg; and Renal Dialysis Unit, Klerksdorp Hospital, South Africa 2 Division of Nephrology, Charlotte Maxeke Johannesburg Academic Hospital; and School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: A M Meyers (nkfsa@mweb.co.za)

The burden of chronic kidney disease (CKD) is considerably higher in low- and middle-income countries, which are less able than the developed world to cope with treating advanced renal failure owing to financial constraints. Prevention, early diagnosis and implementation of existing knowledge can improve outcomes. This review presents several recent advances to assist with avoiding and slowing down CKD progression and reducing common comorbid complications. The following are discussed: the possible use of metformin in patients with type 2 diabetes-related CKD; recent inexpensive important developments in the treatment of autosomal-dominant polycystic kidney disease; prevention of acidosis and the early dietary reduction of red meat consumption; and the therapeutic lowering of uric acid in persistent hyperuricaemia. Finally, an active and monitored exercise programme should be undertaken whenever possible. All of these recommendations have been shown to significantly slow the progression of CKD and increase cardiovascular protection. S Afr Med J 2017;107(9):730-733. DOI:10.7196/SAMJ.2017.v107i9.12366

The global burden of non-communicable diseases (NCDs) is of grave concern and has recently been highlighted by the World Health Organization (WHO) and a plethora of publications in prominent journals.[1-3] Chronic kidney disease (CKD) has often been indicated as a major contributing factor to this burden, especially in low- and middle-income countries.[4] Initial figures stated that CKD was present in 10% of the world’s population. Recently, this figure has risen to 14% in the USA, and by 2030, 27% of North Americans >30 years of age are predicted to have CKD.[4] An added burden to the recent number of people with CKD >45 years old will be markedly increased, taking into consideration that the estimated glomerular filtration rate (eGFR) decreases by 0.75 - 1.00 mL/min and, for example, 50% of UK children born in 2007 will live to the age of 103 years.[5] Although no figures for CKD are available in South Africa (SA), it is highly likely that these will be higher in the majority of the SA public, given that end-stage renal failure (ESRF) (CKD stage 5) is 3 - 4 times more prevalent in Afro-Americans.[6] Mayosi et al.[7] have shown that chronic renal failure (CRF) was the fifth most common cause of death in SA in 2006. The graph depicted in their article refers to deaths from nephritis/nephrosis only; therefore, the figure would probably have been much higher on the list if other causes of ‘renal death’, i.e. ESRF, were included. Permutations on how to prevent, diagnose, effectively treat and slow progression to ESRF, published in the CME section of the March and April 2015 editions of the SAMJ, were supported by a guest editorial written by the Minister of Health, Dr A Motsoaledi.[8-10] This was followed by a ministerial summit held in Ekurhuleni in March 2015 on how to handle the burden of CKD in our resource-limited country. An additional burden is that the 2014 Renal Registry reported that 9.3% of all patients with ESRD on dialysis are HIV-positive. We believe that prevention, early detection and significantly slowing the progression of renal functional deterioration are of pivotal importance. The guidelines on how to achieve these skills are well illustrated in the SAMJ CME articles and in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for CKD[11] (the latter are

currently being reviewed, specifically for low- and middle-income countries). We urge all relevant health personnel in the public, private and government sectors to read these guidelines. To clarify the classification of CKD, a simplified version is shown in Table 1. As ˂10% of the calculated potential sufferers of ESRF in the public sector of SA are able to receive renal replacement therapy (RRT), prevention strategies demand the utmost attention and are of essential importance in all healthcare protocols. Since the publication of the guideline of the National Kidney Foundation of South Africa (NKFSA), various new avenues for prevention/slowing progression have come to light. The six ‘caveats’, which form the basis of this article, are shown in Table 2 and are discussed in that order.

Diabetes and metformin

Metformin (MF) must be regarded as the gold standard of treatment in patients with type 2 diabetes mellitus (DM).[12] Its advantages are shown in Table 3. Of particular relevance is the continually increasing number of patients ˂50 years of age diagnosed with diabetes. In Table 1. Clinical stages of chronic kidney disease Stage

Glomerular filtration rate (mL/min)

Comments

CKD 1

90 - 110

Normal function

CKD 2

60 - 89

Asymptomatic

CKD 3a

45 - 59

Subclinical symptoms

CKD 3b

30 - 44

Mild clinical symptoms

CKD 4

15 - 29

Moderate to severe symptoms

CKD 5

<15

At or nearly at ESRF

CKD = chronic kidney disease; ESRF = end-stage renal failure.

September 2017, Print edition

CME

Table 2. Recent advances in slowing the progression of chronic kidney disease

Table 4. Factors precipitating lactic acidosis in patients with type 2 diabetes mellitus

Modality

Method and mode of functional stabilisation

Type 2 diabetes

Safety data on the use of MF in diabetes in CKD stages

ADPKD

Slowing CKD with statin therapy

Acidosis

Early treatment of mild acidosis using bicarbonate (oral)

Gut metabolites

TMAO in CKD reduced by red meat avoidance from CKD stage 3b onwards

• • • • • • • •

Uric acid

Allopurinol to slow down progression from CKD stage 3b onwards

Exercise

From CKD stage 3 onwards

CKD = chronic kidney disease; MF = metformin; ADPKD = autosomal-dominant polycystic kidney disease; TMAO = trimethylamine N-oxide.

Table 3. Advantages of metformin • Excellent absorption and widespread distribution • Increases intracellular glucose uptake, especially in muscular tissue • Decreases insulin resistance • Decreases hepatic glycogenolysis • Decreases appetite • Decreases the intensity of diabetic macro- and microvascular disease and thereby prevents/slows cardiovascular complications of diabetes • Does not cause hypoglycaemia • Improves quality of life • Moderate lowering effect on low-density lipoprotein cholesterol and triglycerides • Inexpensive

addition to the multiple cardiovascular and renal complications of DM, renal dysfunction in the elderly is further compounded by the slow but progressive fall in glomerular filtration rate (GFR) in persons >45 years of age (i.e. ±1 mL/min/year) and also because people live longer. For many years the US Food and Drug Administration (FDA), the Regulatory Cooperation Council (RCC) in Canada and other regulatory bodies have indicated that the use of MF is contraindicated in patients with mild and moderate CKD (stages 3a and 3b) owing to the rarely reported but life-threatening complication of lactic acidosis (LA) (serum lactate levels ≥15 mmol/L). That LA does not occur in patients who receive MF, with an estimated GFR (eGFR) of 50 - 30 mL/min., has been indicated in studies conducted by Inzucchi et al.[13] They showed that MF can be safely used in these patients, provided that certain guidelines are always followed. A Cochrane meta-analysis conducted on 47 096 patients with a follow-up of 86 067 patient-years compared the incidence of LA in patients who received MF with those who did not, irrespective of the eGFR.[14] They found that for the upper limit of 95% confidence the true incidence of LA was 6.3/100 000 patient-years for the MF group and 7.8/100 000 patient-years for the non-MF group. It is important to remember that before prescribing MF for any degree of renal function, certain rules are essential and must be fully adhered to. As many practitioners are either unaware or uncertain of the predisposing conditions, these are set out in Table 4. Mechanisms of MF-associated LA are not well elucidated, but include conversion of glucose to lactate in the splanchnic bed and inhibition of hepatic gluconeogenesis (i.e. from lactate, pyruvate and adenine).[15,16]

Cardiac failure Myocardial infarction Hepatic failure Any hypoxic state Clinical dehydration Shock (especially septic shock) Severe sepsis and haemodynamic instability Major surgery

It is essential that any patient with the abovementioned precipitating disorders is instructed to immediately but temporarily withdraw the use of MF and present to a doctor. Patients have to be instructed in writing of the abovementioned dangers. If the warnings are adhered to, it is uncertain whether even CKD stage 4 or 5 per se could cause LA. However, it still remains preferable to avoid MF in the abovementioned patient cohorts until further information is available. Of note, to date only 4 patients with ESRF on peritoneal dialysis, who were on MF, have developed LA. Three of the 4 had LA-precipitating factors, as mentioned in Table 4.[17] The dialysate in continuous ambulatory peritoneal dialysis (CAPD) contains lactate that may predispose to LA, even in the presence of normal hepatic function; it is a definite contraindication to the use of MF. A literature search on LA in haemodialysis (HD) yielded no data, probably because of non-usage of MF. However, HD utilises a bicarbonate buffer in the dialysate and, therefore, carefully conducted research into MF use may be of value. The reason for emphasising the use of MF in CKD relates to both its immense value in glucose control in DM and to the necessity of slowing/preventing progression of both ESRF and cardiovascular disease (CVD) complications in a country with limited resources for the adequate funding of RRT. The last important consideration is that for many reasons patients with CKD stage 4 or 5 or those on dialysis commonly exhibit widely fluctuating glucose levels. Hypoglycaemia is extremely common, not only in patients receiving insulin but also because of drug accumulation in those on oral antidiabetic drugs. Dipeptidyl peptidase-4 inhibitors (i.e. incretins) together with basal long-acting insulin would be the safest in the case of HD.[18] The addition of MF would need to be carefully studied, if considered. Also to be noted in the treatment of diabetes is the development of a novel, potentially life-saving, antidiabetic class of drug, the sodiumglucose cotransporter-2 (SGLT-2) inhibitors.[19] These drugs block the proximal tubular reabsorption of glucose, leading to glycosuria. It also results in increased sodium loss. Other beneficial effects described were: (i) excellent diabetic control; (ii) no side-effects and very well tolerated; (iii) marked reduction in hypertension and vascular morbidity; and (iv) significant renoprotection. If used early on in the disease, it could theoretically prevent most of the comorbid vascular and renal effects of sub-optimally treated type 2 diabetes. The first of this new class of drug has recently been registered in SA, i.e. empagliflozin.

Autosomal-dominant polycystic kidney disease

It has been reported that autosomal-dominant polycystic kidney disease (ADPKD) occurs in ~1:1 000 people.[20] The AD in ADPKD has been changed from adult to autosomal-dominant because the disease can manifest not only in childhood, but even in utero.[21,22] In an excellent and recent review of genetics and pathogenetic mechanisms of cyst formation, clinical and diagnostic investigation parameters

September 2017, Print edition

CME

and recent treatments, Mochizuki et al.[20] outlined several potential therapies for ADPKD. Tolvaptan and the vasopressin V2-receptor antagonists that inhibit cyst and kidney volume growth have been shown to be of value in the treatment of ADPKD. However, the effects are partial, there are many side-effects and the agents would probably be prohibitively expensive in SA. Likewise, somatostatin (octreotide) and the mammalian target of rapamycin (mTOR) inhibitor rapamycin have been used, but with limited or disappointing results, and are also excessively expensive.[20,23] Cadnapaphornchai et al.[24] recently reported on the prevention of a reduction in kidney volume and cyst growth, which was accompanied by kidney functional stability, using pravastatin in children and adults, with striking results. The use of statins is not new and both experimental and clinical mechanisms of renal protection in ADPKD have previously been shown. The mechanisms underlying the effects of statins on renal structural protection are still speculative, but may be related to their ability to prevent synthesis of certain isoprenoids that prevent post-translational modification of proteins such as Ras and Rho. Their signal translation would be altered, affecting cell proliferation and polarity. The blockage of these isoprenoids would reduce formation and growth of kidney cysts. In addition, statins inhibit angiogenesis.[24] It would be interesting to investigate whether the production of glycogen synthase kinase-3β (GSK3β) is altered. GSK3β has recently been shown to play a role in ADPKD via induction of proliferation of cystic epithelial cells. The following recommendations have been suggested. All children from the age of ~10 years and all adults from ADPKD families should be screened using magnetic resonance imaging (MRI) or computed tomography (CT), but not renal ultrasound (due to the considerable number of negative results). High-dose statins must be administered, e.g. atorvastatin 40 - 80 mg or rosuvastatin 20 - 40 mg is probably preferable to pravastatin. Even at these doses, generics are inexpensive, but the usual side-effects should be monitored. It should be noted that statins have not been approved for use in ADPKD. The risks and benefits should be discussed with patients and relatives, and should include either signed parental or patient consent. In a disease that is responsible for 5 - 8% of all cases of ESRF, statins present a major and affordable preventive treatment in patients with ADPKD and constitute a significant advance in the management of these patients.

Acidosis

Recent studies have focused on the harm that small changes in the level of blood acidity can cause, even in patients with mild renal dysfunction (CKD stage 2). Łoniewski and Wesson[25] discuss various possible causes of renal damage caused by chronic acidosis, such as increased endothelin, aldosterone and angiotensin II production, inflammation and renal fibrosis. In support of the necessity to control acidosis, there are two further studies. Banerjee et al.[26] have clearly shown that dietinduced acid load is associated with increased risk of ESRF. They demonstrated that worsening of metabolic acidosis was highly significantly associated with a decrease in GFR and concluded that acidosis in CKD is independently associated with an increased risk of ESRF.[26] Secondly, a recent study from the University of Manchester, UK, showed that small changes in blood acidity are associated with an increase in parathyroid secretion, resulting in removal of calcium and phosphate from bones with arterial metastatic deposition.[27] The optimal NaHCO3 dose remains to be determined, but the current recommendations state a dose of 0.5 - 1.0 mmol of NaHCO3/kg body weight in three divided doses per day, i.e. 1 or 2 small salt spoons of baking soda three times a day with meals.

Many pathogenetic mechanisms in the progression of renal dysfunction associated with metabolic acidosis have been demonstrated, which mandates active and ongoing prevention of acidosis in patients with moderate to mild CKD. Of note is the recommendation that only sodium bicarbonate should be used, as agents such as sodium citrate could pose a threat of increased dietary aluminium absorption in patients with more advanced CKD, but who are not yet on dialysis.[28,29]

Gut bacterial by-products linked to CKD progression and CKD-associated cardiovascular disease

Recent studies have suggested involvement of gut bacteria in the generation of metabolites that display uraemic toxicity. Further experiments by Tang et al.[30] investigated the effects of gut microbial-dependent trimethylamine N-oxide (TMAO) in patients with CKD. Elevated TMAO plasma levels were demonstrated in patients with CKD and have been shown to contribute significantly to progressive renal fibrosis, CVD and poorer long-term survival. Studies in animals that were fed an increased content of TMAO in their diet confirmed a marked increase in renal fibrosis and dysfunction. Furthermore, in a cohort of people with normal renal function but on a high meat diet, the risk of microalbuminuria has been clearly demonstrated.[31,32] TMAO metabolites comprise choline, phosphatidylcholine (lecithin) and L-carnitine, and the levels are particularly high in red meat, liver, other meats and egg yolk. Lower levels are found in poultry. It is important to remember that choline is an essential nutrient that can be obtained from red meat, as well as from fish, poultry and eggs. Therefore, in recommending avoidance of or a stringent reduction in the ingestion of red meat and pork, one could reasonably anticipate that this will significantly slow renal functional decline even before the results of interventional studies are available. Two further strong theoretical points support the supposition that avoidance of red meat significantly reduces the hydrogen ion dietary load (discussed above). Red meats contain significantly more phosphate than poultry and fish. It is known that, because a decrease in renal phosphate clearance occurs early on in CKD, even a mild tendency to increase the body’s phosphate levels increases the production of fibroblast growth factor 23 (FGF23) and depresses the Klotho FGF23-receptor pathway.[33,34] This effect will result in a decrease in the activity of the renal tubular 1α-reductase enzyme, resulting in a significant reduction in the conversion of inactive vitamin D3 into active vitamin D3 (calcitriol). Therefore, less calcium will be absorbed in the gut, eventually resulting in hypocalcaemia and secondary hypoparathyroidism, which is a well-known factor in the genesis of progressive renal functional deterioration. Because of severe financial constraints in the treatment of advanced CKD in SA, it seems prudent to suggest this dietary advice in anyone with an eGFR of ≤50 mL/min.

Serum uric acid

Observational studies suggest that uric acid (UA) is an independent predictor of both progression of CKD and increased mortality from CVD. It has also been proposed that an elevated UA may have a role in initiating hypertension, nephrosclerosis and insulin resistance.[35-38] These are not new findings, but it is currently uncertain whether a raised UA acts as a nephrotoxin, vasculotoxin, or marker of a high acid-ash (protein) diet or reduced eGFR. Although trials have demonstrated slowing of CKD progression in patients treated with allopurinol, the numbers are limited. Both the KDIGO, USA, and

September 2017, Print edition

CME

the National Institute for Clinical Excellence (NICE), UK, do not recommend UA-lowering therapy. However, there is a plethora of experimental studies that support the notion that UA reduction may not only be renoprotective but may be important in reducing CVD mortality.[39] As CVD is a major risk factor in CKD, and as RRT is so limited, it would not seem unreasonable to recommend careful use of allopurinol in patients with asymptomatic hyperuricaemia from CKD stage 3 onwards, commencing when the UA level rises above the normal range. All dietary measures should be tried before administering allopurinol. In a key article, Kang and Nakagawa[38] stated that experimental data using hyperuricaemic animals and cultured cells provide robust evidence regarding hypertension, proteinuria, vascular disease and progressive renal scaring. Nevertheless, in 1984 Hande et al.[40] reported on severe allopurinol toxicity with fever, rash, eosinophilia and worsening of renal function in 78 patients with varying degrees of CKD. However, all 78 patients received concomitant thiazide diuretics for hypertension. Since that publication, rare cases of this syndrome have been reported in patients with CKD and normal renal function. It is considered as an idiosyncratic reaction that occurs very rarely. Our advice is to start allopurinol in small doses (e.g. 100 mg/day), monitor the patient and titrate up to produce an adequate UA-lowering effect if no toxicity is found. Furthermore, we would recommend that if a CKD patient is receiving a thiazide, allopurinol should be avoided.

Exercise

There are many studies investigating the effects of exercise in patients with CKD who are not on dialysis. The results are encouraging and have demonstrated multiple benefits in both slowing progression and reducing mortality (Table 5).[41] All exercise training programmes should be evaluated and supervised by trained medical personnel and the patient’s clinical status carefully evaluated before prescribing exercise. Table 5. Exercise and chronic kidney disease Type of exercise

Benefit

Resistance training

Decrease in CRP and IL-6

Swimming

Decrease in oxidative stress and BP, and increase in eGFR

General exercise

Improved VO2 max, BP and eGFR

CRP = C-reactive protein; IL-6 = interleukin 6; VO2 max = maximum volume of oxygen; BP = blood pressure; eGFR = estimated glomerular filtration rate.

Conclusion

As financial constraints in SA permit that only a fraction of public sector ESRF patients are able to receive RRT, it would be logical to use all safe mechanisms to slow progressive loss of GFR. Therefore, apart from the usual advice of smoking cessation, alcohol moderation, maintaining ideal body weight, avoiding nephrotoxins, maintaining blood pressure and blood sugar at target levels, and reducing proteinuria using well-known prescribed methods, we advise the use of all other possible but safe modalities to slow functional deterioration. The safe use of MF in CKD (excluding CKD stage 5), early screening and safe inexpensive treatment of patients with ADPKD, use of allopurinol in the absence of gout to decrease UA levels, treatment of acidosis and dietary and prescribed exercise programmes should be included in the list of progression-slowing procedures. Of note is that even this extended list indicates that changes in lifestyle as well as therapeutic measures should be employed.

1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: Global dimension and perspectives. Lancet 2013;382(9888):260-272. https://doi.org/10.1016/S0140-6736(13)60687-X 2. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int 2011;80(12):1258-1270. https://doi.org/10.1038/ki.2011.368 3. World Health Organization. Preventing Chronic Diseases: A Vital Investment. Geneva: WHO, 2005. 4. Hoerger TJ, Simpson SA, Yarnoff BO, et al. The future burden of CKD in the United States: A simulation model for the CDC CKD Initiative. Am J Kidney Dis 2015;65(3):403-411. https://doi.org/10.1053/j.ajkd.2014.09.023 5. Select Committee on Public Service and Demographic Change, House of Lords, London, UK. Ready for ageing? 2013. http://www.publications.parliament.uk/pa/ld201213/ldselect/ldpublic/140/14003. htm (accessed 4 April 2017). 6. World Kidney Day. Kidney health for all. 2015. www.worldkidneyday.org/resource/kidney-healthpress-release-2015/ (accessed 4 April 2017). 7. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet 2009;374(9693):934-947. https://doi.org/10.1016/S0140-6736(09)61087-4 8. Motsoaledi A. Chronic kidney disease. S Afr Med J 2015;105(4). https://doi.org/10.7196/samj.9620 9. Meyers AM, Assounga AG, Gerntholtz T, et al. Chronic kidney disease. S Afr Med J 2015;105(3):232-237. https://doi.org/10.7196/samj.9444/9412/9414/9417/9413 10. Meyers AM, Mahala B, Moosa MR, et al. Chronic kidney disease. S Afr Med J 2015;105(4):316-322. https://doi.org/10.7196/samj.9532/9535/9536/9537 11. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;(Suppl 3):1-150. https://doi.org/10.1038/kisup.2012.76 12. Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P. Metformin, the Gold Standard – A Scientific Handbook. Chichester, UK: John Wiley, 2007. 13. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: A systematic review. JAMA 2014;312(24):2668-2675. https://doi.org/10.1001/jama.2014.15298 14. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Systematic Review 2006;25(1):CD002967. https:// doi.org/10.1002/14651858.CD002967.pub2 15. Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992;105(4):1009-1013. https://doi.org/10.1111/j.1476-5381.1992.tb09093.x 16. Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: Mechanism of action and tolerability. Pharmacol Res 1994;30(3):187-228. https://doi.org/10.1016/1043-6618(94)80104-5 17. Almaleki N, Ashraf M, Hussein MM, Mohiuddin SA. Metformin-associated lactic acidosis in a peritoneal dialysis patient. Saudi J Kidney Dis Transpl 2015;26(2):325-328. https://doi.org/10.4103/1319-2442.152498 18. Perkovic V, Agarwal R, Fioretto P, et al. Management of patients with diabetes and CKD: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2016;90(6):1175-1183. https://doi.org/10.1016/j.kint.2016.09.010 19. Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 2017;28(1):368-375. https://doi.org/10.1681/ASN.2016030278 20. Mochizuki T, Tsuchiya K, Nitta K. Autosomal dominant polycystic kidney disease: Recent advances in pathogenesis and potential therapies. Clin Exp Nephrol 2013;17(3):317-326. https://doi.org/10.1007/ s10157-012-0741-0 21. Somlo S, Chapman AB. Autosomal dominant polycystic kidney disease. In: Schrier RW, Coffman TM, Falk RJ, Molitoris BA, Neilson EG. Schrier’s Diseases of the Kidney. 9th ed. Philadelphia, USA: Lippincott Williams & Wilkens, 2012:519-563. 22. MacDermot KD, Saggar-Malik AK, Economides DL, Jeffery S. Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD 1) presenting in utero and prognosis for very early onset disease. J Med Genet 1998;35(1):13-16. 23. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):2407-2418. https://doi.org/10.1056/NEJMoa1205511 24. Cadnapaphornchai MA, George DM, McFann K, et al. Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2014;9(5):889-896. https://doi.org/10.2215/CJN.08350813 25. Łoniewski I, Wesson DE. Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int 2014; 85(3):529-535. https://doi.org/10.1038/ki.2013.401 26. Banerjee T, Crews DC, Wesson DE, et al. High dietary acid load predicts ESRD among adults with CKD. J Am Soc Nephrol 2015;26(7):1693-1700. https://doi.org/10.1681/ASN.2014040332 27. Campion KL, McCormick WD, Warwicker J, et al. Pathophysiologic changes in extracellular ph modulate parathyroid calcium-sensing receptor activity and secretion via a histidine-independent mechanism. J Am Soc Nephrol 2015;26(9):2163-2171. https://doi.org/10.1681/ASN.2014070653 28. Nestel AW, Meyers AM, Paiker J, Rollin HB. Effect of calcium supplement preparation containing small amounts of citrate on the absorption of aluminium in normal subjects and in renal failure patients. Nephron 1994;8(2):197-201. 29. Meyers AM. Regarding mini-review on bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int 2015;87(6):1260-1261. https://doi.org/10.1038/ki.2015.81 30. Tang WH, Wang Z, Kennedy DJ, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 2015;116(3):448-455. https://doi.org/10.1161/CIRCRESAHA.116.305360 31. Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol 2014;9(3):399-410. https://doi.org/10.2217/fmb.13.165 32. Vaziri ND, Wong J, Pahl M, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int 2013;83(2):308-315. https://doi.org/10.1038/ki.2012.345 33. Saito T, Fukumoto S. Fibroblast growth factor 23 (FGF23) and disorders of phosphate metabolism. Int J Pediatr Endocrinol 2009;496-514. https://doi.org/10.1155/2009/496514 34. Wahl P, Wolf M. FGF23 in chronic kidney disease. Adv Exp Med Biol 2012;728:107-125. https://doi. org/10.1007/978-1-4614-0887-1_8 35. Zoccali C, Mallamaci F. Uric acid, hypertension, and cardiovascular and renal complications. Curr Hypertens Rep 2013;15(6):531-537. https://doi.org/10.1007/s11906-013-0391-y 36. Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47(1):51-59. https://doi. org/10.1053/j.ajkd.2005.10.006 37. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5(8):388-393. https://doi.org/10.2215/CJN.01580210 38. Kang DH, Nakagawa T. Uric acid and chronic renal disease: Possible implication of hyperuricemia on progression of renal disease. Semin Nephrol 2005;25(1):43-49. https://doi.org/10.1016/j.semne phrol.2004.10.001 39. Rekhraj S, Gandy SJ, Szwejkowski BR, et al. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol 2013;61(9):926-932. https://doi.org/10.1016/j. jacc.2012.09.066 40. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity – description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76(1):47-56. https://doi.org/10.1016/0002-9343(84)90743-5 41. Morishita Y, Nagata D. Strategies to improve physical activity by exercise training in patients with chronic kidney disease. Int J Nephrol Renovasc Dis 2015;8:19-24. https://doi.org/10.2147/IJNRD.S65702

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

CLINICAL UPDATE

Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test M E Mothibe,1 MSc (Med) (Pharmacology), N Dip Med Tech, PhD; E Osuch,2 MD, PhD, FCP (ACCP), MSc (Med) Pharmacol, Dip Fam Med; C P Kahler-Venter,2 MSc (Med) (Pharmacology), PhD 1 2

Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, South Africa Department of Pharmacology and Therapeutics, School of Medicine, Sefako Makgatho Health Sciences University, Pretoria, South Africa

Corresponding author: M E Mothibe (mamza.mothibe@smu.ac.za) Background. The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. Objective. To investigate the cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) using a qualitative rapid urinalysis assay. Methods. The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. Results. The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. Conclusion. An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused false-negative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests. S Afr Med J 2017;107(9):734-737. DOI:10.7196/SAMJ.2017.v107i9.12197

The prevalent use of African traditional medicine (ATM) by the general public in South Africa (SA) has been reported.[1] It has been documented that most people consult a traditional health practitioner before a primary health practitioner,[2] and may not disclose this fact during consultation with a healthcare provider. [3] As a result of commercialisation and marketing, some herbal medicines (HMs) are readily available over the counter, most of them being punted as immune boosters. The use of these commercial herbal medicines (CHMs) with modern packaging and marketing practices is said to be widespread in SA.[4] The National Department of Health in SA has made progress towards institutionalisation and regulation of traditional medicine,[5] but there are as yet no regulations that govern the labelling and packaging of CHMs used as ATM. Since these herbal mixtures have not been tested and validated, the effect of their presence on laboratory diagnostic tests is unknown. During the 2010 FIFA World Cup hosted in SA, a concern was raised that the use of ATMs extracted from local plants may have granted unfair advantage to soccer players who used them, as they may contain undetectable amounts of stimulants.[6] The officials were concerned that some herbal materials used may have produced compounds undetectable by the laboratory tests available at the time, while other products of the medicinal plants used may not have been included in the list of banned substances of the World Anti-Doping Agency (WADA). The only plants or plant-related compounds on

the official list of WADA are cannabis, cocaine and ephedra, and they are listed as stimulants.[6,7] There are no listed compounds related to ATM. However, there could be more issues concerning the use of HMs by sportspeople. The HMs may have properties similar to some banned substances, so that when tested, a sportsperson could unknowingly test positive for banned substances. Common substances known to cause false-positive results on urine screening tests for drugs of abuse (DoA) include the Vicks inhaler testing positive for amphetamine, non-steroidal anti-inflammatory drugs such as ibuprofen testing positive for barbiturates, and cannabinoids and some fluoroquinolones testing positive for opiates.[8,9] Ma huang, a Chinese HM, caused a false-positive screening test for amphetamines, which was confirmed to be a cross-reaction of the ephedrine in the product.[10] Another area of concern is adulteration of samples. Adulteration is a process of deliberate interference with the process of specimen collection, transport or analysis, with the intention of avoiding a positive test outcome. In vivo adulteration is the intake of interfering substances such as drugs, or lots of water, before sample collection. In vitro adulteration is when substances are added into the urine sample after collection to alter the results, mainly to cause a false negative. Substances commonly used for adulteration include drug-free human, animal or synthetic urine or assay interferants.[11,12]

September 2017, Print edition

IN PRACTICE

Generally, urine is tested routinely for DoA in health facilities to aid the diagnosis of potential abusers and some psychiatry patients on admission. The other important testing is for banned substances in special populations such as those whose work environment requires that they be drug free, and people involved in professional sport. Qualitative screening tests are initially used to test for the presence of the DoA, as they are quick, sensitive, relatively economical and simple to use.[8,11] Results of screening assays are used to indicate whether further testing is required (as illustrated in Fig. 1) and provide a guide for follow-up action from a clinical perspective. A rapid urinalysis assay based on an immunoassay method is the screening test commonly used for DoA. It is based on the principle of antigen-antibody reaction in which the drug or drug metabolite present in urine will interact with a labelled polyclonal or monoclonal antibody provided.[13,14] Various substances may interfere with immunoassays by cross-reacting with the test reagents and resulting in false-negative, false-positive or invalid results.

sample and the immobilised drug-protein conjugate. If the drug is absent in the urine, or is present in below cut-off levels, a coloured conjugate will interact with the drug antigen immobilised in the test line and form a coloured line. If the drug or metabolite is present, it will bind to and saturate all the binding sites on the antibody conjugate, preventing any binding by the drug antigen at the test area. The results are negative if two colour lines appear, one in the test area and the other in the control area, regardless of the intensity of the line. The results are positive when only one colour line appears in the control site and are invalid if no colour line appears on the test as well as the control site. A 10-test dipstick kit from Labstix Diagnostics was used to test qualitatively for pH and specific gravity (SG).

The herbal mixtures and preparation

Literature searches provided no results for cross-reactivity of ATMs, or the influence of ATMs on laboratory tests. This study therefore sought to establish whether any of the commonly used CHMs may affect the outcomes of a rapid qualitative screening test for DoA. It was intended to show whether the presence of the CHMs would alter the results of a rapid urinalysis assay.

The six CHMs selected for the study are used as immune boosters or to strengthen the body and are commonly sold in many retail outlets; they were bought from local pharmacies. They were Intlamba Zifo (denoted HM1 for the purposes of this study), Maphilisa HM (HM2), Matla African Medicine for All Diseases (HM3), Ngoma Herbal Tonic Immune Booster (HM4), Stametta Body Healing Liquid (HM5) and Vuka Uphile Immune Booster (HM6). From each of the six CHMs, three serial dilutions of 10, 100 and 1 000 times were made with distilled water. These HMs were taken through the test procedure outlined in Fig. 2.

Methods

Testing drug-free urine (DFU)

Objective

Permission for the study (ref. no. MREC/M/09/2011:PG) was granted by the Sefako Makgatho Health Sciences University (SMU) Research Committee and the Superintendent of Dr George Mukhari Academic Hospital.

The rapid urinalysis assay

The test kit used was the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics (SA). It consists of test cassettes, each with six panels for concurrent testing of amphetamine, cocaine, methamphetamine, morphine, tetra-hydrocannabinol (THC) and methylenedioxymethamphetamine. The test is a one-step lateral flow chromatographic immunoassay. Each panel contains drug-protein conjugate immobilised on a porous membrane support. The test is based on the principle of competition for limited binding sites on the antibody between the drug or drug metabolite present in the urine Urine sample Qualitative rapid test (immunoassay)

Ten urine samples were collected from healthy volunteers, each of whom confirmed that they had not taken any drugs, HMs or overthe-counter medicines within the preceding 7 days. The samples were pooled as DFU. Both the individual samples and the DFU were tested with the dipsticks for pH and SG. The remaining pooled DFU was stored in the refrigerator at 4°C. Four samples of 9 mL each of DFU were made for each of the six CHMs. A volume of 1 mL each of the neat HM and the three dilutions were added to the samples. A dipstick test was done on each spiked DFU sample and the results were recorded. The spiked DFU samples were then tested using the Instant View Multi-Drug of Abuse Test cassette, following the instructions in the test kit manual. The test was repeated at time intervals of 8, 24, 48, 72, 96 and 120 hours and the results were recorded. Following up on the results of the test, six aliquots of the DFU were each spiked with the HMs at 40% v/v (2 400 µL DFU + 1 600 µL CHM). The control for each sample was composed of 2 400 µL DFU plus 1 600 µL of distilled water to make up for the dilution. Urine testing positive for DoA (D-U)

Urine testing negative for DoA (DFU)

Positive results

Negative results

Quantitative confirmation test (e.g. immunoassay method, HPLC, GC-MS methods)

Report results as negative

Spiked with HMs at • low concentrations (10, 100 and 1 000 × dilutions) • high concentrations (40% v/v)

Qualitative rapid urine screening test (Instant View Multi-Drug of Abuse Test)

Report results with actual levels of tested substance

RESULTS

Fig. 1. Flow diagram for routine urine testing for drugs of abuse. (HPLC = high-performance liquid chromatography; GC-MS = gas chromatographymass spectrometry).

Fig. 2. Outline of the method used. (DoA = drugs of abuse; DFU = drug-free urine; D-U = positive urine samples; HMs = herbal medicines.)

September 2017, Print edition

IN PRACTICE

Testing urine positive for DoA

Urine samples that had been sent to SMU’s Department of Pharmacology and Therapeutics laboratory for routine testing and had tested positive for any of the tested substances were collected. The positive urine samples (D-U) were labelled accordingly, and centrifuged for 5 minutes at 1 000 rpm (250 g). Each supernatant was collected and stored in the refrigerator at 4°C until needed. Six aliquots of the D-U samples were each spiked with one of the six HMs at 40% v/v. The positive control for each sample was composed of 2 400 µL D-U plus 1 600 µL DFU. These samples were tested following the same procedure according to the test kit instructions.

Results

Testing DFU

The urine samples obtained from healthy volunteers appeared normal. The colour of the samples was various shades of amber, but none of the observed parameters deviated from the normal ranges as indicated by the dipstick test. The pH and SG of the individual urine samples differed, but the pooled sample values were pH 6.0 and SG 1.020. The results of the rapid qualitative test on the spiked DFU samples were all negative for the tested DoA and remained negative from day 1 till day 5. The dipstick results for pH and SG also remained the same for each of the samples throughout the 5 days of testing. The results for the 40% v/v spiked urine samples were also negative, and remained negative throughout the 5 days. The mean SG and pH for the DFU spiked with the HMs were 1.020 and 5.5, respectively.

Testing urine that was positive for DoA

Eight urine samples (D-U) that had tested positive for THC were used in this assay. The pH of samples ranged from 5 to 7.5 and the SG from 1.005 to 1.030. The pH of the controls was between 5 and 6.5 and the SG between 1.010 and 1.030. The controls for all the D-U samples remained positive for THC. The results of seven D-U samples spiked with HM1, HM2, HM3, HM5 and HM6 remained positive for THC in all concentrations of the HMs tested, from the lowest to the highest (40% v/v). The D-U samples spiked with HM4 at the highest concentration (40% v/v) tested negative for THC. Because this HM was the only one that was alcohol based, alcohol had to be excluded as a possible cause of the false-negative result. A 13.5% methanol solution was used to spike some D-U samples, which were then taken through the same procedure. The results of the spiked D-U samples remained positive, confirming that alcohol did not alter the results.

Discussion

Five of the six HMs tested had no influence on the quantitative rapid urinalysis assay. HM4, Ngoma Herbal Tonic Immune Booster, showed false-negative results for THC in the urine samples that were positive for THC when spiked at 40% v/v with HM4. It is stated on the container of this HM that it contains Sutherlandia, Echinacea, dandelion, alfalfa (lucerne), Aloe ferox, Harpagophytum (devil’s claw) and alcohol (13.5%). Alcohol was excluded as a possible cause of the false-negative result. The plausible explanation for the false-negative result could therefore be that alcohol as a solvent extracted some lipophilic compounds from the plants used, which would not be extracted by water as a solvent. These compounds would have then interfered with the test reagents, resulting in the false-negative results. For the test to be positive, the drug metabolites in the urine sample compete for binding on the immobilised protein conjugate

(antibody) with the colour-coded drug antigen on the test panel. A negative test result occurs when the colour-coded drug antigen binds to the antibody. The compounds in HM4 interacted with the test reagents and the THC in the sample in such a way that the drug metabolite could not bind to the antibody. There are several ways in which false-negative results could occur for a particular drug when using immunoassays. A false negative may occur when the drug is present in the sample but the detection limit of the method is too high, or when the actual concentration of the drug in the sample is very low.[8,13] Most screening tests have cut-off concentrations above which the results would be reported as positive. [8,14-16] It may also be caused by cross-reactivity of the antibody in the assay, the time lapse between drug ingestion and specimen collection, or adulteration of the sample.[15] For HM4, the false-negative results occurred at high concentration (40% v/v). Although the test used is a qualitative test, it has a quantitative part due to the cut-off levels, which give a guide to the possible concentration of the substance if positive.[14] The suggestion here is that the presence of HM4 at low levels, which are the most likely in vivo physiological levels, would not affect the screening test. The high concentration used would be most likely to be achieved by in vitro sample manipulation, therefore suggesting that HM4 could be an adulterant for THC. Dilution of a sample, which would normally cause reduced concentration to below cut-off levels[11] is not a factor in this case because the control sample remained positive. The false-negative results could also have been caused by crossreactivity of the antibody in the assay with one or more plant compounds present in the HM. As is well known in HMs, there could be undeclared ingredients in the mixture owing to either deliberate or unintentional contamination,[4,17] and also because manufacturers of commercial HMs protect their recipes, as they consider themselves to hold unofficial patents thereof.[18] Screening tests are designed to detect classes of drugs, so although they are sensitive they have low specificity.[11] THC is a highly lipid-soluble compound of plant origin. It could be that the antibody to THC in the assay has variable degrees of reactivity or affinity towards drugs or metabolites with identical chemical structure to THC, or with unrelated chemical structures. HM4 may contain one or more plant compounds that are structurally related to THC, since THC is of plant origin. Plant compounds that are extracted in alcohol include glycosides, sugars, amino acids, terpenoids, alkaloids and polyphenols.[19,20] Whether these were the compounds that interfered with the test is speculative at this stage, as there could be more compounds present. The result cannot be extrapolated to physiological levels, as it was observed at a high concentration (40% v/v) of HM4. However, the result permits the possibility of the risk of the use of HM4 as an adulterant. The cannabinoid assay was recognised to be the assay most susceptible to false-negative results after six out of 16 chemicals commonly used as adulterants reported false-negative results.[21] The substances interfering with cannabinoid immunoassays included ibuprofen, tolmetin[10] and common household chemicals such as drain cleaner, ammonia and bleach.[15,21] This is the first report of an ATM, particularly one available over the counter, being a potential adulterant to a cannabinoid urine screening test using a quantitative lateral flow chromatography immunoassay. The outcome also signifies the importance of appropriate labelling of CHMs, which may provide information on the range of possible compounds that may be present in a herbal mixture.

Study limitations

The sample set for this study was small, so a wider study with more samples and replicates and including more herbal medicinal products

September 2017, Print edition

IN PRACTICE

should be done. The study method used a rapid screening test from only one manufacturer. The results may therefore not be generalisable to the test kits from other manufacturers.

Conclusion

Of the six HMs tested, only one showed the potential of interfering with a rapid, qualitative urine test for DoA. Ngoma Herbal Tonic Immune Booster caused false-negative results for THC. This is the first finding of the possibility of commercial HMs used as ATMs interfering with rapid, qualitative screening tests. The findings therefore facilitate the route for further studies investigating whether the use of these medicines interferes with diagnostic tests in general. Acknowledgements. We thank the SMU Department of Pharmacology and Therapeutics laboratory staff members, who assisted with acquiring the urine samples. Author contributions. MEM conducted the research as part of her PhD studies, and drafted the manuscript. EO and CPKV were co-supervisor and supervisor, respectively; they proofread the draft. All authors approved the final manuscript. Funding. Sefako Makgatho Health Sciences University. Conflicts of interest. None 1. Peltzer K. Utilisation and practice of traditional/complementary/alternative medicine (TM/CAM) in South Africa. Afr J Trad Complement Altern Med 2009;6(2):175-185. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC2816568/ (accessed 6 August 2017). 2. Truter I. African traditional healers: Cultural and religious beliefs intertwined in a holistic way. S Afr Pharm J 2007;74(8):56-60. https://www.sapj.co.za/index.php/SAPJ/article/download/239/231 (accessed 6 August 2017). 3. Ernst E. Prevalence of use of complementary medicine: A systematic review. Bull World Health Organ 2000;78(2):252-257. https://doi.org/10.1590/S0042-96862000000200015

4. Ndhlala AR, van Staden J. Smokescreens and mirrors in safety and quality of herbal medicines: A case of commercialized herbal preparations. S Afr J Bot 2012;82(Sept):4-10. https://doi.org/10.1016/j. sajb.2012.06.008 5. South Africa. Traditional Health Practitioners Act 22 of 2007. 6. Stafford L. Herbalgram: Concerns over use of African herbs during 2010 World Cup. 2010. http://cms. herbalgram.org/herbalgram/issue86/article3520.html?issue=86 (accessed 8 August 2017). 7. World Anti-Doping Code. The 2015 Prohibited List. https://www.usada.org/wp-content/uploads/ wada-2015-prohibited-list-en.pdf (accessed 8 August 2017). 8. Vincent CE, Zebelman A, Goodwin C. What common substances can cause false positives on urine screens for drugs of abuse? J Fam Pract 2006;55(10):893-897. http://www.mdedge.com/sites/default/ files/issues/articles/5510JFP_ClinicalInquiries1.pdf (accessed 6 August 2017). 9. Reisfield GM, Goldberger BA, Bertholf RL. ‘False-positive’ and ‘false-negative’ test results in clinical urine drug testing. Bioanalysis 2009;(5):937-952. https://doi.org/10.4155%2Fbio.09.81 10. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-1838. https://doi.org /10.1056%2Fnejm200012213432502 11. Reisfield GM, Salazar E, Bertholf RL. Review: Rational use and interpretation of urine drug testing in chronic opioid therapy. Ann Clin Lab Sci 2007;37(4):301-314. http://www.annclinlabsci.org/ content/37/4/301.long (accessed 6 August 2017). 12. Jaffe WB, Trucco E, Levy S, Weiss RD. Is this urine really negative? A systematic review of tampering methods in urine drug screening and testing. J Subst Abuse Treat 2007;33(1):33-42. https://doi. org/10.1016/j.jsat.2006.11.008 13. Kapur BM. Drug testing methods and clinical interpretations of test results. Encyclopedia of Drugs, Alcohol and Addictive Behaviour 2001. http://www.encyclopedia.com/doc/1G2-3403100184.html (accessed 8 December 2014). 14. Moeller KE, Lee KC, Kissack JC. Urine drug screening: Practical guide for clinicians. Mayo Clin Proc 2008;83(1):66-76. https://doi.org/10.4065%2F83.1.66 15. Uebel RA, Wium CA. Toxicological screening for drugs of abuse in samples adulterated with household chemicals. S Afr Med J 2002;92(7):547-549 16. Dasgupta A. Review of abnormal laboratory test results and toxic effects due to the use of herbal medicines. Am J Clin Pathol 2003;120(1):127-137. https://doi.org/10.1309%2Fp024-k7vr-ddpj-ctvn 17. Kamboj A. Analytical evaluation of herbal drugs. In: Vallisuta O, Olimat SM, eds. Drug Discovery Research in Pharmacognosy. InTech, 2012. https://doi.org/10.5772%2F26109 18. Ndhlala AR, Stafford GI, Finnie JF. et al. In vitro pharmacological effects of manufactured herbal concoctions used in KwaZulu-Natal South Africa. J Ethnopharmacol 2009;122(1):117-122. https://doi. org/10.1016%2Fj.jep.2008.12.017 19. Tiwari P, Kumar B, Kaur M, et al. Phytochemical screening and extraction: A review. Internationale Pharmaceutica Scientia 2011;1(1):98-106. https://www.scribd.com/doc/94036813/PhytochemicalScreening-and-Extraction-a-Review (accessed 6 August 2017). 20. Houghton PJ, Raman A. Laboratory Handbook for the Fractionation of Natural Extracts. London: Chapman & Hall, 1998:113-138. https://doi.org/10.1007%2F978-1-4615-5809-5 21. Schwarzhoff R, Cody JT. The effects of adulterating agents on FPIA analysis of urine for drugs of abuse. J Anal Toxicol 1993;17(1):14-17. https://doi.org/10.1093/jat/17.1.14

Accepted 19 April 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

ISSUES IN PUBLIC HEALTH

How front-line healthcare workers respond to stock-outs of essential medicines in the Eastern Cape Province of South Africa R Hodes,1 DPhil, MSc; I Price,2 BSc; N Bungane,1 BCur Hons, E Toska,1 DPhil, MSc; L Cluver,3 DPhil, MPhil AIDS and Society Research Unit, Centre for Social Science Research, University of Cape Town, South Africa Mathematical Institute, Oxford University, UK 3 Child and Family Social Work, Department of Social Policy and Intervention, Oxford University, UK; and Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: R Hodes (rebecca.hodes@gmail.com)

Shortages of essential medicines are a daily occurrence in many of South Africa (SA)’s public health facilities. This study focuses on the responses of healthcare workers to stock-outs, investigating how actors at the ‘front line’ of public health delivery understand, experience and respond to shortages of essential medicines and equipment in their facilities. Findings are based on focus groups, observations and interviews with healthcare workers and patients at healthcare facilities in the Eastern Cape Province of SA, conducted as part of the Mzantsi Wakho study. The research revealed a discrepancy between ‘informal’ definitions of stock-outs and their reporting through formal stockout management channels. Front-line healthcare workers had designed their own systems for classifying the severity of stock-outs, based on the product in question, and on their potential to access stocks from other facilities. Beyond formal systems of procurement and supply, healthcare workers had established vast networks of alternative communication and action, often using personal resources to procure medical supplies. Stock-outs were only reported when informal methods of stock-sharing did not secure top-up supplies. These findings have implications for understanding the frequency and severity of stock-outs, and for taking action to prevent and manage stock-outs effectively. S Afr Med J 2017;107(9):738-740. DOI:10.7196/SAMJ.2017.v107i9.12476

In the decades since South Africa (SA)’s first democratic elections, the policies and programmes that direct the provision of public healthcare have been radically revised.[1-3] A growing literature reveals gaps between the state’s policy and legislative commitments to improving public healthcare,[3-8] and on-the-ground challenges that continue to obstruct public access.[1,9,10] It focuses on the functioning of health systems[ 3,11-13] and on the operational aspects of clinical care.[14-19] While the National Department of Health is committed to improving access to medicine, the procurement and distribution of medical supplies remains inadequate in many health districts. [20] Research on stock-outs has strived to quantify the extent and severity of shortages of medical supplies. It has identified which drugs and medical products are most commonly depleted, including through research on tracer medicines that represent procurement and provision challenges.[21-25] A national audit published by the Health Systems Trust (HST) of healthcare facilities’ compliance with key priorities included a measure on ‘availability of medicines and supplies’. The Eastern Cape Province’s compliance score for this was 54% in 2012. The audit also found an extremely high failure percentage (77%) in clinics for the measure ‘Tracer medicines as per applicable Essential Drugs List or formulary are available in the pharmacy/medicine’.[3] Stock-outs arise from an inability to manage medical supplies, report shortages, and act swiftly and effectively to prevent their recurrence. Stock-outs are intertwined with other challenges in the health sector, including shortages of healthcare workers, inadequate training, weak oversight and management, and inadequate monitoring and evaluation of clinic data.[3]

From research and policy perspectives, it is crucial to understand: (i) whether formal reporting is an accurate measure of available medical supplies; and (ii) how front-line healthcare providers experience and respond to stock-outs at facilities level. Insights from healthcare workers are key to design and implement interventions to reduce stock-outs and limit their adverse effects on patients.

Methods

This study focused on the qualitative dimension of stock-outs, examining how healthcare providers perceived and responded to shortages of medical supplies in their facilities. It was conducted as a sub-study within the Mzantsi Wakho study on the health of adolescents in the Eastern Cape.[23,26] Facilities were selected on two bases: range of service level (including two clinics, a community health centre, a district hospital and a tertiary hospital) and willingness of healthcare workers to participate in direct observations and interviews, including within waiting rooms and dispensaries. Ethical approval for this study was provided by research ethics committees at the University of Cape Town (ref. no. UCT/CSSR/1/2014(ii)) and the University of Oxford (ref. no. SSD/CUREC2/12-21). Between December 2013 and May 2016, researchers conducted over 1 000 hours of observation at public healthcare facilities. We interviewed 15 healthcare workers, including senior staff (hospital CEOs, doctors, nurse managers, nurses and community health workers), administrative staff (receptionists and data managers) and ground staff (including cleaners, gardeners and security guards). In April 2016, we conducted five interviews with healthcare workers involved specifically in providing and monitoring medical supplies at five facilities. We conducted a focus group with 19 research staff

September 2017, Print edition

IN PRACTICE

of the Mzantsi Wakho study, which included nurses and community healthcare workers. The focus group was recorded and transcribed, translated and coded by two qualitative researchers and the study’s senior clinics researcher. To ensure the confidentiality of research participants at clinics, interviews at healthcare facilities were not audio-recorded. Findings are based on the themes that emerged from these multiple qualitative methods and data sources, developed iteratively, over the course of 31 months of observations, interviews and participatory research. This primary research was supplemented by a review of public health research, policy plans and guidelines on stock-outs in SA.

Findings

The management of medical stocks, including ordering, receiving, dispensing and reporting, depended on the structure and staffing of facilities. In better-resourced facilities, such as hospitals, these roles were performed by dedicated pharmacists and pharmacy assistants. In smaller facilities, including those serving large patient populations, nurses performed these roles alongside other duties as healthcare providers and administrators. Of the 3 074 clinics surveyed in the HST’s National Healthcare Facilities Baseline Audit, ‘a high 84% had no input from a Pharmacist or Pharmacy Assistant Post-Basic’.[3] At one clinic within this dedicated study, a nurse who also served as clinic manager laughed when asked if her facility had a pharmacist. ‘You are looking at her,’ she replied.

Stock-outs and supply-sharing networks

Definitions and understandings of stock-outs varied considerably between different facilities, and in relation to different drugs. All five facilities in this study reported frequent stock-outs of numerous products listed on the Essential Medicines List.[7] At a rural clinic, the dispensary was run by a nurse who served as the facility’s operations manager. The clinic had no pharmacist or pharmacy assistant, and at the time of the interview had stocked out of Kaletra. At a larger urban clinic, the pharmacy assistant reported having no stock of folic acid, simvastatin, electrolyte solution or gauze on the day of the interview. The nurse at the first clinic contacted other clinics in the district and borrowed Kaletra to avoid turning patients away without their medicines. However, because she did not capture and report the shortage, no stock-out had officially occurred. At the second facility, items reported as stock-outs were those that the pharmacy assistant was not able to borrow from nearby clinics – either because they were experiencing the same shortages or because they lacked sufficient ‘buffer stock’ to share. The front-line healthcare workers interviewed did not generally report drug shortages using official channels if they could access top-up supplies from a neighbouring facility. Only stock-outs of supplies that were ‘unborrowable’ were reported. The ‘borrowing’ phenomenon is a crucial component of practical monitoring and oversight of medical supplies in the Eastern Cape. While this is the phrase commonly used by healthcare workers, ‘borrowing’ is not strictly an accurate description of this practice. As the head pharmacist at a public hospital explained, ‘We say “borrowed”, but no-one ever returns.’ Nurses, pharmacists and pharmacy assistants within the province had established networks of communication and exchange to manage this alternative supply system. These networks were informal and internal, established by healthcare workers as a means of dealing directly with stock-outs themselves. Their boundaries did not correspond with the official zoning of health districts and municipalities. This study explored how these networks functioned. When a clinic was running low on a particular drug or piece of equipment, the staff member tasked with managing medical supplies would contact a

staff member from another clinic – often via Whatsapp – and ask if they could ‘lend’ supply. Healthcare workers used personal resources to tap into these networks, including personal cell phones (mobile phones) and ‘airtime’.[27] This practice of sharing essential medicines happened ‘all the time’, according to the head pharmacist at a district hospital, and was recounted by staff members within all facilities in the study. Staff reported that, through this exchange, they were ‘almost always’ able to deal with the shortages they faced. This thriving parallel economy in medicines supply is far from the ideal of robust procurement and regulation. All facilities within this study, with the exception of the hospitals, struggled to provide sustained, uninterrupted access to essential medical supplies. But this study also demonstrated that informal economies of medicines exchange, established by healthcare workers, often had the potential to address stock-outs quickly and effectively, providing healthcare workers with direct, rapid access to ‘buffer stocks’ from neighbouring facilities. The successes of these informal networks were premised on high degrees of personal motivation among staff, their ability to design, implement and adapt contingency plans, their collegiality, and their investment in providing continuous, reliable treatment. While some stock-outs may have been dealt with effectively by ‘borrowing and sharing’, ‘full-blown’ stock-outs were also reported among healthcare workers and patients in this study. A full-blown stock-out was when borrowing medical supply in advance of a total depletion, or as an interim short-term strategy, had failed. This resulted in patients being turned away from facilities without prescribed medicines. At times, patients were advised by nurses or community healthcare workers to travel to other facilities presumed to have better stocks. Through trial and error, patients had themselves ascertained which facilities reliably stocked the chronic medicines they needed, and sought healthcare there despite greater travel and time costs. At a day hospital, a community health worker recounted common ‘full-blown’ stock-outs of paracetamol and vitamin B complex. While she acknowledged that these medicines were unavailable at the facility, she maintained that shortages were minor in comparison with primary facilities in urban townships and rural areas in the district: ‘There are clinics in the location – yoh, people are moaning. They are running out of things. Then the patients flock here … [My patient]’s grandmother is staying in a rural area. She [the grandmother] and grandfather didn’t get their medication for two months. And another lady … she was supposed to get 10 of her [blood pressure] medicines. But she only got two of the 10.’ This healthcare worker described another strategy used by frontline providers to limit the negative health impacts of stock-outs on patients. In cases of diminishing supply, healthcare workers might provide patients with a partial prescription, advising them to return to the clinic for the rest of their regimen in the coming days. The effects of this practice on patient retention require further research, particularly in the context of chronic conditions that require consistent, reliable access to medicines.

Discussion

The government has recognised the urgency of stock-outs, and committed to improving monitoring and accountability in the health sector. A proliferation of plans and circulars captures attempts to improve procurement and oversight of medical supplies, and to systematise how these are reported and resolved. A proposed digital stock-monitoring system has the potential to improve how stock-outs are detected, but its success depends on investments in

September 2017, Print edition

IN PRACTICE

technology and infrastructure at facility level. If proposed initiatives for improving medical supplies are to have an optimal impact, they must be accompanied by attendant investments in human resources. For the front-line healthcare workers in this study, reporting on medicines supply was already a distraction from primary care. A shortage of data capturers in facilities meant that nurses were often tasked with completing paperwork for monitoring and evaluation, with the risk that reporting on healthcare delivery took priority over delivery itself. Different definitions of stock-outs must be considered in designing accurate monitoring mechanisms, and in conducting future research with healthcare providers. The impact of stock-outs on patients and staff would be far more severe were it not for the existence of collaborative and resourceful informal networks of healthcare workers and facilities who share and redistribute medical supplies. The number of ‘full-blown’ stock-outs was considerably smaller than the number of ‘minor’ stock-outs, that were managed through borrowing, and often went unreported. Moreover, healthcare workers were more likely to report shortages or absences of ‘high-profile’ drugs, for conditions that attracted greater clinical and public scrutiny. Shortages of ‘routine’ medical supplies, such as surgical scissors, and ‘nice-to-haves’, such as pain medications and vitamins, were accepted as an everyday reality and feature of the constrained public health system.

Conclusion

Informal networks of communication and exchange enable frontline healthcare workers to respond quickly and effectively to stockouts of essential medical supplies. Interviews and observations with these healthcare workers, conducted within a longitudinal study on healthcare in the Eastern Cape, reveal how these networks function outside of formal supply chains and management structures. Interventions to improve the monitoring of medical supplies should recognise that interpretations of stock-outs vary widely, and that healthcare workers may circumvent formal processes to expedite access to buffer stocks at neighbouring facilities. This study points to the latent capacity for drug supply monitoring, and reveals a flourishing informal system of supply and exchange within the public health system. Acknowledgements. We thank the healthcare workers and patients interviewed. The Mzantsi Wakho research team hosted this sub-study. We gratefully acknowledge the collaboration of Lizzy Button, Craig Carty, Marisa Casale, Jenny Doubt, Lesley Gittings, Nonkumbuzo Galela, Eda He, Chunyiswa Kama, Ntombohlanga Beauty Kamile, Bulelani Kinana, Vuyiseka Luke, Zoliswa Marikeni, Thembani Mampangashe, Amanda Mbiko, Franziska Meinck, Philiswa Mjo, Sindiswa Mona, Mavis Mpumlwana, Siyavuya Mqalo, Sinazo Mwellie, Moses Neel, Nisso Nurova, Bongiwe Saliwe, Izidora Skracic and Prince Tshefote. Francois Venter, Sue Tafeni, Mara Kardas-Nelson, Musaed Abrahams, Catherine Tomlison, Sarah Goodwin, Deborah Posel and Gil Yaron provided further insights. Author contributions. RH, IP and NB designed the study and conducted primary research. All the authors analysed and reviewed findings. RH and IP drafted the first version of the manuscript, which all the authors edited and reviewed. Funding. Funding for this research was provided by Evidence for HIV Prevention in Southern Africa, a programme of the UK Department for

International Development, managed by Mott MacDonald (MM/EHPSA/ UCT/05150014), the Nuffield Foundation under grant CPF/41513, UNICEF South Africa, and the Make All Voices Count Initiative, through Stop Stockouts. Conflicts of interest. None. 1. Harrison D. An Overview of Health and Health Care in South Africa 1994 - 2010: Priorities, Progress and Prospects for New Gains. Washington, DC: Henry J Kaiser Family Foundation, 2009. 2. Sanders D, Chopra M. Key challenges to achieving health for all in an inequitable society: The case of South Africa. Am J Public Health 2006;96(1):73-78. https://doi.org/10.2105%2Fajph.2005.062679 3. Visser R, Bhana R, Monticelli F. The National Health Care Facilities Baseline Audit National Summary Report. Durban: Health Systems Trust, 2012. 4. National Department of Health, South Africa. National Core Standards for Health Establishments in South Africa. Pretoria: NDoH, 2011. http://www.rhap.org.za/wp-content/uploads/2014/05/NationalCore-Standards-2011-1.pdf (accessed 18 January 2017). 5. National Department of Health, South Africa. National Strategic Plan on HIV, STIs and TB, 2012 - 2016. Pretoria: NDoH, 2011. http://www.gov.za/sites/www.gov.za/files/national%20strategic%20 plan%20on%20hiv%20stis%20and%20tb_0.pdf (accessed 18 January 2017). 6. National Department of Health, South Africa. Policy on Quality in Health Care for South Africa. Pretoria: NDoH, 2007. http://www.gov.za/sites/www.gov.za/files/qhc-policy.pdf (accessed 18 January 2017). 7. Leong T, de Waal R, Munsamy J, van de Wal B, Jamaloodien K, eds. Standard Treatment Guidelines and Essential Medicines List for South Africa. Pretoria: National Department of Health, 2014 http://www. kznhealth.gov.za/pharmacy/edlphc2014a.pdf (accessed 17 January 2017). 8. Republic of South Africa. Operation Phakisa: Ideal Clinic Realisation and Maintenance: Final Lab Report. 2015. https://www.idealclinic.org.za/docs/2016/phakisa/Operation%20Phakisa%20Ideal%20 Clinic%20Realisaation%20&%20Maintenance%20Final%20report%20May%202015.pdf (accessed 17 January 2017). 9. Schneider H, Blaauw D, Gilson L, Chabikuli N, Goudge J. Health systems and access to antiretroviral drugs for HIV in southern Africa: Service delivery and human resources challenges. Reprod Health Matters 2006;14(27):12-23. https://doi.org/10.1016%2Fs0968-8080%2806%2927232-x 10. Suri A, Gan K, Carpenter S. Voices from the field: Perspectives from community health workers on health care delivery in rural KwaZulu-Natal, South Africa. J Infect Dis 2007;196(Suppl 3):S505-S511. https://doi.org/10.1086%2F521122 11. Schneider H, Coetzee D, van Rensburg D, Gilson L. Differences in antiretroviral scale up in three South African provinces: The role of implementation management. BMC Health Serv Res 2010;10(1):S4. http://dx.doi.org/10.1186%2F1472-6963-10-s1-s4 12. Pattinson RC, ed. Saving Mothers 2011-2013: The Sixth Report of the National Committee for Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: Government Printer, 2014. http://www.kznhealth.gov.za/mcwh/Maternal/Saving-Mothers-2011-2013-short-report.pdf (accessed 18 January 2017). 13. Bateman C. Inept drug supply management causing stock-outs. S Afr Med J 2015;105(9):706-707. https://doi.org/10.7196%2Fsamjnew.8543 14. Harries AD, Zachariah R, Lawn SD, Rosen S. Strategies to improve patient retention on antiretroviral therapy in sub‐Saharan Africa. Trop Med Int Health 2010;15(s1):70-75. https://doi. org/10.1111%2Fj.1365-3156.2010.02506.x 15. Bekker LG, Venter F, Cohen K, et al. Provision of antiretroviral therapy in South Africa: The nuts and bolts. Antivir Ther 2014;19(Suppl 3):105-116. https://doi.org/10.3851/IMP2905 16. Van Wyk SS, Reid AJ, Mandalakas AM, et al. Operational challenges in managing isoniazid preventive therapy in child contacts: A high-burden setting perspective. BMC Public Health 2011;11(1):544. https://doi.org/10.1186/1471-2458-11-544 17. Mayosi BM, Benatar SR. Health and healthcare in South Africa – 20 years after Mandela. N Engl J Med 2014;371(14):1344-1353. https://doi.org/10.1056/NEJMsr1405012 18. Churchyard GJ, Mametja LD, Mvusi L, et al. Tuberculosis control in South Africa: Successes, challenges and recommendations. S Afr Med J 2014;104(3):234-248. https://doi.org/10.7196/SAMJ.7689 19. Goudge J, Gilson L, Russell S, Gumede T, Mills A. Affordability, availability and acceptability barriers to health care for the chronically ill: Longitudinal case studies from South Africa. BMC Health Serv Res 2009;9(1):75. https://doi.org/10.1186/1472-6963-9-75 20. Coovadia H, Jewkes R, Barron P, Sanders D, McIntyre D. The health and health system of South Africa: Historical roots of current public health challenges. Lancet 2009;374(9692):817-834. https://doi. org/10.1016%2Fs0140-6736%2809%2960951-x 21. Stop Stockouts. South Africa: Monitoring Essential Medicines Consortium. South Africa: Stop Stockouts, 2016 (updated 18 January 2017). http://www.stockouts.org (accessed 22 January 2017). 22. Stop Stockouts, South Africa. Stockouts in South Africa – a national crisis. 2013. http://stockouts.org/ Downloads/stop_stockouts_report_2013pdf_1.pdf (accessed 20 January 2017). 23. Cluver LD, Toska E, Orkin FM, et al. Achieving equity in HIV-treatment outcomes: Can social protection improve adolescent ART-adherence in South Africa? AIDS Care 2016;28(Suppl 2):73-82. https://doi.org/10.1080%2F09540121.2016.1179008 24. Doctors Without Borders, Rural Doctors Association of Southern Africa, Rural Health Advocacy Project, Treatment Action Campaign, SECTION27, Southern African HIV Clinicians Society. 2015 Stock Outs National Survey. South Africa: Stop Stockouts, June 2016. http://stockouts.org/ Downloads/2015_stock_outs_national_survey.pdf (accessed 18 January 2017). 25. Magadzire BP, Ward K, Leng HM, Sanders D. Inefficient procurement processes undermine access to medicines in the Western Cape Province of South Africa. S Afr Med J 2017;107(7):581-584. https://doi. org/10.7196/SAMJ.2017.v107i7.11356 26. Mzantsi Wakho. 2010 [updated 17 November 2016]. http://www.mzantsiwakho.org.za (accessed 22 January 2017). 27. Sips I, Mazanderani AH, Schneider H, Greeff M, Barten F, Moshabela M. Community care workers, poor referral networks and consumption of personal resources in rural South Africa. PLoS One 2014;9(4):e95324. http://dx.doi.org/10.1371%2Fjournal.pone.0095324

Accepted 6 April 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

MEDICINE AND THE LAW

Facilitating access to adolescent sexual and reproductive health services through legislative reform: Lessons from the South African experience A Strode,1,2 LLM, PhD; Z Essack,1,2,3 MSS (Research Psychology), PhD School of Law, University of KwaZulu-Natal, Pietermaritzburg, South Africa HIV AIDS Vaccines Ethics Group (HAVEG), University of KwaZulu-Natal, Pietermaritzburg, South Africa 3 Human and Social Development Programme, Human Sciences Research Council, Pietermaritzburg, South Africa 1 2

Corresponding author: A Strode (StrodeA@ukzn.ac.za)

South Africa (SA) has progressive legislation enabling adolescents to access various sexual- and reproductive-health services (SRH) independently, without consent from parents or legal guardians. This article reviews the SA legislative framework for adolescent access to SRH interventions. It outlines the five approaches adopted in current legislation to address adolescents’ capacity to independently consent to specified health interventions, based on age, capacity and public policy requirements, or combinations thereof. Rather than subsume various health interventions under the umbrella of medical treatment, SA has separately legislated on many SRH interventions (e.g. HIV testing, contraceptives and terminations of pregnancy, among others). We identify strengths and weaknesses of the SA approach, and conclude with lessons learned from the SA experience which could inform discussion and debate on the most appropriate ways for countries to consider law reform that facilitates adolescent access to SRH services. S Afr Med J 2017;107(9):741-744. DOI:10.7196/SAMJ.2017.v107i9.12525

The South African (SA) Constitutional Court found that in certain specific circumstances, adolescents have a constitutional right to engage in sexual behaviour without incurring criminal sanctions. [1] This rights-based approach to adolescent sexuality is reflected in the recently revised Criminal Law (Sexual Offences and Related Matters) Amendment Act No. 32 of 2007 (hereafter the Sexual Offences Act).[2] The Sexual Offences Act provides that the age of consent to sex in SA is 16 years;[2] nevertheless, it also provides that adolescents aged 12 - 15 years old may engage in consensual sex with peers in the same age category (12 - 15 years) without criminal sanction.[2] Likewise, adolescents aged 12 - 15 may have sex with 16 - 17-yearolds, provided that there is no more than a 2-year age gap between them. [2] This new approach follows from the Constitutional Court’s finding that sexual activity and exploration is part of normative development from adolescence to adulthood.[1,3] The right to have sex at 16 must be understood in the context of the age at which adolescents can consent to a range of other sexualand reproductive-health (SRH) services. This article uses the World Health Organization’s (WHO’s) definition of adolescents as young persons between the ages of 10 and 19.[4] Currently in SA, adolescents have the right to access five SRH services. These rights are expressly provided for in legislation (Table 1). The Children’s Act No. 38 of 2005[5] states that children may consent independently to HIV testing, male circumcision, contraceptives (including contraceptive advice) and virginity testing at various points before the age of 18. The Choice of Termination of Pregnancy Act No. 92 of 2007[6] allows a woman (including a girl child) of any age to consent to a termination of pregnancy without assistance. The legal framework also refers to a number of general health rights which facilitate independent access to SRH services, including consent to medical treatment[5] and scheduled drugs on the presentation of a prescription.[7] The only SRH service which adolescents <18 and their proxies are prohibited from consenting to is sterilisation.[8]

There have been increasing calls for legislative frameworks to enable adolescent access to SRH services.[9] Reviewing the ages of consent to SRH services is considered one way of achieving this objective, as it enables an assessment of the extent to which the framework hinders or facilitates access to such services.[10] This article builds on earlier work which reviewed the ages of consent to various health interventions in SA.[11,12] It develops this preliminary work by critically interrogating the current SA legislative approach to the evolving capacity of adolescents to consent to SRH services. SA provides a good case study on adolescent SRH, given the extensive law reform relating to SRH over the last 2 decades. The article reviews the SA legislative framework and discusses the strengths and weaknesses of the SA approach. It identifies lessons that can be learned from SA’s legislative approach that could inform discussion and debate on the most appropriate ways for countries to consider law reform that facilitates adolescent access to SRH services.

Potential legal barriers to adolescents’ access to SRH services

Adolescents’ right to engage in sexual intercourse, and the imperative to address potential legal barriers to accessing SRH services, is set within the context of their many health risks. SA adolescents are at risk of HIV, sexually transmitted infections and pregnancy owing to high-risk sexual behaviour, physical, social and structural challenges, and limited access to key primary SRH services,[13] among other factors. Approximately 30% of teenagers (aged 13 - 19 years) in SA report ever being pregnant,[14] and in 2013, Statistics SA[15] reported that 99 000 school-going adolescent girls were pregnant. The most recent National HIV Prevalence, Incidence and Behaviour Survey found an HIV prevalence of 7.1% for youth aged 12 - 24 years.[16] The HIV incidence among young women (15 - 24 years old) is particularly alarming, with 113 000 new infections annually, four times higher than that of their male peers.[16]

September 2017, Print edition

IN PRACTICE

Laws permitting independent consent to SRH services are an important mechanism to ensure accessible services for adolescents. It is argued that requiring parental permission may deter adolescents from accessing SRH services,[17] including HIV testing.[18] For example, an empirical study in Connecticut, USA found that a significantly higher proportion of adolescents volunteered for HIV testing once the parental consent requirement was abolished.[19] Parental consent may be a barrier to adolescents’ accessing services for several reasons, such as that adolescents may not wish to disclose their sexual activity to their parents.[20,21] Commentators have reported that the most common reason for non-disclosure to parents appears to be a concern for the parents’ feelings, including a fear of disappointment or embarrassment and expected negative results, such as physical punishments or other forms of retaliation.[19] In the SA context, the requirement for parental consent is also problematic for those adolescents who do not live with their parents (e.g. child-headed households or children living with other caregivers). Parental consent is not the only potential legal barrier to adolescent access to SRH services. Disparate approaches to the ages at which children can consent to sex and make use of SRH services can be a problem.[9,22,23] Previously in SA, the Children’s Act[5] enabled adolescent access to a range of SRH services, while the Sexual Offences Act[2] continued to criminalise underage sex. This hindered access because children who used such services could be reported to the police.[23] This was compounded by the requirements in the Sexual Offences Act that any person with ‘knowledge’ of a sexual offence against a child (including a consensual offence) had to report it.[23,24]

The legal framework dealing with access to SRH services in SA

The primary principle on which access to SRH services is based is the capacity to consent, as this is an essential element of informed consent. Consent can only be provided by a person with the ‘intellectual and emotional capacity for the required knowledge, appreciation and consent’.[25] Furthermore, the ‘capacity to consent depends on the ability to form an intelligent will on the basis of an appreciation of the nature and consequences of the act consented to’.[25] In SA law, children are considered minors until the age of 18, and do not have the capacity to make legally binding decisions. However, in line with their evolving capacity, the legislature has expressly described a number of SRH rights that are applicable to adolescents. There are eight SRH and related rights which have a range of consent requirements based on age, capacity and/or public policy criteria (Table 1). The legislature appears to view access to contraceptives as requiring the least capacity and consent, with sterilisations requiring the most. Age 12 also marks the beginning of many of the SRH rights, despite this being 2 years after the age at which the WHO views adolescence as having started. Nevertheless, this is in line with criminal law, which provides that adolescents under the age of 12 do not have the capacity to consent to sex,[2] as discussed below. An examination of the capacity requirements suggests that the legislature has used five broad approaches to addressing adolescent capacity to consent to SRH services (Table 2). The first approach only sets an age requirement. Consent to contraceptives and contraceptive advice may be provided to a child from the age of 12,[5] prescribed drugs from 14,[7] and sterilisations from 18.[8] Children are also able to consent to sex from the age of 16.[2] This approach presumes that a child of the specified age has the capacity to consent.[26] The second approach requires both age and an express capacity requirement. Medical treatment is the only intervention that requires

the child to be 12 years and older, and to have ‘sufficient maturity’ and the ‘mental capacity to understand the benefits, risks, social and other implications of the treatment’.[5] This means that a child must be developmentally sufficiently mature to consent, and able to weigh up the various important factors that must be considered. The third approach combines age and an express public policy requirement. HIV testing, male circumcision and virginity testing require a child to be a certain age and for a certain public policy norm to be satisfied. For HIV testing, the adolescent must be 12 years or older, and the test must be in their ‘best interests’ and be accompanied by counselling.[5] For male circumcision and virginity testing, adolescents must be 16 years or older and receive ‘proper counselling’.[5] The fourth approach requires only an express public policy requirement. For terminations of pregnancy, there are no specified age or capacity requirements, but the healthcare worker performing the procedure must ‘advise such minor to consult with her parents, guardian, family members or friends before the pregnancy is terminated’.[6] The fifth approach is a complete prohibition of the service for adolescents under the age of 18. Sterilisations are the only SRH service which may not be offered to persons under the age of 18, even with proxy consent.[8] Older adolescents, aged 18 - 19 years, can, however, consent to a sterilisation.

Discussion

To its credit, SA expressly identifies an age of consent to sex. Importantly, the age of consent applies equally to boys and girls, and does not discriminate based on sexual orientation. Further, recent law reform increases the protection of adolescents, as it ensures that children below the age of consent (12 - 15-year-olds) who have consensual sex with their peers will not face criminal sanction.[2] A key barrier to accessing SRH services is concern about confidentiality – but since service providers are now absolved of reporting consensual sex in certain age categories to authorities, this may improve the uptake of these services.[27] International guidelines recommend that legislators ensure that adolescents can consent independently to medical treatment before the age of 18.[28] SA has addressed this issue by creating both an age and a capacity requirement for consent to medical treatment (Table 1). The age requirement of 12 years is moderated by the capacity requirement of ‘sufficient maturity’. The advantage of this approach is that it does not treat all forms of medical treatment alike, as it assumes that more complex forms of treatment may require greater capacity. This approach of having a low age of consent, but introducing a capacity requirement, is an inversion of the principle established in Gillick v West Norfolk and Wisbeck Area Health Authority and the DHSS 1985,[29] where the court held that children under the age of 16 years (the age of consent to medical treatment in the UK) did not lack legal capacity to make their own decisions by age alone. They had the capacity to make such decisions when they had sufficient understanding and intelligence to fully understand what was proposed.[29] SA has also elected to deal with consent to accessing prescribed drugs, contraceptives, HIV testing and male circumcision separately from medical treatment. In many other countries, these would be subsumed within a broad definition of medical treatment.[8] Separating these services has allowed for specific and different obligations to be put in place in relation to each service (Table 1). The only SRH service which could arguably form part of medical treatment that adolescents under the age of 18 are expressly

September 2017, Print edition

IN PRACTICE

Table 1. The sexual- and reproductive-health rights of adolescents Interventions Contraceptives HIV testing

Age of consent (yr) 12 12

Capacity requirement, if any Not specified None, unless the child is under 12, when they must show ‘sufficient maturity and the mental capacity to understand the benefits, risks, social and other implications of the test’ ‘Sufficient maturity and the mental capacity to understand the benefits, risks, social and other implications of the treatment’ None

Medical treatment

Prescribed drugs

Male circumcision

14 (to change to 12 when amendments to the Act are brought into operation in the future) 16 None

Virginity testing

Sterilisations

Termination of pregnancy

No specified age

Public policy requirement, if any None Testing must be in the ‘best interests’ of the child Pre- and post-test counselling must be provided

Capacity category Age Age and express public policy requirement

None

Age and an express capacity requirement

None

Age

Circumcision must be preceded Age and express public by ‘proper counselling’ policy requirement Only after ‘proper counselling’ Age and express public policy requirement None Prohibition of service to adolescents under 18 The medical practitioner/ Express public policy midwife to advise the child requirement to consult with her parents, guardian, family members or friends before the pregnancy is terminated

Table 2. Overview of age, capacity and public policy requirements for independent consent to sexual- and reproductive-health rights (SRH) services Independent consent requirements Age Age and capacity Age and public policy requirements Public policy and implied capacity Prohibition on the procedure during childhood (under 18)

SRH services Contraceptives; prescribed drugs Medical treatment HIV testing; male circumcision; virginity testing Termination of pregnancy Sterilisation

excluded from consenting to is sterilisation. This is an important and appropriate protective mechanism, given that the WHO[28] does not ordinarily recommend that the procedure be carried out before a person is 30 years old. Despite this liberal approach, some key concerns remain. Firstly, there remains some disjuncture between the approach in criminal and children’s law pertaining to adolescents: when there is more than a 2-year age gap between older (16 - 17 years) and younger (12 - 15 years) adolescents who engage in consensual sex with each other, both parties could still be prosecuted.[3] This has a disparate impact on girls, who are more likely to have older partners.[16] Where such cases are reported, young girls may be required to testify against their older partners, which may result in social harm to them.[3] Furthermore, the legislature retained the strict mandatory reporting requirements, and as a result, if adolescents declare that they have older partners whilst seeking SRH services, this information would have to be reported to the police.[3,27]

Secondly, the legal framework only recognises SRH rights for adolescents over the age of 12 years. This ensures that there is consistency between criminal and children’s law in this regard, as the Sexual Offences Act provides that adolescents below the age of 12 do not have the capacity to consent to sex.[2] However, it also means that the Act is not in sync with the WHO approach or with recent empirical research showing that children aged 10 - 11 have the capacity to consent to medical research.[31,32] It is argued that many research-related decisions would be similar to SRH choices. Thirdly, incorporating capacity requirements into consent norms has its disadvantages, including in terms of how best to assess capacity.[11] Commentators recommend that assessing ‘sufficient maturity’, for example, involves ensuring that the adolescent understands the risks, benefits and implications of the SRH services.[18] Such assessments should also consider the adolescent’s circumstances at the time, including their age, knowledge, experience and judgement.[18] Fourthly, the Children’s Act[5] does not define medical treatment, and this has left some uncertainty regarding new forms of HIV

September 2017, Print edition

IN PRACTICE

prevention, such as vaccines and microbicides. If these HIVprevention methods are registered in future, it is unclear whether adolescents will be able to access them as a form of medical treatment. Fifthly, the Children’s Act[5] has legitimated the cultural practice of virginity testing. The Act allows girls who are over the age of 16 years to consent to be physically examined to establish whether they are virgins.[5] Mubangizi[33] argues that by making this customary practice lawful in certain circumstances, children’s rights to privacy, bodily integrity and dignity are being violated. These provisions are out of step with the pro-children’s rights approach to other SRH interventions. Finally, SA has adopted a novel approach by linking publicpolicy requirements to consent for four SRH services: HIV testing, male circumcision, terminations of pregnancy and virginity testing. Public-policy requirements can serve to strengthen protection for adolescents generally. However, the HIV-testing standard, which requires the test to be in the best interests of the child, has been criticised as being unwieldy and a barrier to HIV testing.[18]

Conclusion

Post-apartheid SA has created a comprehensive SRH-rights framework for adolescents. The SA framework is different from that of many other countries, as it has legislated separately on many SRH services rather than simply creating a blanket age of consent to medical treatment. It has also introduced a number of protective public-policy measures to ensure that children are supported in making SRH decisions. There are several lessons that can be learned from the SA legislative experience. Firstly, legislating on the ages of consent to SRH services creates a framework within which youth-friendly services can be designed and implemented. Secondly, progressive new legislation that has decriminalised certain categories of underage consensual sex enables services to be provided in an accessible manner without state sanction. The age of consent to sex should not be a barrier to accessing SRH services. This requires that countries ensure harmony between the ages of consent to sex, medical treatment and any other SRH services, such as HIV testing. Thirdly, specifying that access to contraceptives, HIV testing and male circumcision fall outside the area of medical treatment creates clarity regarding the capacity requirements for each of these interventions. Countries are encouraged to follow this nuanced approach. If this is not possible, they should, at a minimum, provide that children can consent to medical treatment below the age of 18, and clarify the issue of specific SRH services through policies and regulations. SA has made a disputed cultural practice into a lawful SRH service. Other countries should be very cautious regarding this approach, and should carefully consider the value of this type of legal provision visà-vis the protection of children. Finally, as described, SA has a divergent approach to the evolving capacity of adolescents, with some anomalies. Careful consideration should be given to the capacity requirements for each intervention, in order to ensure that there is consistency in any legislative approach. Pragmatic guidance for service providers on how to assess capacity should also be drafted. In conclusion, SRH research with adolescents is critically important, but must occur alongside efforts to ensure that the legal framework is conducive to facilitating access to such improved services and products. Acknowledgements. The authors would like to thank reviewers for their helpful comments on this manuscript.

Author contributions. AS conceptualised the paper. AS and ZE both contributed to the content of the paper and revisions of drafts. Funding. The work described here was supported by the SA AIDS Vaccines Initiative (SAAVI) and the National Institutes of Health award (1RO1 A1094586) CHAMPS (Choices for Adolescent Methods of Prevention in SA). The content is solely the responsibility of the authors and does not necessarily represent the official views of SAAVI or the National Institutes of Health. This paper does not necessarily reflect the views of any institution or committee or council with which the authors are affiliated. Conflict of interest. None. 1. Teddy Bear Clinic for Abused Children, and Resources Aimed at the Prevention of Child Abuse and Neglect (RAPCAN) v Minister Of Justice And Constitutional Development And Another 2012 (Case Number 73300/10). 2. Department of Justice and Constitutional Development, South Africa. Criminal Law (Sexual Offences and Related Matters) Amendment Act No. 32 of 2007. 3. Bhamjee S, Essack Z, Strode AE. Amendments to the Sexual Offences Act dealing with consensual underage sex: Implications for doctors and researchers. S Afr Med J 2016;106(3):256-259. https://doi. org/10.7196/samj.2016.v106i3.9877 4. Sacks D, Canadian Pediatric Society. Age limits and adolescents. Paediatr Child Health 2003;8(9): 577. 5. South Africa. Children’s Act No. 38 of 2005. 6. South Africa. Choice of Termination of Pregnancy Act No 92 of 2007. 7. South Africa. Medicines and Related Substances Control Amendment Act No. 90 of 1997. 8. South Africa. Sterilisation Act No. 44 of 1998. 9. United Nations Development Programme. Global commission on HIV and the law: Risk, rights and health. New York: UNDP, 2012. 10. Joint United Nations Programme on HIV/AIDS (UNAIDS). All In To #EndAdolescentAIDS. Geneva: UNAIDS, 2015. 11. Strode A, Slack C, Essack Z. Child consent in South African law: Implications for researchers, service providers and policy-makers. S Afr Med J 2010;100(4):247-249. 12. Strode A, Slack C, Essack Z. Child consent in South African law – implications for researchers, service providers and policy-makers. S Afr Med J 2011;101(9):604-606. 13. Beksinska ME, Pillay L, Milford C, Smit JA. The sexual and reproductive health needs of youth in South Africa – history in context. S Afr Med J 2014;104(10):676-678. https://doi.org/10.7196/SAMJ.8809 14. Willan S. A review of teenage pregnancy in South Africa – experiences of schooling, and knowledge and access to sexual & reproductive health services. Partners in Sexual Health 2013:1-63. 15. Stats SA. General household survey. Statistical release P0318. 2012;318:1-164. 16. Shisana O, Rehle T, Simbayi LC, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Cape Town: HSRC Press, 2014. 17. Wood K, Jewkes R. Blood blockages and scolding nurses: Barriers to adolescent contraceptive use in South Africa. Reprod Health Matters 2006;14(27):109-118. https://doi.org/10.1016/S09688080(06)27231-8 18. Van Rooyen HE, Strode AE, Slack CM. HIV testing of children is not simple for health providers and researchers: Legal and policy frameworks guidance in South Africa. S Afr Med J 2016;106(5):451-453. https://doi.org/10.7196/samj.2016.v106i5.10484 19. Jackson S, Hafemeister TL. Impact of parental consent and notification policies on the decisions of adolescents to be tested for HIV. J Adolesc Health 2001;29(2):81-93. https://doi.org/10.1016/S1054139X(00)00178-6 20. Delany-Moretlwe S, Cowan FM, Busza J, Bolton-Moore C, Kelley K, Fairlie L. Providing comprehensive health services for young key populations: Needs, barriers and gaps. J Int AIDS Soc 2015;18(Suppl 1):S29. https://doi.org/10.7448/IAS.18.2.19833 21. Moodley N, Gray G. Global evidence reaffirms the case for routine HPV and potential HIV adolescent vaccination in South Africa. Future Virol 2014;9(2):207-220. https://doi.org/10.2217/fvl.13.131 22. Strode A, Toohey J, Slack C, Bhamjee S. Reporting underage consensual sex after the Teddy Bear case: A different perspective. S Afr J Bioeth Law 2013;6(2):45-47. https://doi.org/10.7196/SAJBL.289 23. Strode A, Slack C. Sex, lies and disclosures: Researchers and the reporting of under-age sex. S Afr J HIV Med 2009;10(2):8-10. 24. Essack Z, Strode A. The mandatory reporting of consensual, underage sex: Knowledge, practices and perspectives of social workers in KwaZulu-Natal. S Afr J Bioeth Law. 2015;8(2):21-25. https://doi. org/10.7196/SAJBL.435 25. Christian Lawyers Association v Minister of Health and Others (Reproductive Health Alliance as Amicus Curiae) 2005 (1) SA 509 (TDP). 26. Van Wyk C. HIV preventative vaccine research on children. Is it possible in terms of South African law and research guideline? Tydskrif vir Hedendaagse Romeins-Hollandse Reg 2005;68:35-50. 27. Essack Z, Toohey J, Strode A. Reflecting on adolescents’ evolving sexual and reproductive health rights: Canvassing the opinion of social workers in KwaZulu-Natal, South Africa. Reprod Health Matters 2016;24(47):195-204. https://doi.org/10.1016/j.rhm.2016.06.005 28. United Nations General Assembly. Convention on the Rights of the Child. Geneva: UN, 1989. 29. Gillick v West Norfolk and Wisbeck Area Health Authority and the DHSS, 1985 (3) All England Law Reports 402. House of Lords. 30. World Health Organization. Reproductive Health. Medical eligibility criteria for contraceptive use. Geneva: WHO , 2010. 31. Hein IM, Troost PW, Lindeboom R, et al. Accuracy of the MacArthur competence assessment tool for clinical research (MacCAT-CR) for measuring children’s competence to consent to clinical research. JAMA Pediatr 2014;168(12):1147-1153. https://doi.org/10.1001/jamapediatrics.2014.1694 32. Nelson LR, Stupiansky NW, Ott MA. The influence of age, health literacy, and affluence on adolescents’ capacity to consent to research. J Empir Res Hum Res Ethics 2016;11(2):115-121. https://doi. org/10.1177/1556264616636232 33. Mubangizi JC. A South African perspective on the clash between culture and human rights, with particular reference to gender-related cultural practices and traditions. J Int Womens Studies 2012;13(3):33.

Accepted 8 June 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

Building capacity for development and implementation of clinical practice guidelines Q Louw,1 PhD, MASP, BSc (Physio); J M Dizon,2,3 PhD, MSPT, BSPT; K Grimmer,1.2 PhD, MMedSc, LMusA, BPt, Cert Health Economics; MÂ McCaul,3 MSc (Clin Epi), BTech (EMC); T Kredo,4 5 MMed (Clin Pharm), MB ChB, Dip HIV Man; T Young,3,4 PhD, MMed, FCPHM, MB ChB Department of Physiotherapy, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa International Centre for Allied Health Evidence, School of Health Sciences, University of South Australia, Australia 3 Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 4 Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa 1 2

Corresponding author: Q Louw (qalouw@sun.ac.za)

Robust, reliable and transparent methodologies are necessary to ensure that clinical practice guidelines (CPGs) meet international criteria. In South Africa (SA) and other low- and middle-income countries, upskilling and training of individuals in the processes of CPG development is needed. Since de novo CPG development is time-consuming and expensive, new emerging CPG-development approaches (adopting, contextualising, adapting and updating existing good-quality CPGs) are potentially more appropriate for our context. These emerging CPG-development methods are either not included or sparsely covered in existing training opportunities. The SA Guidelines Excellence (SAGE) team has responded innovatively to the need for CPG training in SA. We have revised an existing SA course and developed an online, open-access CPG-development toolkit. This Guideline Toolkit is a comprehensive guideline resource designed to assist individuals who are interested in knowing how to develop CPGs. Findings from the SAGE project can now be implemented with this innovative CPG training programme. This level of CPG capacity development has the potential to influence CPG knowledge, development, practices and uptake by clinicians, managers, academics and policy-makers around the country. S Afr Med J 2017;107(9):745-746. DOI:10.7196/SAMJ.2017.v107i9.12527

Robust, reliable and transparent methodologies must be followed to ensure that clinical practice guidelines (CPGs) meet international criteria. Over the past few years, leading international guideline groups have made significant strides in refining and describing the rigour required when developing good-quality CPGs.[1] These quality standards require the inclusion of a diverse team of stakeholders.[2] However, these stakeholders often have varying backgrounds, limited experience in CPG development and limited competency in determining the strength of the body of evidence and how this underpins recommendations. Within our context and in other lowand middle-income countries, upskilling and training individuals in the processes of CPG development is crucial to facilitate uniformity and quality in how CPGs are developed, written and implemented. In addition, training an increasing number of individuals in CPGdevelopment skills will build capacity in CPG development, which will continue to advance progress to standardising practices of care. One of the main goals of the South Africa Guidelines Excellence (SAGE) project[3] is capacity building in developing, implementing and evaluating training for best-practice training modules regarding CPG activities. To understand the international landscape in CPG training, the SAGE team conducted a review of all CPG courses currently being conducted globally. We found that CPG training courses, albeit limited, are mostly delivered by universities (as component courses of professional degrees) and professional groups (as short courses). In addition, groups dedicated to CPG activities (such as the Guideline International Networks) have published information about CPG development on their websites, which provides some guidance. Our assessment of CPG courses also showed that all currently available courses focus on developing de novo (new) guidelines.[1] The focus of the course content includes identifying a topic or condition of

interest, searching for the evidence, appraising the evidence, synthesising the evidence and formulating recommendations. Since de novo CPG development is time-consuming and expensive, there are new emerging CPG-development approaches (adopting, contextualising, adapting, and updating existing good-quality CPGs[4] that are potentially more appropriate in low- and middle-income settings, where there is a need for practical and efficient evidence translation rather than recreating the wheel of evidence synthesis. These emerging CPG-development methods, as well as other important topics linked to CPGs, such as updating and implementation, are either not included or sparsely covered in existing training opportunities. The SAGE team has responded innovatively to the need for CPG training in South Africa (SA), as well as to addressing the gaps in currently available training courses. Using an already-available CPG module offered as part of the Masters in Clinical Epidemiology at Stellenbosch University (www.sun.ac.za/clinepi), we have transformed the content of this module. The main outcomes of the module (which is also registered as a short course) are shown in Table 1. There is currently no available standard set of requirements and training for planning, conducting and evaluating CPG courses. We also found in our assessment of existing courses that the duration and delivery of CPG courses varied considerably.[4] CPG courses were delivered in different formats, such as face-to-face, in online sessions and in group discussions. Our course uses adult learning strategies delivered in a blended mode of contact and e-learning platforms. The course is presented over one semester, and participants have the option of completing the course based on attendance or on competence, in which case all assessments must be completed. We have further enhanced the SA course by developing an online, open-access CPG-development toolkit.[5] This Guideline Toolkit

September 2017, Print edition

IN PRACTICE

Table 1. Main outcomes of clinical-practice-guideline module objectives 1. Outline principles of evidence-based healthcare and study designs 2. Describe principles and different methods of evidence-based clinical-guideline development (de novo and alternative methods) 3. Critically appraise clinical guidelines using rapid and complex tools 4. Outline principles of grading the quality of evidence to inform clinical-guideline development 5. Discuss approaches in moving from evidence to recommendations 6. Understand concepts in writing recommendations 7. Outline principles of implementation of clinical guidelines including consideration of stakeholders, and barriers and facilitators to successful guideline implementation 8. Develop a plan for implementation of a clinical guideline using appropriate strategies 9. Outline methods of monitoring and evaluating a clinical guideline

(guidelinetoolkit.org.za) is a comprehensive guideline resource designed to assist individuals who are interested in learning how to develop CPGs. Presented in a user-friendly manner, this online toolkit facilitates access to relevant available global resources to support each of the processes involved in guideline writing. This toolkit includes a decision-making algorithm to assist users in making a decision on which CPG approach should be followed (i.e. de novo development or alternative methods such as adopting, adapting and/or contextualising). Descriptions and resources for each of these CPG methods are hosted on the site.

Conclusion

Project SAGE has provided a unique opportunity in SA to research CPG processes and outcomes. Findings from the project are now able to be implemented in this innovative CPG training programme, which has the potential to influence CPG knowledge, practices and uptake by clinicians, managers, academics and policy-makers around the country. Acknowledgements. We would like to acknowledge Dr Linzette Morris, who assisted with the development of the online resource.

Author contributions. All authors contributed to the conceptualisation and drafting of this paper. Funding. The authors were funded, partially or in full, by the SAGE project, a 3-year (2014 - 2017) Flagship Grant from the SA Medical Research Council. The Flagship Grant programme was not involved in the conceptualisation or conduct of this study. Conflict of interest. None. 1. Schünemann R, Brożek H, Guyatt G, Oxman A, eds. GRADE Handbook: Handbook for Grading the Quality of Evidence and the Strength of Recommendations using the GRADE Approach. Hamilton, Canada: The Grade Working Group, 2013. 2. Grimmer K, Dizon JM, Louw Q, Kredo T, Young T, Machingaidze S. South African Guidelines Excellence (SAGE): Efficient, effective and unbiased clinical practice guideline teams. S Afr Med J 2016;106(5):26-27. https://doi.org/10.7196/SAMJ.2016.v106i5.10770 3. South African Medical Research Council. South African Guideline Excellence Project. http://www. mrc.ac.za/cochrane/sage.htm (accessed March 2017). 4. Dizon JMR, Ochodo E, Young T, et al. A review of teaching and learning strategies and existing CPG courses for effective training in clinical practice guideline development approaches. Presented at the Guidelines International Network (GIN) Conference, 26 - 30 September, Philadelphia, USA, 2016. 5. SAGE Project. SAGE – Guideline Toolkit. https://guidelineto olkit.org.za/ (accessed 23 March 2017).

Accepted 24 April 2017.

CASE REPORT

This open-access article is distributed under CC-BY-NC 4.0.

Orbital apex syndrome after trauma in a 6-year-old – a rare occurrence A Ahmed, MB BCh, Dip Ophth (SA)

Registrar, Department of Ophthalmology, Grey’s Hospital, Pietermaritzburg, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: A Ahmed (afrozeahmed242@gmail.com)

Orbital apex syndrome is rare, but can occur as a consequence of trauma from fracture of the medial orbit. This case report highlights the fact that a high index of suspicion is needed when a patient presents with a facial injury, especially in children who cannot give an account of the actual events that transpired. Radiological investigation should be done early when an underlying injury is suspected in a trauma patient. A low threshold for computed tomography should be maintained when proptosis and vision loss are present. S Afr Med J 2017;107(9):747-749. DOI:10.7196/SAMJ.2017.v107i9.12465

September 2017, Print edition

IN PRACTICE

Case report

A 6-year-old boy was brought to the casualty department at Northdale Hospital, Pietermaritzburg, South Africa, after having fallen onto a tree stump while playing in a park. There was no history of loss of consciousness, vomiting or seizures after the fall. He was awake and orientated to person, place and time when he arrived at the hospital. On examination he was found to have swelling and abrasions on the middle of the forehead, the left cheek and the left upper eyelid. There were no eyelid lacerations. The pupils were equal and reactive. There was no documented hyphaema or chemosis of the eye, but there was conjunctivitis. There was no objective documentation or examination of the eye movements. A skull radiograph was done, and no fractures were noted. The final assessment of the patient by the casualty officer was blunt-force trauma with no vision loss, and he was discharged with analgesics and chloromycetin ointment. Nine days later the patient was brought to casualty again, complaining of headaches and pain originating from the left eye. There was also an unusual complaint of bleeding from the eye. According to the notes, his vital signs were documented as stable. On examination of the eye, there was chemosis but no hyphaema or conjunctivitis. All eye movements were documented as having a full range in all directions. The eyes were irrigated, and the patient was discharged again with chloromycetin ointment and analgesics. Of note, this was a different doctor from the first, and no further radiological investigations were done. Three days later the patient’s mother brought him to Northdale Hospital for the third time, and he was finally referred to the eye clinic. In the eye clinic his visual acuity was assessed as 6/18 in the right eye and poor light perception in the left eye. The intraocular pressure (IOP) in the right eye was 22 mmHg and that the left eye 33 mmHg. There was a 4 mm proptosis of the left eye compared with the right eye, measured with an exophthalmometer. The findings on anterior segment examination of the right eye were normal. Examination of the fundus showed a normal pink disc with a 0.1 cup/disc ratio. The macula of both eyes was normal. Examination of the left eye showed the following: • There was complete ptosis of the left eyelid. • Proptosis was evident. • The conjunctiva was clear. • The cornea was clear. • The anterior chamber was deep and no cells or flare were noted. • The lens was clear, but the pupil was mid-dilated. • There was a reactive afferent pupillary defect. • The extraocular muscles showed no movement in all cardinal directions of the eye, and it was centrally fixed in the orbit. • Fundus examination showed a pink disc, a cup/disc ratio of 0.2, and no swelling of the optic disc. The patient was assessed as having complete ophthalmoplegia, ptosis and proptosis of the left eye. He was immediately referred to a tertiary hospital and an emergency computed tomography (CT) scan of the brain and orbits with contrast was booked for the same day. The scan revealed a left medial blow-out fracture through the anterior lamina papyracea with no extraocular muscle entrapment. There was a haematoma of the left extraocular muscles and enlargement of the left optic nerve. A small haematoma extended through to the cavernous sinus. All the paranasal sinuses were normal. Further details from the CT report are given below. Intravenous dexamethasone, analgesia and antibiotics were prescribed. There was no improvement over the following 3 days

in the ward, and the patient was discharged with a review date. Unfortunately owing to the delay in diagnosis the eye was permanently damaged and the outcome was poor.

Further details from the CT report

• Orbits. There was enhancement and thickening of the left inferior oblique muscle measuring 8.31 mm. The right inferior oblique muscle measured 3.02 mm. It caused indentation of the globe inferomedially, and lateral displacement of the globe. The left medial rectus muscle was thickened (left medial rectus 6.48 mm, right medial rectus 3.66 mm). Retrobulbar intraconal fat stranding was present. There was no evidence of vitreous haemorrhage. The globe was intact. The left optic nerve was enlarged (left optic nerve 7.37 mm, right optic nerve 6.16 mm). There was a blowout fracture of the anterior lamina papyracea with extrusion of fat but no extraocular muscle entrapment. No orbital emphysema was seen. Sellar and suprasellar structures were normal. Fig. 1 shows the fracture, the intraconal fat stranding and the enlarged optic nerve. • Brain. There were no intra- or extra-axial collections and no evidence of a haematoma formation or mass effect. The basal ganglia and posterior fossa structures were normal. No parenchymal or focal abnormality was seen. The basal cisterns and foramen magnum were patent. No fracture was seen on the calvarium. • Conclusion. Left medial blow-out fracture through the anterior lamina papyracea with no entrapment of the extraocular muscles. Haematoma of the left extraocular muscles as described. Enlargement of the left optic nerve in keeping with orbital trauma.

Discussion

Orbital apex syndrome (OAS) has been described as a syndrome involving damage to the oculomotor nerve (CN3), trochlear nerve (CN4), ophthalmic branch of the trigeminal nerve (CN5) and

Fig. 1. Computed tomography scan showing medial fracture of the lamina papyracea with intraconal fat stranding (red arrow). The left optic nerve is thickened (yellow arrow).

September 2017, Print edition

IN PRACTICE

abducens nerve (CN6) in association with optic nerve dysfunction.[1] OAS consists of paralysis of all the extraocular muscles and a sensory deficit in the distribution of the first division of the trigeminal nerve, combined with an optic nerve lesion.[2] The orbital apex is defined as the region between the posterior ethmoidal foramen and the openings of the optic canal and the superior orbital fissure.[3] The apex of the orbital bone is the entry portal for all the nerves and vessels of the eye and the site of origin of all the extraocular muscles except the inferior oblique.[4] OAS can be classified as having neoplastic, inflammatory, viral, fungal, traumatic or vascular causes.[5] Although trauma is one of the main causes,[6] reports of OAS associated with facial bone fractures are relatively rare.[7-10] There are only 17 reported cases in the literature, with the locations of the fractures as follows: 7 medial wall, 7 lateral wall, 1 floor, 1 roof, 1 floor and roof.[6-10] These fractures were probably due to a globe-to-wall contact mechanism.[12] In the treatment of OAS associated with orbital fractures, the therapeutic targets are saving the globe, saving the third to sixth cranial nerves, and saving the optic nerve.[5] The globe itself is highly vulnerable to permanent injury after an orbital fracture. Many complications from the trauma itself, such as hyphaema, lens dislocations or retinal detachments, as well as scleral rupture, may occur at the time of injury and contribute to permanent visual impairment.[5] Early ophthalmological referral and management are imperative after any diagnosis of orbital fracture.[5] Our patient was not referred early, and there was a 2-week delay before he was seen by an ophthalmologist. The nature of the fracture was not recognised at the first visit, and only a radiograph of the skull and facial bones was done. It was interpreted by the casualty officer, with no formal report by the radiologist, and the patient was sent home. He was next seen 9 days after the initial consultation, and by a different doctor. Only later, on suspicion that all was not well, was he referred to the eye clinic at the hospital. It was therefore 2 weeks after the initial injury that a CT scan of the brain and orbits was done. He was admitted to a tertiary hospital and given pulse steroid therapy over 3 days. This did not improve his condition, and there was no restoration of vision to the affected eye. Non-operative intervention in OAS may consist of administration of high doses of corticosteroids to reduce microcirculatory spasm, oedema and nerve cell necrosis.[13] The best outcomes occur with early diagnosis and early use of steroids, because irreversible ischaemic damage occurs within several hours. Treatment with steroids was unsuccessful in our patient because the time lapse between the injury and steroid administration was too great.[5] In such cases, delayed and progressive loss of vision implies that a viable nerve is being compressed by blood and oedema. Early treatment may improve the prospects of recovery.[14]

Conclusion

This case report highlights the significance of prompt and appropriate radiological investigation of the patient with ocular injury, in the form of a CT scan at the time of first presentation. Importantly, if like ours the patient comes back to casualty repeatedly, the attending doctor should suspect that all is not well and there is an underlying pathology. A skull radiograph was not adequate in this case owing to the nature of the complaint, the age of the patient and the scanty history. Appropriate referral is important, as visual acuity was not assessed at the patient’s first two visits, the IOP was not measured, and there was therefore no comment on what the condition of or vision in the eye was at the initial visit. The child has been left with permanent loss of vision in the left eye, and it is quite possible that this could have been avoided with prompt intervention and referral. Acknowledgements. The patient’s parents gave formal written consent for the use of his CT images and medical case notes in this article. I also thank Prof. A Stulting for reviewing the article. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. Yeh S, Foroozan R. Orbital apex syndrome. Curr Opin Ophthalmol 2004;15(6):490-498. https://doi. org/10.1097/01.icu.0000144387.12739.9c 2. Bray WH, Gianciacomo J, Ide CH. Orbital apex syndrome. Surv Ophthalmol 1987;32(2):136-140. https://doi.org/10.1016/0039-6257(87)90106-8 3. Ettl A, Zwrtek K, Daxer A, Salomonowitz E. Anatomy of the orbital apex and cavernous sinus on high resolution magnetic resonance images. Surv Ophthalmol 2000;44(4):303-323. https://doi.org/10.1016/ S0039-6257(99)00115-0 4. Shahid A, Ahmad I. Mucormycosis causing palatal necrosis and orbital apex syndrome. J Coll Physicians Surg Pak 2005;15(3):182-183. 5. Sugamata A. Orbital apex syndrome associated with fractures of the inferomedial orbital wall. Clin Ophthalmol 2013;7:475-478. https://doi.org/10.2147/OPTH.S42811 6. Peter NM, Peterson A. Orbital apex syndrome from blunt ocular trauma. Orbit 2010;29(1):42-44. https://doi.org/10.3109/01676830903190123 7. Bernard A, Sadowsky D. Monocular blindness secondary to a non displaced molar fracture. Int J Oral Maxillofac Surg 1986;15(2):206-208. https://doi.org/10.1016/S0300-9785(86)80143-0 8. Acarturk S, Dalay C, Kivanc O, Varinli I. Orbital apex syndrome associated with fractures of the zygoma and orbital floor. Eur J Plast Surg 1993;16(2):67-69. https://doi.org/10.1007/BF00196434 9. Martello JY, Vasconez HC. Supraorbital roof fractures: A formidable entity with which to contend. Ann Plast Surg 1997;38(3):223-227. https://doi.org/10.1097/00000637-199703000-00006 10. Li Y, Wu W, Xiao Z, Peng A. Study on the treatment of traumatic orbital apex syndrome by nasal endoscopic surgery. Eur Arch Otorhinolaryngol 2011;268(3):341-349. https://doi.org/10.1007/s00405010-1409-6 11. Bater MC, Ramchandani PL, Ramchandani M, Flood TR. An orbital apex fracture resulting in multiple cranial neuropathies. Br J Oral Maxillofac Surg 2008;46(2):163-164. https://doi.org/10.1016/j. bjoms.2007.03.001 12. Sugamata A, Yoshizawa N. Clinical analysis of orbital blowout fractures caused by a globe to wall contact mechanism. J Plast Surg Hand Surg 2010;4(6):278-281. https://doi.org/10.3109/2000656X.2010.534614 13. Eo S, Kim JY, Azari K. Temporary orbital apex syndrome after repair of orbital wall fracture. Plast Reconstr Surg 2005;116(5):85e-89e. https://doi.org/10.1097/01.prs.0000182351.29929.7a 14. Lipkin IF, Woodson GE, Miller RH. Visual loss due to orbital fracture: The role of early reduction. Arch Otolaryngol Head Neck Surg 1987;113(1):81-83. https://doi.org/10.1001/archotol.1987. 01860010085021

Accepted 5 June 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria O Ijarotimi,1 FWACP; D O Soyoye,1 FMCP; O Adekanle,1 FMCP; D A Ndububa,1 FWACP; B I Umoru,2 FWACP; O I Alatise,3 FMCS, FWACS Department of Medicine, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria Department of Medicine, Federal Medical Center, Lokoja, Nigeria 3 Department of Surgery, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria 1 2

Corresponding author: O Ijarotimi (segjarot@hotmail.com) Background. Duodenal ulcer is the most common peptic ulcer disease worldwide. In the past, sub-Saharan Africa has been described as an area of mixed prevalence for peptic ulcer disease, but recent reports have disputed this. Changes in the prevalence of duodenal ulcer have been reported, with various reasons given for these. Objective. To describe the change in endoscopic prevalence of duodenal ulcer at Obafemi Awolowo University Teaching Hospital (OAUTH), Ile-Ife, Nigeria, between January 2000 and December 2010. Methods. This was a retrospective, descriptive study of patients who underwent upper gastrointestinal endoscopy in the endoscopy unit of OAUTH between January 2000 and December 2010. The data were obtained from the endoscopy register, demographic indices, presenting symptoms and post-endoscopic diagnoses being retrieved for each patient. The study period was divided into the years 2000 - 2004 and 2005 - 2010, the frequencies of duodenal ulcer and other post-endoscopic diagnoses being compared between these two time periods to see whether there were changes. Results. Over the study period, 292 patients (15.8%) were diagnosed with duodenal ulcer, second only to 471 patients (26.2%) with acute gastritis. The prevalence of duodenal ulcer for 2000 - 2004 was 22.9% (n=211 patients) compared with 9.2% (n=81) for 2005 - 2010 (p<0.001). Conclusion. There was a significant decline in the endoscopic prevalence of duodenal ulcer over the decade. S Afr Med J 2017; 107(9): 750-753. DOI: 10.7196/SAMJ.2017.v107i9.12342

Duodenal ulcer is the most common peptic ulcer disease worldwide. It is commoner than gastric ulcer.[1] It is not easy to distinguish between the two on the basis of the clinical presentation alone, so patients require upper gastrointestinal endoscopy to visualise and identify each ulcer. A decreasing prevalence of peptic ulcer disease has been observed in North America[2] and the Asia-Pacific region.[3] Several reasons have been suggested for this decline. The actual prevalence of duodenal ulcer in the general population is difficult to determine, because upper gastrointestinal endoscopy is not routinely done for every patient with dyspepsia. Most patients who do not undergo endoscopy are aged <45 years, with previously uninvestigated and uncomplicated dyspepsia.[4] This age cut-off may vary between countries, depending on the prevalence of gastric cancer. Over-prescription and indiscriminate use of drugs such as antibiotics[5] and proton pump inhibitors[6] can also affect the prevalence of duodenal ulcer. Both drugs have activity against Helicobacter pylori, a major risk factor for peptic ulcer disease worldwide.[7] Their effects can be curative when both are used as part of triple or quadruple anti-Helicobacter therapy. However, they can lead to temporary resolution of ulcer symptoms even when they are not correctly used as part of such a regimen. They can also cause temporary suppression of the H. pylori activity in such cases.

Objective

To describe the changing endoscopic prevalence of duodenal ulcer between January 2000 and December 2010 at Obafemi Awolowo University Teaching Hospital (OAUTH), Ile-Ife, Nigeria.

Methods

This was a retrospective, descriptive study of patients who underwent upper gastrointestinal endoscopy at the endoscopy unit of OAUTH.

The study data were retrieved from the endoscopy register, where the demographic data, indications for the procedure and endoscopic findings are recorded for all patients. The study participants were all patients who underwent complete upper gastrointestinal endoscopy during the study period January 2000â&#x20AC;&#x2026;-â&#x20AC;&#x2026;December 2010. The data were collected per endoscopy and not per patient, i.e. the information was based on the number of procedures done over this time period and not the number of patients. This allowed for quick and easy data collection. (In the article, however, we refer to patients and give numbers of patients. Although the data were collected based on the number of procedures, so some patients may have had more than one procedure during the study period, we believe that the incomplete procedures and missing diagnoses that were excluded from the study probably negate the effect of data duplication and bring the situation closer to one patientÂ = one procedure. We also believe that the large sample size makes any minimal data duplication insignificant with regard to the main outcome of the study.) All aborted procedures were excluded from the study, as the full extent of the diagnosis might not be known. They were mostly rescheduled for another time. This was helpful in limiting the duplication of data. Variables analysed were demographic data (age and sex of patients), presenting symptoms (the indications for upper gastrointestinal endoscopy), and post-endoscopic diagnoses (the diagnoses made on the basis of the findings).

Procedure

All the patients fasted overnight before the procedure. They all consented to the procedure after full information had been provided to them. The procedure was done with the patient conscious and lying in the left lateral position.

September 2017, Print edition

RESEARCH

Topical pharyngeal anaesthesia was achieved with 10% xylocaine spray. This was followed by the intravenous injection of midazolam 2.5 mg or diazepam 5 mg, depending on which was available at the time. The exceptions were individuals in whom sedatives/hypnotics were contraindicated. Patients were also given 20 mg hyoscine butylbromide intravenously before the start of the procedure.

2005 - 2010 (p=0.169) (Table 1). However, there was a significant difference in median ages between the years 2000 - 2004 and 2005 2010 (p=0.044) (Table 1).

Presenting symptoms

The data were collected between the years 2000 and 2010. Demographic data, presenting symptoms and post-endoscopic diagnoses, where available, were retrieved for each patient over this time period. The study period was divided into the years 2000 - 2004 and 2005 - 2010, and the variables were compared between these two periods to see whether there were changes in their frequency of occurrence between the first half of the study period and the latter half.

Dyspepsia was the commonest indication for upper gastrointestinal endoscopy (Table 1). Of the patients, 1 335 (74.6%) presented with dyspepsia and 166 (9.2%) with upper gastrointestinal bleeding. There was a significant decline in the number of patients who underwent upper gastrointestinal endoscopy for investigation of dyspepsia in 2005 - 2010 compared with 2000 - 2004 (p<0.001) (Table 1). The number of patients who underwent upper gastrointestinal endoscopy for investigation of upper gastrointestinal bleeding and suspected mitotic lesion increased significantly over the same time periods (p<0.001) (Table 1).

Statistical analysis

Post-endoscopic diagnoses

Data collection

Data were analysed using the Statistical Package for the Social Sciences (SPSS), version 21.0 (IBM, USA). Medians and ranges were calculated for continuous variables, whereas proportions and frequency tables were used to summarise categorical variables. The Mann-Whitney U-test, a non-parametric test, was used to compare the median ages between the two study periods. The χ2 test and logistic regression analysis were used to test for significance of association between the independent (predictor) and dependent (outcome) variables for categorical variables. The level of significance was set at p<0.05.

Ethics and approval

All patients gave written informed consent for the procedure. Ethical clearance was obtained from the OAUTH Ethics and Research Committee (ref. no. IRB/IEC/0004553: NHREC/27/02/2009a).

Results

Demographic characteristics

A total of 1 937 patients underwent upper gastrointestinal endoscopy during the study period, of whom 138 were excluded owing to missing post-endoscopic diagnoses or incomplete procedures. A total of 1 799 patients were therefore included in the study, of whom 986 were males (54.8%) and 813 females (45.2%). The ages of the patients ranged from 3 to 100 years (median 45). There was no significant difference in the sex distribution between the years 2000 - 2004 and

Duodenal ulcers were found in 292 patients (15.8%); this was second only to acute gastritis (n=471, 26.2%) (Table 2). Gastric ulcers were found in 237 patients (13.2%), while gastric erosions were seen in 158 (8.8%). The frequency of occurrence of duodenal ulcer in 2000 - 2004 was 22.9% (n=211), compared with 9.2% (n=81) in 2005 - 2010 (p<0.001) (odds ratio 0.298, 95% confidence interval 0.222 - 0.400) (Table 3). There was a significant difference in the prevalence of duodenal ulcer between the two time periods, duodenal ulcer being 3.3 times less common in 2005 - 2010 compared with 2000 - 2004.

Discussion

The overall prevalence of duodenal ulcer in this study was 15.8% between 2000 and 2010. This is much lower than the 38.7% reported by Ndububa et al.[8] for the years 1992 - 1999. The two studies were done at the same institution but at different times. There was a significant decline in the prevalence of duodenal ulcer, from 22.9% in 2000 - 2004 to 9.2% in 2005 - 2010. Unexpectedly, the prevalence of gastric ulcer, a peptic ulcer disease like duodenal ulcer, did not fall over the same study periods. The trend of a decline in duodenal ulcer prevalence has also been reported by other studies in Nigeria,[9] North America[2] and the Asia-Pacific region.[3] It is therefore not unique to our centre. The significant decline in the number of patients who underwent

Table 1. Comparison of age, sex and presenting symptoms of patients undergoing upper gastrointestinal endoscopy between 2000 - 2004 and 2005 - 2010 Variables Sex, n (%) Male Female Age (yr), median Presenting symptom, n (%) Dyspepsia Gastrointestinal bleeding Suspected mitotic lesion Gastric outlet obstruction Liver cirrhosis Foreign body Other†

2000 - 2004 (N=921)

2005 - 2010 (N=878)

2000 - 2010 (N=1 799)

490 (53.2) 431 (46.8) 45

496 (56.5) 382 (43.5) 46.5

986 (54.8) 813 (45.2) 45

0.044*

733 (79.6) 58 (6.3) 53 (5.8) 39 (4.2) 20 (2.2) 4 (0.4) 10 (1.1)

602 (68.6) 108 (12.3) 95 (10.8) 36 (4.1) 9 (1.0) 2 (0.2) 16 (1.8)

1 335 (74.6) 166 (9.2) 148 (8.2) 75 (4.2) 29 (1.6) 6 (0.3) 26 (1.4)

<0.001 <0.001 <0.001 0.907 0.061 0.688 0.236

*Mann-Whitney U-test. † Suspected achalasia, motility disorders.

September 2017, Print edition

p-value 0.169

RESEARCH

Table 2. Post-endoscopic diagnoses (N=1 799) Variables Acute gastritis Duodenal ulcer Gastric ulcer Atrophic gastritis GORD Gastric erosion Normal endoscopic finding Gastric tumour Oesophageal varices Gastric polyp Duodenal polyp Oesophageal tumour Early gastric cancer Other†

Patients, n (%)* 471 (26.2) 292 (15.8) 237 (13.2) 188 (10.5) 176 (9.8) 158 (8.8) 155 (8.6) 100 (5.6) 79 (4.4) 20 (1.1) 12 (0.7) 13 (0.7) 26 (1.4) 69 (3.8)

GORD = gastro-oesophageal reflux disease. *Some patients had multiple pathologies, so the post-endoscopic diagnoses outnumber the total number of patients and the percentages total more than 100%. † Oesophageal stricture/ulcers/erosions, achalasia, foreign-body ingestion, external compression of the stomach/duodenum.

upper gastrointestinal endoscopy to investigate dyspepsia over the study period further supports a true decline in the prevalence of duodenal ulcer. Several reasons were given for this decline in North America and the Asia-Pacific region. They were a reduced prevalence of H. pylori infection, improved hygiene and improved eradication of H. pylori.[2,3] This is not the case in Nigeria, where the incidence of H. pylori infection is still very high.[10] Overprescription and widespread use of drugs such as antibiotics[5] and proton pump inhibitors [6] could also be responsible for the decline in duodenal ulcer prevalence. H. pylori is a major risk factor for duodenal ulcer.[7] It is responsive to both proton pump inhibitors and antibiotics, either partially or completely. Increased use of proton pump inhibitors and antibiotics, albeit for other reasons, could therefore suppress this organism and encourage temporary healing and resolution of the symptoms of duodenal ulcer. There is widespread indiscriminate use of antibiotics in Nigeria.[5] We did not document the overuse of proton pump inhibitors in our patients, our study being a retrospective one; in fact, there are currently no Nigerian studies documenting this. However, overuse of these drugs,

which have anti-H. pylori and mucosal healing properties, has been documented in other parts of the world.[6] The personal experience of the first author (OI) is that proton pump inhibitors are widely used by patients who come to our centre complaining of dyspepsia. Patients are likely to have used both proton pump inhibitors and antibiotics before they undergo upper gastrointestinal endoscopy, which is usually performed because these empirical treatments have failed. However, the above reason does not explain the non-decline of gastric ulcer prevalence in this study. H. pylori is also a causal agent for gastric ulcer.[7] The widespread use of antibiotics and proton pump inhibitors should also affect the prevalence of gastric ulcer and cause a decline like that of duodenal ulcer, but the prevalence of gastric ulcer was steady over the study period. There was even a rise in prevalence compared with the study done by Ndububa et al.,[8] from 4.7% in 1992 - 1999[8] to 13.2% for our study period 2000 2010. Even the prevalence of gastric erosions, which should also be affected by the overuse of proton pump inhibitors, increased – from 2.9%[8] to 8.8% in our study. The reasons for the above anomaly are not very clear, considering the decline in the prevalence of duodenal ulcer over the same periods. However, it could be due to the increased use of aspirin and non-steroidal anti-inflammatory drugs in Nigeria over the past two decades.[11] These drugs are prominent causes of gastric ulcers and erosions, and can also cause upper gastrointestinal bleeding. The increased incidence of upper gastrointestinal bleeding in our study could also be due to increased use of aspirin and nonsteroidal anti-inflammatory drugs in Nigeria. Other factors that may be responsible for the decline in the prevalence of duodenal ulcer over the study period should be considered because of the unexpected difference in the changing prevalence patterns of duodenal ulcer and gastric ulcer. One of these is the expertise of the endoscopist – his or her ability to achieve duodenal intubation and to recognise gastrointestinal lesions, including duodenal ulcer. Several endoscopists did the endoscopies in our study, from both the surgical and medical specialties. They had differing levels of competence. Whether this variation in competence is sufficient to affect the apparent prevalence of duodenal ulcer is a question that is difficult to answer. Auditing the upper gastrointestinal endoscopic procedures done by each individual endoscopist would show each one’s contribution to the prevalence of duodenal ulcer over the study period. Only then would we know whether levels of competence in fact played a major role.

Table 3. Comparison of prevalences of post-endoscopic diagnoses between 2000 - 2004 and 2005 - 2010

Diagnosis Duodenal ulcer Gastric ulcer Acute gastritis Atrophic gastritis GORD Gastric erosion Oesophageal varices Gastric tumour Oesophageal tumour Gastric polyp Duodenal polyp

2000 - 2004* (N=921), n (%)† 211 (22.9) 117 (12.7) 249 (27.0) 93 (10.1) 90 (9.8) 79 (8.6) 29 (3.1) 61 (6.6) 10 (1.1) 11 (1.2) 3 (0.3)

2005 - 2010 (N=878), n (%)† 81 (9.2) 120 (13.7) 222 (25.3) 95 (10.8) 86 (9.8) 79 (9.0) 50 (5.7) 39 (4.4) 3 (0.3) 9 (1) 9 (1)

B –1.211 –0.140 –0.304 –0.158 –0.212 –0.065 0.287 –0.683 –1.446 –0.251 0.859

p-value <0.001 0.352 0.010 0.333 0.202 0.708 0.242 0.002 0.029 0.586 0.201

OR 0.298 0.870 0.738 0.854 0.809 0.937 1.332 0.505 0.235 0.778 2.361

GORD = gastro-oesophageal reflux disease; B = beta coefficient; OR = odds ratio; CI = confidence interval. *2000 - 2004 is the reference category for the dependent variable. Negative post-endoscopic diagnoses are the reference categories for each of the independent variables. † Some patients had multiple pathologies, so the post-endoscopic diagnoses outnumber the total number of patients and the percentages total more than 100%.

September 2017, Print edition

95% CI 0.222 - 0.400 0.648 - 1.167 0.586 - 0.929 0.620 - 1.175 0.585 - 1.120 0.668 - 1.315 0.823 - 2.156 0.330- 0.774 0.064 - 0.863 0.315 - 1.922 0.633 - 8.807

RESEARCH

Our hospital is a tertiary institution and referral centre, and we probably do not see many uncomplicated cases of peptic ulcer disease. These patients are likely to consult their primary care physicians because of ease of access, and will only be referred if they develop complications. This apparent reduction in the burden of duodenal ulcer could be misinterpreted as a reduction in its prevalence. There was an increase in the number of patients who underwent upper gastrointestinal endoscopy in our study (N=1 799) compared with the study by Ndububa et al.[8] in the same endoscopy unit (N=834). However, this did not translate into an increased prevalence of duodenal ulcer – instead, there was a decrease in prevalence over the two decades. The reduction in duodenal ulcer prevalence was therefore not due to a reduced number of endoscopic referrals, as the reverse is the case. Instead it may be due to the choice of patients being referred, as explained above. However, referral bias may not have as much effect as would be expected, because most endoscopies are done in tertiary institutions like ours. Our results were based mainly on endoscopic diagnoses of duodenal ulcer, and not symptomatic diagnoses. Furthermore, referral bias does not explain why the prevalence of duodenal ulcer decreased, while that of gastric ulcer did not. Upper gastrointestinal endoscopy is not routinely done for patients with dyspepsia, especially those aged <45 years,[4] despite dyspepsia being a major symptom of peptic ulcer disease (the exceptions being patients with symptoms or signs that may suggest gastrointestinal bleeding, gastrointestinal malignancy or gastric outlet obstruction). [12] This is because the risk of gastric cancer is low in this age group and most of these patients have negative endoscopic findings. This is intended as a cost-saving measure, and a means of avoiding the possible complications of endoscopy. However, it would prevent the actual prevalence of duodenal ulcer from being known, especially in patients aged <45, as it would lead to a falsely reduced endoscopic prevalence of duodenal ulcer. Most patients aged <45 are treated empirically or on the basis of non-invasive tests for H. pylori such as a urea breath test and a stool antigen test. However, this also does not explain the difference in prevalence between gastric and duodenal ulcer.

Study limitations

A limitation of the study is that it is retrospective. The information was collected from a joint surgical and medical endoscopy register, and there was no way to obtain more than what was recorded there. Furthermore, there was no way to go back and review the diagnoses, as they were based on a one-time-look procedure by the endoscopist. Another important limitation of this study is that the patients whose records were analysed may not be representative of the general population, because it was a hospital-based study and not a community-based one. A further limitation is that the data were collected on a per endoscopy basis and not per patient. This would have led to duplication of some data and could have affected the validity of the results. However, it is difficult to ascertain the magnitude of this effect, and whether it would have led to an increase or a decrease in the endoscopic prevalence of duodenal ulcer.

Conclusion

This study showed a decline in the endoscopic prevalence of duodenal ulcer over the decade 2000 - 2010 in our institution. The significant reduction in the number of patients who underwent upper gastrointestinal endoscopy to investigate dyspepsia over the study

period further supports a true decline in the prevalence of duodenal ulcer. The reasons for this decline are not entirely clear, although several have been considered. These include widespread use of proton pump inhibitors and antibiotics by patients before endoscopy, differing competences of the endoscopists who contributed to the endoscopic data, non-referral of many uncomplicated cases of dyspepsia to our tertiary institution, and the general rule of not routinely doing upper gastrointestinal endoscopy for patients with uncomplicated dyspepsia, especially those aged <45 years. Studies done in North America and the Asia-Pacific region have attributed this decline to increased eradication and a reduced prevalence of H. pylori infection.[2,3] Although studies in Nigeria have shown that the prevalence of H. pylori is still high,[10] we recommend that future research includes the H. pylori status of patients. This will help to ascertain whether a reduction in H. pylori prevalence is also responsible for the decline in duodenal ulcer prevalence in our environment. Acknowledgements. We thank the members of the nursing staff of the endoscopy unit for their help in data retrieval. Author contributions. OI: Study conception and design, retrieval and collation of data, data analysis and interpretation of data after analysis, writing up the article; DOS: collation of data, data analysis and interpretation of data after analysis, revising the article and approval of the final version; OA: collation of data and interpretation of data after analysis, revising the article and approval of the final version; DAN: study conception, collation of data and interpretation of data after analysis, revising the article and approval of the final version; BIU: collation of data and interpretation of data after analysis, revising the article and approval of the final version; OIA: collation of data and interpretation of data after analysis, revising the article and approval of the final version. All the authors except DOS are endoscopists whose patients were included as part of the data. Funding. None (the study was self-funded). Conflicts of interest. None.

1. Longmore M, Wilkinson I, Baldwin A, Wallin E. Oxford Handbook of Clinical Medicine. Oxford: Oxford University Press, 2014. 2. El-Serag H, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gut 1998;43(3):327-333. https://doi.org/10.1136/gut.43.3.327 3. Wong SN, Sollano JD, Chan MM, et al. Changing trends in peptic ulcer prevalence in a tertiary care setting in the Philippines: A seven‐year study. J Gastroenterol Hepatol 2005;20(4):628-632. https://doi. org/10.1111/j.1440-1746.2005.03719.x 4. Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: The Maastricht III Consensus Report. Gut 2007;56(6):772-781. https://doi. org/10.1136/gut.2006.101634 5. Olayemi O, Olayinka B, Musa A. Evaluation of antibiotic self-medication pattern amongst undergraduate students of Ahmadu Bello University (Main Campus), Zaria. Res J Appl Sci Eng Technol 2010;2(1):35-38. 6. Naunton M, Peterson G, Bleasel M. Overuse of proton pump inhibitors. J Clin Pharm Ther 2000;25(5):333-340. https://doi.org/10.1111/j.1365-2710.2000.00312.x 7. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015;64(9):1353-1367. https://doi.org/10.1136/gutjnl-2015-309252 8. Ndububa D, Agbakwuru A, Adebayo R, et al. Upper gastrointestinal findings and incidence of Helicobacter pylori infection among Nigerian patients with dyspepsia. West Afr J Med 2000;20(2):140-145. 9. Nwokediuko SC, Ijoma U, Obienu O, Picardo N. Time trends of upper gastrointestinal diseases in Nigeria. Ann Gastroenterol 2012;25(1):52-56. 10. Olokoba A, Gashau W, Bwala S, Adamu A, Salawu F. Helicobacter pylori infection in Nigerians with dyspepsia. Ghana Med J 2013;47(2):79-81. 11. Awofisayo O, Awofisayo O, Iferi I, Akpan O. The pattern of sale and use of non-steroidal antiinflammatory drugs in rural and urban centres in Nigeria. Trop J Pharm Res 2008;7(3):1013-1018. https://doi.org/10.4314/tjpr.v7i3.14685 12. Barkun A, Leontiadis G. Systematic review of the symptom burden, quality of life impairment and costs associated with peptic ulcer disease. Am J Med 2010;123(4):358-366.e2. https://doi.org/10.1016/j. amjmed.2009.09.031

Accepted 22 March 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Osteosarcoma outcomes at a South African tertiary hospital L Lisenda,1 MB ChB BAO, MMed, MRCS, FC Orth (SA); Z A Linda,1 MB BCh, FC Orth (SA); F P J Snyman,2 MB BCh, MMed; R D Kyte,1,2,3 MB BCh, FC Orth (SA), M Lukhele,1 MB BCh, MMed, FC Orth (SA) Division of Orthopaedic Surgery, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Milpark Hospital, Johannesburg, South Africa 3 Wits Donald Gordon Medical Centre, Johannesburg, South Africa 1

Corresponding author: L Lisenda (lisendal@hotmail.com) Background. Osteosarcoma is the most common primary malignant bone tumour. There is a high incidence of late presentation in the developing world, posing additional challenges in the treatment of this aggressive disease. Objective. To evaluate clinical outcomes of patients with osteosarcoma at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), a tertiary hospital in South Africa, and compare these with similar studies in the developing world. Methods. This was a retrospective study of 61 patients treated at CMJAH between 2007 and 2011, with a minimum follow-up of 1.3 years (range 1.3 - 6.3). Results. An average of 4.5 months elapsed before patients were first seen at the CMJAH tumour unit. Fifty-eight patients (95.1%) initially sought conventional medical care. Three patients (4.9%) presented with pathological fractures. All the patients underwent biopsy, performed an average of 3 weeks after arrival at the tumour unit. In most cases the delay was due to limited access to magnetic resonance imaging. Most patients (n=41, 67.2%) were at Enneking stage 2B, 4 (6.6%) were at stage 2A and 16 (26.2%) were at stage 3. Of the patients, 13 (21.3%) underwent limb salvage procedures, 33 (54.1%) had amputations, 4 (6.6%) refused further treatment and 11 (18.0%) received palliative care only; 55 patients (90.2%) received chemotherapy. Two patients developed local recurrence, one of whom had an amputation and the other further wide excision. Two patients received palliative radiotherapy. Of the patients, 82.0% were HIV-negative, 4.9% HIVpositive and the rest of unknown status. At the time of the study, all but two patients, who came from other countries, were traceable or known to have died. Our overall 1-year and 5-year survival rates were 62.7% (95% confidence interval (CI) 49.1 - 73.9) and 38.1% (95% CIÂ 24.6 - 51.4), respectively. Male patients and those with a higher Enneking stage had a poorer prognosis. Conclusion. Although most patients sought conventional medical care, unacceptable delays worsened survival. However, our survival rates are better than those in other developing countries. We advocate that professional, public and political awareness of osteosarcoma be improved as a matter of urgency, to facilitate rapid tertiary referral and expedite management. S Afr Med J 2017;107(9):754-757. DOI:10.7196/SAMJ.2017.v107i9.11424

Osteosarcoma is the most common primary malignancy of bone.[1] It is relatively rare, however, with an incidence of 4 per million population per annum.[1,2] The peak incidence is in the second decade of life, with a smaller peak in the 7th and 8th decades, these cases usually being secondary.[2-4] The tumour is more common in males than in females[5,6] and has a higher prevalence among blacks than among whites.[7] The cause is unknown, but individuals with germline mutations in the retinoblastoma (Rb) and tumour protein p53 (TP53) genes have been shown to be at increased risk.[8,9] Survival was as low as 5% in the 1950s, with a 5-year survival rate of only 22%, most patients undergoing amputation and adjuvant radiation only or pioneering chemotherapy.[10] During the 1970s there was a marked improvement in 5-year survival rates, which were reportedly as high as 81.6% in one study,[11,12] largely owing to significant advances in chemotherapy, with utilisation of high-dose and multiagent regimens. In addition, tumour necrosis induced by neoadjuvant chemotherapy assisted in reducing the size of the surgical margin required for wide tumour excision, facilitating successful limb salvage without negatively affecting overall survival.[13,14] Unfortunately, improvements in osteosarcoma management that are routine in the developed world are still not common in developing countries, because of limitations in human resources and lack of equipment and access to new and more effective chemotherapy regimens. Furthermore, it has been reported that

cultural beliefs and reliance on traditional medicine in developing countries have resulted in late presentation to conventional hospitals, resulting in poorer outcomes.[5,15-17] Reliable data from clinical outcome and epidemiological studies in developing countries are also scarce. [17] Consequently, accurate benchmarking of evidence-based management protocols is extremely difficult to achieve. Muthupei and Mariba[15] reported a 5-year survival rate of 7.5% in their 2000 study of 66 osteosarcoma patients at a tertiary hospital in South Africa (SA), which is comparable to outcomes from the 1950s in developed countries.[10] In 2010, Shipley and Beukes[16] reported on 30 patients with osteosarcoma treated at another SA tertiary institution. Half of their patients presented with metastases.[16] The majority of patients in these studies from developing countries presented with advanced disease, to which the authors attributed their poor outcomes compared with the far better survival rates in developed countries.[5,15-17] Noor et al.[17] had similar findings in a study in Cambodia, with a 5-year survival rate of only 8%, citing late presentation and cultural preferences as the main factors responsible for the poor outcomes.[17]

Objective

To evaluate clinical outcomes of patients with osteosarcoma at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), a tertiary hospital in SA, and compare these with similar studies

September 2017, Print edition

RESEARCH

from the developing world to evaluate factors contributing to any differences encountered.

Methods

This was a retrospective study of 61 patients treated for osteosarcoma at the CMJAH tumour unit over the 5-year period January 2007 December 2011. The minimum follow-up was 1.3 years (mean 3.1, range 1.3 - 6.3). CMJAH is a level 1 trauma centre and one of the two main teaching hospitals of the University of the Witwatersrand, catering not only for the city of Johannesburg but also for Gauteng Province and neighbouring provinces and countries. Only patients with biopsy-confirmed osteosarcoma were included in the study. Ethics clearance to conduct the study was obtained from the University of the Witwatersrand (ref. no. M150783). The data were obtained from theatre registry and patient records. All patients admitted to the tumour unit had a comprehensive form (available from the first author at lisendal@hotmail.com) completed on admission, throughout the course of admission and during followup. The tumour form had three main sections: (i) history and clinical findings; (ii) investigations (blood tests and radiography) and procedures (biopsy/surgical operations) done; and (iii) follow-up. All patients received a standard osteosarcoma work-up consisting of blood investigations and imaging before biopsy and then definitive treatment. Most patients were followed up at orthopaedic and oncology outpatient clinics, and those who had defaulted were contacted telephonically. The main outcome measures were demographics, tumour stage according to the Enneking staging system, and treatment options offered (surgery (amputation and limb salvage), chemotherapy, radiotherapy) and survival. Survival was calculated in years from the date of presentation to the time of the study. Kaplan-Meier analysis was used to portray survival functions. Equality of survivor functions was investigated using the log-rank test.

Results

A total of 61 patients were included in the study (41 males and 20Â females, male/female ratio 2:1). The mean age was 19.4 years (range 7 - 48). Most of the patients (n=36, 59.0%) were in their second decade, followed by the third decade (n=13, 21.3%) and then Table 1. Histological typing (World Health Organization classification) (N=61) Type Conventional Chondroblastic Fibroblastic Osteoblastic Not specified Periosteal Pariosteal Telangiectatic Small cell, low-grade surface, secondary

Patients, n (%) 57 (93.4) 9 5 22 19 1 (1.6) 2 (3.3) 1 (1.6) 0

the first (n=5, 8.2%). The fourth and fifth decades accounted for 4 (6.6%) and 3 (4.9%) patients, respectively. Of the patients, 43 (70.5%) and 15 (25.6%) initially sought care from their local clinic and general practitioner, respectively, before being referred to the tumour unit. Only 3 (4.9%) went to a traditional healer before being referred. On average, it took 4.5 months for patients to be seen in the tumour unit for the first time. Most patients (n=42, 68.9%) were from the CMJAH catchment area of Gauteng Province, the other SA provinces and other countries accounting for 16 (26.2%) and 3 (4.9%), respectively. The majority of the patients (n=58, 95.1%) presented with a painful swollen limb and the rest (n=3, 4.9%) with pathological fractures. The tibia was the most common site of involvement, accounting for 30 cases (49.2%), with the femur and humerus accounting for 19 (31.1%) and 12 (19.7%), respectively. Only 3 patients (4.9%) were HIV-positive; 8 (13.1%) were of unknown status, and the rest (n=50, 82.0%) were HIV-negative. Biopsy was done at a mean of 3 weeks after presentation. In most cases, the delay was because magnetic resonance imaging (MRI) was not readily available. The majority of the patients (n=41, 67.2%) were at Enneking stage 2B, 4 (6.6%) were at stage 2A, and 16 (26.2%) presented with metastases (stage 3). Conventional osteosarcoma was the most common histological type, accounting for 93.4% of cases (Table 1). In 46 cases (75.4%) surgery was undertaken with the aim of achieving wide local resection margins (Table 2). Of these 46Â patients, 13 (28.3%) had limb salvage procedures and 33 (71.7%) had amputations. Four patients (6.6%) refused any form of treatment despite multidisciplinary counselling and were discharged from the hospital for home-based care, and the rest (n=11, 18.0%) received palliative care (palliative care only without amputation) because they presented late (these included two patients who received radiotherapy). Fifty-five patients (90.2%) received chemotherapy. Of these, 52 (94.5%) had both neoadjuvant and post-adjuvant chemotherapy and 3 (5.5%) post-adjuvant chemotherapy only. Palliative radiotherapy was administered to 2/61 patients (3.3%) who were not fit for surgery. Two patients developed local recurrence, of whom one was treated with amputation and the other with further excision. At the time of the study, 59 patients (96.7%) were traceable or known to have died. The two untraceable patients were from other countries and had been referred home for further treatment after limb salvage. Of the patients who were alive (25/59, 42.4%), 10/13 (76.9%) had been treated with limb salvage and 14/33 (42.4%) with amputation, and the rest (1/4, 25.0%) had refused surgery. Of the 34/59 patients who were dead, 1/11 (9.1%) had been treated with limb salvage and 19/33 (57.6%) with amputation, and 3/4 had refused surgery (Table 2). Of the 13/61 patients (21.3%, including the two untraceable patients) who defaulted from follow-up or had refused treatment, 3/13 (23.1%) had been treated with limb salvage and 9/33 with amputation (27.3%). Our 1-year survival rate was 62.7% (95% confidence interval (CI) 49.1 - 73.9) and our 5-year survival rate 38.1% (95% CI 24.6Â 51.4) (Fig. 1). Fig. 2 shows that there was a statistically significant

Table 2. Survival v. treatment options Alive Dead Unknown Total

Limb salvage 10 1 2 13

Amputation 14 19 0 33

Palliative 0 11 0 11

September 2017, Print edition

Refused treatment 1 3 0 4

Total 25 34 2 61

0.00

Female 0

Male

Years Female

Male

RESEARCH 1.00

0.75

Survival, proportion

0.50 1.00 0.25 0.75 0.00 0.50 0

Survival, proportion Survival, proportion

Survival, proportion

1.00

Years

0.25

0.75 1.00 0.50 0.75 0.25 0.50 0.00

0.25

Years 0.00

<2 months before arrival 2

4 2 - 6 months before6arrival

>6 months before arrival Years

0.00 0

2 - 6 months before arrival

<2 months before arrival

Years

>6 months before arrival

Fig. 1. Overall Kaplan-Meier survival estimate in years. Fig. 3. Overall Kaplan-Meier survival estimates by time that elapsed before patients presented at Charlotte Maxeke Johannesburg Academic Hospital.

1.00

0.75 0.50

Survival, proportion

1.00 0.25 0.75 0.00 0

0.50

Years

Survival, proportion Survival, proportion

Survival, proportion

1.00

0.75 1.00

0.50 0.75 0.25 0.50 0.00 0.25

0.00

0.25

Female

Male

0.00

Fig. 2. Overall Kaplan-Meier survival estimates by sex. 0

calculated by the log-rank test, with males being worse off. However, Male at CMJAH did survival according to time (in Female months) before arrival not differ significantly (p=0.587) (Fig. 3). All the patients who were staged as Enneking 2A were alive at 1.00 5 years (range 5.08 - 6) without recurrences. Patients with Enneking stage 2B disease had 1-year and 5-year survival rates of 69.2% (95% 0.75 CI 52.2 - 81.2) and 47.9% (95% CI 30.4 - 63.4), respectively. For patients with Enneking stage 3 disease, the 1- and 5-year survival rates were 0.50 37.5% (95% CI 15.4 - 59.7) and 3.75% (95% CI 0.06 - 23.4), respectively (Fig. 4). This difference is statistically significant (p=0.0008). 0.25 1.00 Only one patient who refused treatment was alive, 24 months after discharging herself from the hospital. She had presented with 0.00 a 9-month history of a painful swollen knee and was subsequently 0.75 4 proximal tibia,6 diagnosed 0with conventional2 osteosarcoma of the Years Enneking 0.50 stage 2B. Only one of the three patients who initially presented with a <2 months before without arrival 2 - 6 months arrival pathological fracture was alive, recurrence at 54 before months. 0.25 She was a 12-year-old girl who had a pathological fracture of the left >6 months before arrival proximal 0.00 tibia and was treated with above-knee amputation (AKA).

Stage 2A Years Stage 3

Stage 2A

Years difference between the survival curves for the two sexes (p=0.009) as

Years 4

Stage 2B

Stage 3

Fig. 4. Overall Kaplan-Meier survival estimates by Enneking stage.

Survival, proportion

reported 1- and 5-year survival of 53.6% and 8% in Cambodia. [15,17] Our 5-year survival figure is worse than the corresponding figures for developed countries, which average >50%.[18-20] Several factors may account for our relatively poor outcomes. Our patients presented on average 4.5 months after the onset of symptoms, with Enneking stages 2B and 3 accounting for a combined 93.4% compared with 6.6% with stage 2A. The delays may be attributable to poor accessibility of health facilities, especially for individuals living in rural areas. The higher the Enneking stage on presentation the poorer the prognosis, as has been reported in the literature[12] and shown by our results. Although only 4.9% of patients admitted to first attending a traditional healer, most patients would have consulted them, as evidenced by the presence of ‘traditional’ scarifications. Almost a third of the patients came from outside our catchment area, which could have led to delays in referral. Limited access to MRI in our hospital, leading to a further average delay of 3 weeks, exacerbated the situation. Biopsies were done approximately a week after the MRI and other investigations were completed, resulting in an overall mean time to diagnosis of 23.5 weeks. In contrast, the median time 0 2 4 6 to diagnosis in developed countries has been reported as 9 weeks. [21] Discussion Years Patients from rural areas depend on doctors in district hospitals Our 1-year and 5-year overall survival rates of 62.7% and 38.1% having a high index of suspicion of ‘painful limbs’ and doing initial are better than those in previous published studies from developing <2 months before - 6 months beforehad arrival investigations (X-rays) of the affected limb. Improving awareness countries.[15-17] Muthuphei and arrival Mariba’s[15] SA2 study in 2000 >6 months before arrival and 7.5%, while Noor et al.[17] through education of the community at large, and district doctors in 1- and 5-year survival rates of 25.8%

ival, proportion

1.00 0.75 0.50

September 2017, Print edition

RESEARCH

particular, could increase early referral to specialised tumour units and hence the cure rate. Amputees had poorer survival rates than patients who underwent limb salvage, because they had more advanced disease. Amputation was offered as ‘palliation surgery’ to relieve malaise and for pain control. More amputees than patients who had undergone limb salvage defaulted from follow-up at outpatient clinics (orthopaedic and oncology), despite multidisciplinary emphasis in hospital on surveillance for recurrence, which could explain their poor outcome. Preservation of the limb with limb salvage procedures, and hence a better self-image, could be a factor explaining the good attendance by these patients. The majority of our patients (95.1%) presented with a painful swollen limb and the rest with pathological fractures. Histological conventional osteosarcoma accounted for 93.4% of cases, while the rest (periosteal, pariosteal and telangiectatic) accounted for 6.6%, as shown in Table 1. The incidence of pathological fractures is reported to be 5 - 10% in the literature.[22-24] Historically, pathological fractures were treated by amputation because of damage to the microcirculation that would result in contamination of adjacent soft tissue and metastasis.[21] Several authors have since shown that there is no difference in terms of survival between patients who have amputation and those who have limb salvage.[22,24,25] Three patients in our study presented with pathological fractures. Two of these patients, who had pathological fractures of the distal femur, had metastases and died in hospital from advanced disease. One patient, who was unfit for surgery, died few days after admission and the other patient, who underwent AKA, 2 months after admission. The only patient with a pathological fracture who survived was a 12-year-old girl with high-grade osteosarcoma of the left distal tibia. She received neoadjuvant and post-adjuvant chemotherapy and was offered AKA because the tumour encapsulated the neurovascular structures. She was alive and free of disease free 54 months after AKA. Most of our patients presented with advanced disease precluding limb salvage. Just over a quarter of our patients presented with metastases on admission. Our 5-year survival of 3.75% for this cohort of patients is very low compared with the mid-20s - 30% in developed countries, which is attributable to late presentation.[12] One of the four patients who refused chemotherapy and surgery was traceable and alive 24 months after discharging herself. She was a 20-year-old woman with high-grade osteosarcoma of the left proximal tibia, Enneking stage 2B. She was being looked after by relatives at home.

Study limitations

Although 96.7% of our patients were traceable (or known to have died) at the time of the study, ~20% of them had defaulted from follow-up. This is a major limiting factor in our study. This high default rate could be due to difficulty in accessing our facility, and also to the fact that ~30% of our patients came from other provinces and countries. The majority of those who had defaulted cited lack of funds as the reason for not attending. Attempted telephonic contact of the two patients from other countries was unsuccessful as the numbers were not in use. Another limiting factor is the retrospective nature of the study, despite the fact that the data were collected prospectively using a comprehensive tumour form.

Conclusion

Treatment of osteosarcoma is challenging, demanding and timeconsuming, and requires meticulous record keeping. Limited resources hamper a multidisciplinary approach in developing

countries. In our setting, both patients and their families need extensive education and counselling to improve access to modern treatments. Despite better overall 1-year and 5-year survival rates than in other developing countries, our 5-year overall survival rates are suboptimal compared with developed countries, mainly because of delayed referral and logistical constraints to rapid work-up. We strongly recommend improved professional and public awareness of the importance of rapid referral, which is vital for the survival of these patients. Acknowledgements. We thank Estelle Viljoen for keeping the database and fellow registrars for completing the tumour forms. Author contributions. LL, ZAL, RDK and ML participated in the planning and design of the study and in interpretation of the results. LL wrote the first draft, and RK and ML edited it and supervised the project. All authors revised, edited and approved the final draft. Funding. None. Conflicts of interest. None. 1. PosthumaDeBoer J, Witlox MA, Kaspers GJ, van Royen BJ. Molecular alterations as target for therapy in metastatic osteosarcoma: A review of literature. Clin Exp Metastasis 2011;28(5):493-503. https://doi. org//10.1007/s10585-011-9384-x 2. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer 2009;115(7):1531-1543. https://doi.org/10.1002/cncr.24121 3. Savage SA, Mirabello L. Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma 2011(2011), Article ID 548151. https://doi.org/10.1155/2011/548151 4. Dean BJ, Whitwell D. Epidemiology of bone and soft-tissue sarcomas. Orthop Trauma 2009;23(4):223230. https://doi.org/10.1016/j.mporth.2009.05.006 5. Geel J. Osteosarcoma: Current and future management in South Africa. S Afr Paediatr Rev 2009;6(3):32-39. https://www.researchgate.net/publication/239799371_Osteosarcoma_Current_and_ Future_Management_in_South_Africa (accessed 7 August 2017). 6. Duong LM, Richardson LC. Descriptive epidemiology of malignant primary osteosarcoma using population-based registries, United States, 1999 - 2008. J Registry Manag 2013;40(2):59-64. 7. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle aged and elderly persons. Int J Cancer 2009;125(1):229-234. https://doi.org/10.1002/ ijc.24320 8. Hansen MF. Genetic and molecular aspects of osteosarcoma. J Musculoskelet Neuronal Interact 2002;2(6):554-560. 9. Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma 2012(2012), Article ID 627254. https://doi.org/10.1155/2012/627254 10. Coventry MB, Dahlin DC. Osteogenic sarcoma. J Bone Joint Surg Am 1957;39(4):741-758. 11. Rosen G. Preoperative (neoadjuvant) chemotherapy for osteogenic sarcoma: A ten year experience. Orthopedics 1985;8(5):659-964. https://doi.org/10.3928/0147-7447-19850501-19 12. Allison DC, Carney SC, Ahlmann ER, et al. A meta-analysis of osteosarcoma outcomes in the modern medical era. Sarcoma 2012(2012), Article ID 704872. https://doi.org/10.1155/2012/704872 13. Li X, Ashana AO, Moretti VM, Lackman RD. The relation of tumour necrosis and survival in patients with osteosarcoma. Int Orthop 2011;35(12):1847-1853. https://doi.org/10.1007/s00264-011-1209-7 14. Li X, Moretti VM, Ashana AO, Lackman RD. Impact of close surgical margin on local recurrence and survival in osteosarcoma. Int Orthop 2012;36(1):131 -137. https://doi.org/10.1007/s00264-011-1230-x 15. Muthuphei MN, Mariba MT. Osteosarcoma in Ga-Rankuwa Hospital: A 10-year experience in an African population. Cent Afr J Med 2000;46(2):41-43. 16. Shipley JA, Beukes CA. Outcomes of osteosarcoma in a tertiary hospital. SA Orthop J 2012;11(1):18-22. http://www.scielo.org.za/pdf/saoj/v11n1/03.pdf (accessed 7 August 2017). 17. Noor S, Þormóðsson HS, Zervas CT, Ly T, Gollogly J. Limb versus life – the outcomes of osteosarcoma in Cambodia. Int Orthop 2014;38(3):579-585. https://doi.org/10.1007/s00264-013-2173-1 18. Henshaw RM, Priebat DA, Perry DJ, Shmookler BM, Malawer MM. Survival after induction chemotherapy and surgical resection for high-grade soft tissue sarcoma. Is radiation necessary? Ann Surg Oncol 2001;8(6):484-495. https://doi.org/10.1007/s00264-013-2173-1 19. Goorin AM, Perez-Atayde A, Gebhardt M, et al. Weekly high-dose methotrexate and doxorubicin for osteosarcoma: The Dana-Farber Cancer Institute/the Children’s Hospital--study III. J Clin Oncol 1987;5(8):1178-1184. https://doi.org/10.1200/JCO.1987.5.8.1178 20. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/ Osteosarcoma-2 protocol: An updated report. J Clin Oncol 2000;18(24):4016-4027. https://doi. org/10.1200/JCO.2000.18.24.4016 21. Brasme JF, Morfouace M, Grill J, et al. Delays in diagnosis of paediatric cancers: A systematic review and comparison with expert testimony in lawsuits. Lancet Oncol 2012;13(10):e445-e459. https://doi. org/10.1016/S1470-2045(12)70361-3 22. Abudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ. The surgical treatment and outcome of pathological fractures in localised osteosarcoma. J Bone Joint Surg Br 1996;78(5):694-698. 23. Jaffe N, Spears R, Eftekhari F, et al. Pathologic fracture in osteosarcoma: Impact of chemotherapy on primary tumor and survival. Cancer 1987;59(4):701-709. https://doi.org/10.1002/10970142(19870215)59:4<701::AID-CNCR2820590407>3.0.CO;2-V 24. Bacci G, Ferrari S, Longhi A, et al. Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: Local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 2003;74(4):449-454. https://doi.org/10.1080/00016470310017776 25. Scully SP, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC. Pathologic fracture in osteosarcoma. J Bone Joint Surg Am 2002;84(1):49-57.

Accepted 7 April 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Central-line-associated bloodstream infections in a resource-limited South African neonatal intensive care unit C Geldenhuys,1 MB ChB, FCPaed (SA), MMed (Paed), DCH; A Dramowski,1 MB ChB, FCPaed (SA), MMed (Paed), Cert ID, DCH; A Jenkins,2 B Nursing, Dipl Paed Nursing, A Bekker,1 MB ChB, FCPaed (SA), MMed (Paed), Cert Neonatology 1 2

Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Neonatal Intensive Care Unit, Tygerberg Childrenâ&#x20AC;&#x2122;s Hospital, Cape Town, South Africa

Corresponding author: C Geldenhuys (chandre.geldenhuys@yahoo.com) Background. The rate of central-line-associated bloodstream infection (CLABSI) in South African (SA) public sector neonatal intensive care units (NICUs) is unknown. Tygerberg Childrenâ&#x20AC;&#x2122;s Hospital (TCH), Cape Town, introduced a neonatal CLABSI surveillance and prevention programme in August 2012. Objectives. To describe CLABSI events and identify risk factors for development of CLABSI in a resource-limited NICU. Methods. A retrospective case-control study was conducted using prospectively collected NICU CLABSI events matched to four randomly selected controls, sampled from the NICU registry between 9 August 2012 and 31 July 2014. Clinical data and laboratory records were reviewed to identify possible risk factors, using stepwise forward logistic regression analysis. Results. A total of 706 central lines were inserted in 530 neonates during the study period. Nineteen CLABSI events were identified, with a CLABSI rate of 5.9/1 000 line days. CLABSI patients were of lower gestational age (28 v. 34 weeks; p=0.003), lower median birth weight (1 170 g v. 1 975 g; p=0.014), had longer catheter dwell times (>4 days) (odds ratio (OR) 5.1 (95% confidence interval (CI) 1.0 - 25.4); p=0.04) and were more likely to have had surgery during their NICU stay (OR 3.5 (95% CI 1.26 - 10); p=0.01). Significant risk factors for CLABSI were length of stay >30 days (OR 20.7 (95% CI 2.1 - 203.2); p=0.009) and central-line insertion in the operating theatre (OR 8.1 (95% CI 1.2 - 54.7); p=0.03). Gram-negative pathogens predominated (12/22; 54%), with most isolates (10/12; 83%) exhibiting multidrug resistance. Conclusion. The TCH NICU CLABSI rate is similar to that reported from resource-limited settings, but exceeds that of high-income countries. Prolonged NICU stay and central-line insertion in the operating theatre were important risk factors for CLABSI development. Intensified neonatal staff training regarding CLABSI maintenance bundle elements and hand hygiene are key to reducing CLABSI rates. S Afr Med J 2017;107(9):758-762. DOI:10.7196/SAMJ.2017.v107i9.12124

In most low-resource countries, surveillance of healthcare-associated infection (HAI) is limited or non-existent. A meta-analysis of HAI in low- and middle-income countries (LMIC) reported infection rates double those of developed countries, and a tripling of HAI rates in intensive care units (ICUs).[1] Central-line-associated bloodstream infections (CLABSI) are a type of device-associated HAI mainly encountered in the ICU setting. Data on CLABSI rates in LMIC are scant, particularly from neonatal intensive care unit (NICU) settings. The use of central lines in NICUs is often unavoidable, with lines used for administration of intravenous fluids, blood products, inotropes, antibiotics and total parenteral nutrition (TPN). Even without the use of invasive devices, hospitalised neonates are at increased risk of infection owing to prematurity, poor skin integrity and prolonged hospitalisation. Resource-limited countries contributing data to the International Nosocomial Infection Control Consortium (INICC) report NICU CLABSI rates of 3 - 4-fold higher than those documented by the US National Health Surveillance System (NHSN).[2,3] In high-income-country NICUs, CLABSI rates declined dramatically following widespread implementation of central-line bundles.[4] A CLABSI bundle is a strategy for insertion and maintenance of central lines, which includes several evidence-based best practices implemented simultaneously.[5,6] Central-line care bundle elements include: hand hygiene, optimal catheter-site selection, maximal barrier precautions at insertion, chlorhexidine skin antisepsis, daily

review of line necessity, sterile line access, use of closed needleless intravascular catheter systems and ensuring the line dressing stays clean and intact.[5,6] Reductions in NICU CLABSI rates have been achieved in developing countries,[7] but data from African NICUs are extremely limited.[2] Our study reports the first CLABSI surveillance programme data from a public sector NICU in South Africa (SA) and aims to identify risk factors for CLABSI in this setting.

Methods

Study setting

Tygerberg Hospital is a public sector teaching hospital in Cape Town, SA. The neonatal service provides care to both inborn babies and neonates referred from surrounding clinics and hospitals. In 2012 and 2013, ~7 800 babies were born per year: 40% were low-birthweight (<2 500 g), 13% were very-low-birth-weight (<1 500 g) and 6% were extremely low-birth-weight (<1 000 g) infants.[8] The neonatal service includes the NICU, with 8 intensive-care beds and 4 high-care beds, as well as 112 ward beds. In 2013, there were 491 admissions to the NICU and 5 265 to the wards.[8] Indications for central-line insertion in the NICU include requirement for TPN and/or inotropes, and neonates who require intravenous fluids and/or antibiotics where peripheral intravenous access is not possible or difficult to obtain. Umbilical venous catheters (UVCs) and peripherally inserted central catheters (PICCs) are first- and second-choice central lines and are inserted by paediatric registrars

September 2017, Print edition

RESEARCH

or medical officers. Central venous catheters (CVCs) and Broviac lines are inserted in patients in whom intravenous access is difficult, where attempts at insertion of other central lines have failed, and/or in post-surgical patients who need TPN. Broviac lines are inserted by the paediatric surgical team and CVCs by either the paediatric surgery or anaesthetic team. The Tygerberg Children’s Hospital (TCH) NICU CLABSI surveillance and prevention programme was implemented on 9 August 2012, with the aim of determining baseline CLABSI rates through prospective surveillance and reducing CLABSI events through the use of central-line insertion and maintenance bundles.

Study design

The prospectively compiled NICU central-line register was used to identify cases and controls. All cases within the 2-year study period (9 August 2012 - 31 July 2014) were included, with 4 randomly selected controls per CLABSI event. Research randomiser (a computer program that generates random numbers) was used to select 4 controls for each CLABSI case, matching only for the year of the programme, i.e. 9 August 2012 - 31 July 2013 or 1 August 2013 - 31 July 2014. Hospital and laboratory records for the cases and controls were retrospectively reviewed. If a ‘control’ folder was not available or the information in the folder was incomplete, the next randomly selected folder number was used. Information obtained from the folders for both cases and controls included: patient demographics, details of their NICU stay, and central-line information. Additional information was obtained for all CLABSI cases: weight closest to CLABSI event onset, number of CLABSIs per patient, date of CLABSI event, pathogen isolated and antibiotic susceptibility, antibiotics used prior to and after CLABSI diagnosis, white cell count, platelet count, haemoglobin and C-reactive protein result 48 - 72 hours prior to CLABSI and 24 - 48 hours after CLABSI. All positive cultures from catheter tips submitted from the NICU during the study period and all blood culture results of babies who died or were transferred to other neonatal wards with central lines in situ were evaluated for possible missed CLABSI cases. Umbilical arterial lines were excluded from this study because surveillance of these lines was not part of the programme initially and none of the CLABSI cases was attributed to them. The CLABSI register was the primary data source used to determine total patients and central-line days to calculate the CLABSI rate.

Definitions

The US Centers for Disease Control and Prevention (CDC)/ National Healthcare Safety Network (NHSN) 2014 definitions for HAI were used.[9] CLABSI is defined as a laboratory-confirmed bloodstream infection (LC-BSI) in a patient with a central line in situ for at least 2 calendar days (where line insertion is day 1). It is still considered a CLABSI if an LC-BSI occurred within 1 day of line removal. The definitions for HAI and LC-BSI must be met before the definition of CLABSI can be applied, and other HAI must be excluded. The CLABSI rate per 1 000 central-line days is calculated by dividing the number of CLABSIs by the number of central-line days and multiplying the result by 1 000. Line days are the total number of days of exposure to central venous catheters by all patients in the selected population and time period. Definitions of multidrug resistance applied from Magiorakos et al.[10] were used to report on the antibiotic-susceptibility profile of pathogens. Mangram et al.’s[11] wound classification was used to classify the wounds of all the study participants who underwent surgery.

Statistical analysis

Normally distributed data were described using means and standard deviations; non-parametric data were described with medians and interquartile ranges. The χ2 test was used to compare demographics of CLABSI cases v. controls; p<0.05 was considered statistically significant. Stepwise forward logistic regression analysis was performed to identify risk factors for CLABSI, reporting odds ratios (ORs) and 95% confidence intervals (CIs).

Ethical approval

Approval of the study (including a waiver of individual informed consent) was obtained from the Health Research Ethics Committee at Stellenbosch University (ref. no. S14/07/153).

Results

Fourteen CLABSI episodes were documented in the CLABSI register. One CLABSI episode was excluded from the study because it did not meet the CLABSI definition as per CDC/NHSN 2014 guidelines. An additional six ‘missed’ CLABSI episodes were added following review of records from babies who died with a central line in situ and those with a positive culture from their catheter tip, yielding a total of 19 CLABSI events, for which 76 controls were selected (a total of 95 study patients). The NICU CLABSI surveillance registers documented insertion of 706 central lines into 530 neonates during the first 2 years of the programme (a total of 3 187 central-line days). Nineteen CLABSI episodes in 17 patients were identified, yielding a CLABSI rate of 5.9/1 000 line days. The demographics of the study population are summarised in Table 1. Nine of the CLABSI patients had medical indications for admission: hyaline membrane disease (n=3), meconium aspiration syndrome (n=2), presumed nosocomial sepsis (n=2), congenital cytomegalovirus infection (n=1) and pulmonary haemorrhage (n=1). Eight patients who had undergone abdominal surgery during their current or previous NICU admission developed CLABSI episodes (10/19; 53%), including one baby who had undergone surgery and who was admitted to the NICU for 107 days, experiencing three CLABSI events with different pathogens on three separate lines. Of the 8 babies who underwent surgery, 5 had a wound class III/IV (contaminated or dirty).[11] Comparison of septic markers 48 hours prior to and at/within 24 hours after the CLABSI event confirmed the possibility of sepsis, with a decrease in white cell count, platelets and/or raised C-reactive protein. Of the 5 neonates who died (26.3%), 3 deaths were directly attributed to the CLABSI event, 1 to necrotising enterocolitis and 1 to congenital abnormalities. The babies who died from CLABSI were of very low birth weight (<1 500 g), premature, had medical indications for NICU admission and died within 48 hours of CLABSI diagnosis. The catheter dwell times in the ICU and time to CLABSI onset after insertion of different central-line types are summarised in Table 2. Of the 19 CLABSI events, 16 were monomicrobial and 3 were polymicrobial, with 2 pathogens each (a total of 22 laboratoryconfirmed pathogens). Gram-negative organisms predominated (12/22; 54%) followed by Gram-positives (5/22; 23%) and fungi (5/22; 23%). Antimicrobial susceptibility testing was performed on all isolates. Gram-negative organisms exhibited high rates of antimicrobial resistance: 6/7 Acinetobacter baumannii were multidrug-resistant and 4/5 Klebsiella pneumoniae produced extended-spectrum betalactamases (Table 2). Fungi isolated were Candida albicans (n=3), C. parapsilosis (n=1) (all fluconazole susceptible), and C. krusei (n=1), susceptible to amphotericin B and voriconazole. For 14/19 CLABSI events, patients were receiving antibiotics for other indications prior to the development of CLABSI. A change in the antimicrobial

September 2017, Print edition

RESEARCH

Table 1. Characteristics of the study population (N=95) Variable assessed

Patients, n (%)* (N=95)

Cases (n=19)

Controls (n=76)

p-value

Gestational age (weeks), median (IQR)

33 (28 - 38)

28 (27 - 36)

34 (30 - 39)

0.003

Gestational age premature (<37 weeks)

66 (69)

15 (79)

51 (67)

0.316

Birth weight (g), median (IQR)

1 670 (1 130 - 2 765)

1 170 (960 - 2 120)

1 975 (1 170 - 2 838)

0.014

7 (4 - 15)

26 (12 - 83)

5 (4 - 10)

<0.001

36 (38) 39 (41) 20 (21)

2 (11) 9 (47) 8 (42)

34 (45) 30 (39) 12 (16)

0.007

Gender (male)

61 (64)

13 (68)

48 (63)

0.669

HIV-exposed

21 (22)

5 (26)

16 (21)

0.621

55 (58) 23 (24) 14 (15) 3 (3)

6 (32) 6 (32) 4 (21) 3 (15)

49 (65) 17 (22) 10 (13) 0 (0)

0.001

82 (86) 8 (8) 5 (5)

12 (63) 6 (32) 1 (5)

70 (92) 2 (3) 4 (5)

0.001

Respiratory support in NICU

86 (91)

18 (95)

68 (89)

0.480

Inotropes in NICU

43 (45)

11 (58)

32 (42)

0.216

TPN via central line

72 (76)

16 (84)

56 (74)

0.338

Surgery during NICU stay

28 (29)

10 (53)

18 (24)

0.013

Final outcome (survived)

75 (79)

14 (74)

61 (80)

0.529

Length of stay in NICU (days), median (IQR) Catheter dwell time in NICU (days)

†

<4 4-8 >8

Type of central line

†

UVC PICC CVC Broviac Insertion venue† NICU Theatre Neonatal ward

IQR = interquartile range; NICU = neonatal intensive care unit; UVC = umbilical venous catheter; PICC = peripherally inserted central catheter; CVC = central venous catheter; TPN = total parenteral nutrition. *Unless specified. † For cells with <5 observations the Fisher’s exact test was used; for cells with >5 observations the χ2 test was used.

treatment was made in 16/19 (84%) of patients, who showed clinical deterioration or had a change in their septic markers while awaiting blood culture results. After results of antimicrobial susceptibility testing were available, 9 patients required a change in treatment, 4 had therapy targeted to the pathogen isolated, 1 had an antimicrobial agent added, 1 remained on broad-spectrum antibiotics for suspected Gramnegative sepsis, and there was 1 for whom the notes were incomplete. Three babies died before susceptibility testing results were available. Two-thirds of the cohort were premature, with a lower median gestational age and birth weight among the cases than the controls (28 v. 34 weeks; p=0.003, and 1 170 v. 1 975 g; p=0.014). The median length of stay in the NICU was 7 days, but significantly longer in neonates who developed CLABSI (26 v. 5 days; p=<0.001). There were a greater proportion of male infants in both groups. HIV exposure rates were similar between cases and controls; of the 5 HIVexposed neonates who developed CLABSI, all tested HIV polymerase chain reaction (PCR)-negative within the first 2 weeks of life. Seven controls were HIV-exposed, but had an unknown HIV-PCR result. The predominant line types used were UVCs (58%) and PICCs (24%). Broviac lines (3%) and CVCs (15%) were less frequently used and almost exclusively inserted in the operating theatre (all three Broviac lines and 3/4 CVCs). Infection rates of lines inserted in the NICU were significantly lower than for those inserted in the operating theatre (12/78 (15%) v. 7/15 (41%); p=0.012). Only three Broviac lines were inserted over the 2-year study period and all three of the patients developed CLABSI.

Table 3 lists the factors associated with the development of CLABSI. In the stepwise forward logistic analysis, significant risk factors included insertion of a central line in the operating theatre (OR 8.1 (95% CI 1.2 - 54.7); p=0.03) and length of NICU stay >30 days (OR 20.7 (95% CI 2.1 - 203.2); p=0.009).

Discussion

The CLABSI rate of 5.9/1 000 lines in our NICU is similar to that reported from other LMIC but much higher than CLABSI rates in high-income settings. Limited resources, understaffing, overcrowding and the high rate of premature and low-birth-weight babies probably contributed to our high CLABSI rate. In our setting, CLABSI cases occurred more commonly in babies of lower gestational age, lower birth weight, those undergoing surgical procedures and those with a catheter dwell time >4 days. Patients with central lines and NICU admission for >30 consecutive days were 20 times more likely to develop a CLABSI event than those with shorter NICU stays. This result remained significant in multivariate analysis, although the CI was very wide. The wide CI can be attributed to the small number of cases. We postulate that the increased risk associated with CLABSI and long NICU stay may be due to increased risk of bacterial colonisation in critically ill patients with complicated and/or multisystem disease.[6,12] In our setting, central lines inserted in the operating theatre (Broviac and CVCs) had an 8-fold increased risk of CLABSI compared with lines inserted in the NICU. The increased risk could arise

September 2017, Print edition

RESEARCH

Table 2. Characteristics of CLABSI episodes (n=19) Characteristics Time to CLABSI after line insertion (days), median (IQR) UVC PICC CVC Broviac Weight closest to CLABSI (g), median (IQR)

2 (2 - 4) 9 (6 - 13) 7 (6 - 10) 20 (19 - 35) 1 400 (1 029 - 2 510)

Catheter dwell time in NICU (days), median (IQR) All line types UVC PICC CVC Broviac

8 (14 - 18) 4 (3 - 5) 13 (8 - 13) 8 (8 - 11) 22 (21 - 36)

Pathogens causing CLABSI (n=22) Gram-positive organisms, n (%) Staphylococcus aureus Coagulase-negative staphylococci Enterococcus faecalis Gram-negative organisms, n (%) Klebsiella pneumoniae Acinetobacter baumannii Yeasts, n (%) Candida albicans C. krusei C. parapsilosis

5 (23) 1 (5) 2 (9) 2 (9) 12 (54) 5 (22) 7 (32) 5 (23) 3 (13) 1 (5) 1 (5)

Conclusion

CLABSI = central-line-associated bloodstream infection; IQR = interquartile range; UVC = umbilical venous catheter; PICC = peripherally inserted central catheter; CVC = central venous catheter; NICU = neonatal intensive care unit.

during the insertion and/or the maintenance of these lines. CLABSI events related to insertion factors usually develop within 48 - 72 hours of line insertion, suggesting that line maintenance issues were more likely responsible for Broviac and CVC CLABSIs (median time to infection onset 20 and 7 days, respectively). Insertion of Broviac lines and CVCs is also technically more difficult and often inserted in patients with difficult venous access, or where attempts at inserting other central-line types have failed. The literature has shown that TPN increases the risk of CLABSI. Broviac lines and CVCs were more likely to be used in patients who required longer periods of TPN, possibly contributing to infection risk. Another notable difference is that central-line insertion checklists are routinely completed for lines inserted in the NICU, but not for lines inserted in theatre. In light of these findings, the insertion bundle checklist should be implemented in theatre and education of all staff (not only NICU staff) involved in maintenance of surgically inserted lines undertaken. Central lines increase the risk of bloodstream infections.[12,13] Known risk factors for CLABSI include administration of TPN,[12,13] frequent manipulation of the line,[14] open vascular systems,[15] not using needleless connections[6] and the use of multiple access ports.[6] Conflicting data exist on which type of central line is associated with the highest risk for CLABSI and when prolonged catheter dwell time becomes a risk factor.[13,16,17] In our study, nearly 80% of neonates who experienced CLABSI events were premature and half of them required surgery. Although surgery during the NICU stay and catheter dwell time in the NICU were not significant in the multivariate analysis, an association was found in the univariate analysis. The limited data available for

neonates undergoing surgery suggest that premature infants, those with stomas and those with multiple surgical interventions are at highest risk of developing a CLABSI.[18] Our study did not confirm TPN administration as a significant risk factor for CLABSI, but we were unable to compare the duration of TPN administration in cases v. controls. Surgery during NICU stay, catheter dwell time and prolonged stay in the NICU could all be risk factors related to a specific group of patients requiring longterm TPN. Future research is required to evaluate these factors and the cost-effectiveness of establishing a TPN unit for babies who are infection free but require long-term central lines for TPN. Predominantly antibiotic-resistant Gram-negative pathogens were isolated. The high rate of antimicrobial resistance highlights the importance of our CLABSI surveillance and prevention programme and the need for continued antibiotic stewardship. Study limitations included the small number of cases, making it difficult to extrapolate findings to the larger population; an unknown baseline CLABSI rate prior to implementing the CLABSI programme; and the retrospective collection of clinical data for the controls. This study did not specifically evaluate adherence to specific maintenance bundle elements (including number of access ports, use of needleless connectors and accessing central lines in a sterile manner). Other important CLABSI prevention strategies not explored in this study include daily assessment of the need for a central line, prevention of prematurity and promotion of early enteral feeding. Although the NICU had established a CLABSI registry, we identified six missed CLABSI events, suggesting a need for improved surveillance methods.

Despite these limitations, to our knowledge, this study is the first to establish CLABSI rates and risk factors in an SA public sector NICU. The establishment of a baseline CLABSI rate has assisted us with setting targets for the programme, assessing the impact of interventions, and benchmarking ourselves against other similar NICUs. LMIC are faced with unique challenges, such as staff shortages, high patient turnover, and limited resources, making prevention of HAIs, such as CLABSI, very difficult. Support from hospital management and ongoing in-service training of all staff involved in the insertion and maintenance of central lines in neonates are vital to sustain and improve our CLABSI prevention and surveillance programme. Other resource-limited NICUs can benefit from our experience in implementing a CLABSI surveillance and prevention programme. Acknowledgements. Stellenbosch University’s Faculty of Medicine and Health Sciences, the Biostatistics Unit of the Centre for Evidence-based Health Care, and the TCH NICU staff and patients. Author contributions. CG, AB, AD, AJ: conceptualisation; CG, AB, AD: formal analysis; CG, AJ: investigation; CG: methodology; CG: writing – original draft; and CG, AB, AD: writing – review and editing. Funding. None. Conflicts of interest. None.

1. Allegranzi B, Nejad SB, Combescure C, et al. Burden of endemic health-care-associated infection in developing countries: Systematic review and meta-analysis. Lancet 2011;377(9761):228-241. https:// doi.org/10.1016/s0140-6736(10)61458-4 2. Rosenthal VD, Maki DG, Mehta Y, et al. International Nosocomial Infection Control Consortium (INICC) report, data summary of 43 countries for 2007 - 2012. Device-associated module. Am J Infect Control 2014;42(9):942-956. 3. Dudeck MA, Edwards JR, Allen-Bridson K, et al. National healthcare safety network report, data summary for 2013, device-associated module. Am J Infect Control 2015;43(3):206-221. https://doi. org/10.1016/j.ajic.2014.11.014

September 2017, Print edition

RESEARCH

Table 3. Risk factors for CLABSI Unadjusted analysis Variable

Adjusted analysis

95% CI

p-value

95% CI

p-value

0.9 - 14.4 5.1 - 146.3

0.07 <0.001

2.3 20.7

0.47 - 11.2 2.1 - 203.2

0.30 0.009

3.1 - 97.1 0.15 - 14.2

0.001 0.74

1 8.12.9

1.2 - 54.7 0.2 - 42.2

0.03 0.437

Length of stay (days) <7 (reference)

7 - 29 >30

3.5 27.3

Insertion venue NICU (reference)

Theatre Ward

17.5 1.5

Catheter dwell time (days) 0 - 3 (reference)

4-8 >8

5.1 11.3

1.0 - 25.4 2.1 - 61.0

0.04 0.005

* *

3.5

1.26 - 10.00

0.01

1.0 - 26.1 0.9 - 15.8 0.3 - 8.1

0.04 0.07 0.65

* * *

Surgery during NICU stay Any surgery performed Birth weight (g) 2 500 (reference)

<1 000 1 000 - 1 499 1 500 - 2 499

5.2 3.7 1.5

CLABSI = central-line-associated bloodstream infection; NICU = neonatal intensive care unit; OR = odds ratio; CI = confidence interval. *Not available.

4. Shepherd EG, Kelly TJ, Vinsel JA, et al. Significant reduction of central-line associated bloodstream infections in a network of diverse neonatal nurseries. J Pediatr 2015;167(1):41-46.e3. https://doi. org/10.1016/j.jpeds.2015.03.046 5. Powers RJ, Wirtschafter DW. Decreasing central line associated bloodstream infection in neonatal intensive care. Clin Perinatol 2010;37(1):247-272. https://doi.org/10.1016/j.clp.2010.01.014 6. Oâ&#x20AC;&#x2122;Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2011;39(4 Suppl 1):S1-S34. https://doi.org/10.1016/j.ajic.2011.01.003 7. Rosenthal VD, DueĂąas L, Sobreyra-Oropeza M, et al. Findings of the International Nosocomial Infection Control Consortium (INICC), part III: Effectiveness of a multidimensional infection control approach to reduce central line-associated bloodstream infections in the neonatal intensive care units of 4 developing countries. Infect Control Hosp Epidemiol 2013;34(3):229-237. https://doi.org/10.1086/669511 8. Western Cape Government. Department of Health. Tygerberg Hospital annual report 2013. http:// www.westerncape.gov.za/dept/health/documents/annual_reports (accessed 23 April 2017). 9. Centers for Disease Control (CDC)/National Healthcare Safety Network (NHSN). National healthcare safety network overview. http://www.cdc.gov/nhsn/PDFs/pscManual/validation/pcsManual-2014-valid.pdf (accessed 23 April 2017). 10. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18(3):268-281. https://doi.org/10.1111/j.1469-0691.2011.03570.x 11. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Am J Infect Control 1999;27(2):97-132. 12. Perlman SE, Saiman L, Larson EL. Risk factors for late-onset health care-associated bloodstream infections in patients in neonatal intensive care units. Am J Infect Control 2007;35(3):177-182. https:// doi.org/10.1016/j.ajic.2006.01.002

13. Chien LY, Macnab Y, Aziz K, et al. Variations in central venous catheter-related infection risks among Canadian neonatal intensive care units. Pediatr Infect Dis J 2002;21(6):505-511. https://doi. org/10.1097/00006454-200206000-00006 14. Mahieu LM, de Dooy JJ, Lenaerts AE, Ieven MM, de Muynck AO. Catheter manipulations and the risk of catheter-associated bloodstream infection in neonatal intensive care unit patients. J Hosp Infect 2001;48(1):20-26. https://doi.org/10.1053/jhin.2000.0930 15. Maki DG, Rosenthal VD, Salomao R, Franzetti F, Rangel-Frausto MS. Impact of switching from an open to a closed infusion system on rates of central line-associated bloodstream infection: A meta-analysis of time-sequence cohort studies in 4 countries. Infect Control Hosp Epidemiol 2011;32(1):50-58. https:// doi.org/10.1086/657632 16. Milstone AM, Reich NG, Advani S, et al. Catheter dwell time and CLABSIs in neonates with PICCs: A multicenter cohort study. Pediatrics 2013;132(6):e1609-e1615. https://doi.org/10.1542/peds.2013-1645 17. Yumani DFJ, van den Dungen FAM, van Weissenbruch MM. Incidence and risk factors for catheterassociated bloodstream infections in neonatal intensive care. Acta Paediatr 2013;102(7):e293-e298. https://doi.org/10.1111/apa.12256 18. Klein MD, Rood K, Graham P. Central venous catheter sepsis in surgical newborns. Pediatr Surg Int 2003;19(7):529-532. https://doi.org/10.1007/s00383-003-0977-6

Accepted 24 April 2017.

September 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Residual allergenicity of amino acid-based and extensively hydrolysed cow’s milk formulas M E Levin,1 MB ChB, FCPaed (SA), MMed (Paed), Diploma Allergy (SA), PhD; D M Blackhurst,2 PhD; F Kirstein,3 PhD; D Kok,4 BSc; G F van der Watt,2 BSc, MB ChB, Dip Anaesth, MMed (Chem Path), FC Path (SA) Chem; A D Marais,2,5 MB ChB, FCP (SA) Division of Allergology, Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 3 Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Faculty of Health Sciences, University of Cape Town; and International Centre for Biotechnology and Genetic Engineering, Cape Town Component, South Africa 4 Division of Organic Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, Cape Town, South Africa 5 National Health Laboratory Service, Cape Town, South Africa 1 2

Corresponding author: M E Levin (michael.levin@uct.ac.za) Background. Criteria for labelling infant feeds as suitable for the dietary management of cow’s milk protein allergy (CMPA) rely on proving the hypoallergenicity of such feeds or clinical studies showing that the feeds are tolerated by 90% of children with proven CMPA. South African (SA) labelling legislation does not indicate what testing is necessary to prove hypoallergenicity. Objectives. To evaluate all extensively hydrolysed cow’s milk formulas and amino acid-based formulas available in SA for residual allergen content, protein size and amino-acid content. Results. All amino-acid and extensively hydrolysed formulas were found to be similar in composition, with no residual cow’s milk allergens detectable by enzyme-linked immunosorbent assay. Furthermore, proteins were absent and only small molecules in the size range of amino acids and possibly of very small oligopeptides were detected. Conclusions. These findings indicate that the formulas are extremely likely to be compliant with the definition of hypoallergenicity as tolerance in 90% of proven sufferers from cow’s milk allergy. The formulas may therefore be labelled as suitable for the dietary management of infants with CMPA. S Afr Med J 2017;107(9):763-767. DOI:10.7196/SAMJ.2017.v107i9.12137

Breastmilk, the white liquid produced by the mammary glands, is the primary source of nutrition for infants before they are able to digest other types of food. Modified cow’s milk formulas are the commonest breastmilk replacement formula, but are not always tolerated by infants with lactose intolerance or cow’s milk protein allergy (CMPA). CMPA is an immune-mediated hypersensitivity reaction to cow’s milk protein,[1] which may be IgE mediated (presenting with urticaria, angio-oedema, and respiratory, abdominal and cardiac signs, and ranging from mild to anaphylactic reactions), or nonIgE mediated (presenting with delayed-type reactions, mainly in the gastrointestinal tract). The prevalence of CMPA is estimated at 2 - 4% worldwide, and preliminary data from the South African Food sensitisation and Food Allergy (SAFFA) study show a 6.4% prevalence of sensitisation and a 0.2% prevalence of challenge-proven CMPA in 1 - 3-year-old unselected urban infants.[2] Cow’s milk comprises casein and whey allergenic proteins. The casein allergens (collectively known as Bos d 8) comprise four different proteins (alpha-S1, alpha-S2, beta and kappa casein). The most important whey allergens include beta-lactoglobulin (Bos d 5, the most abundant cow’s milk whey protein, which occurs in the milk of many other species but is not present in human milk) and alpha-lactalbumin (Bos d 4). Bovine serum albumin (Bos d 6) and bovine immunoglobins (Bos d 7) are less common allergens. The most common cow’s milk antigens are intact proteins of a molecular weight between 14 and 150 kDa.[3] Cow’s milk casein has a molecular weight of 19 - 25.2 kDa. Beta-lactoglobulin has a molecular weight of 18.3 kDa, α-lactalbumin 14.2 kDa, bovine serum albumin 66.3 kDa and bovine immunoglobin G 150 kDa.

Cow’s milk formulas are categorised according to the degree of hydrolysis into intact milk protein formulas, partially hydrolysed formulas (PHFs) or extensively hydrolysed formulas (EHFs). In addition, amino acid-based formulas (AAFs) manufactured from hydrolysis of nonmilk proteins or by combining individual amino acids are available. The nature of the formula may add additional indications to its use apart from its nutritional role, such as for dietary management as a replacement formula in children with established CMPA. The term ‘hypoallergenic formulas’ was first used by Kleinman et al.[4] to refer to formulas that are tolerated by 90% of subjects with proven cow’s milk allergy with a 95% confidence interval, and are therefore used for the treatment of cow’s milk allergy. This definition was subsequently adopted by the World Allergy Organization (WAO).[5] A statement of the European Society for Pediatric Allergology and Clinical Immunology[6] stated in 1998 that infant formulas with a content of immunoreactive protein of <1% of total nitrogen (which translates into the majority of peptides <1.5 kDa[7]) may be labelled as having ‘reduced allergenicity’. In 2000, the American Academy of Pediatrics defined an extensively hydrolysed formula as a formula containing only peptides that have a molecular weight of <3 kDa.[8] The guideline states that formulas with ‘most of the nitrogen in the form of free amino acids and peptides <1.5 kD have been subjected to extensive clinical testing and meet the standard for hypoallergenicity’. In 2008, the American Academy of Pediatrics[9] defined partially hydrolysed formulas as those that contain oligopeptides with a molecular weight generally <5 kDa, extensively hydrolysed formulas as containing only peptides that have a molecular weight <3 kDa and

September 2017, Print edition

RESEARCH

free amino acid-based formulas as peptide-free mixtures of essential and non-essential amino acids. It is possible that individual amino acids can polymerise and form simple (usually di- or tri-) peptides. Cross-linking of Fcε receptor-bound IgE requires that an allergen contains at least two IgE-binding epitopes with a size of at least 15 amino acids. This implies that proteins with a size of <3 kDa are incapable of causing an allergic reaction.[10] PHFs are not considered to be hypoallergenic according to Kleinman et al.’s[4] definition; however, many EHFs have been proven to be hypoallergenic and all AAFs are hypoallergenic. Current milk labelling practices are, however, confusing and contested. For example, many partially hydrolysed feeds are labelled as ‘HA’ and are referred to widely as ‘hypoallergenic’ because there has been some modification of their milk protein content by partial hydrolysis. Such partially hydrolysed feeds may have some efficacy in prevention of CMPA in high-risk subjects whose mothers are unable to breastfeed, but they are not suitable for subjects with confirmed CMPA, as they do not conform to the WAO definition of hypoallergenicity. There have recently been changes to infant formula-labelling legislation in South Africa (SA). South African Department of Health Government Notice 35941 on 6 December 2012 (no. R991) [11] legislated that mandatory statements on the labels of infant formula for special dietary management of infants with specific medical conditions replace claims of formula type or allergenicity (e.g. extensively or partially hydrolysed, allergen free, amino acid or hypoallergenic). Statements allowed include ‘for the dietary management of infants with cow’s milk allergy’ or ‘for the dietary management of infants with cow’s milk allergy, multiple food protein allergies’. The criteria by which such labelling is applied are not clear. South African Department of Health Government Notice 32975 on 1 March 2010 (no. R146)[12] is concerned with hypoallergenic, nonallergenic or allergen-free claims. The notice states that no claim shall be made that a foodstuff is hypoallergenic, non-allergenic or free of a common or uncommon allergen unless it is modified so as to reduce the endogenous antigens in such a way that it is not possible to detect the presence of any possible allergen with testing suitable for the specific allergen, or it has been tested to confirm the absence of such antigens using suitable testing. The definition of what testing is suitable, which antigens should be tested for and in what form (e.g. size, degree of hydrolysis) is not covered by the legislation. With regard to infant formulas, candidates for testing include the native allergens themselves as well as the products of hydrolysis.

Objectives

To evaluate the residual allergen, protein, peptide and amino-acid content of AAFs and EHFs available in SA. This included: • Testing for milk protein allergens (whole milk, β-lactoglobulin, casein, α-lactalbumin) in AAFs and EHFs and comparing these with whole cow’s milk and human breastmilk • Testing for egg albumin, peanut and soy allergens in AAFs, EHFs, whole cow’s milk and human breastmilk • Testing for protein (peptides and amino acids) and the range in protein sizes in AAFs and EHFs and comparing these with whole cow’s milk and human breastmilk.

Methods

Institutional review and ethical approval were sought and obtained (Human Research Ethics Committee, University of Cape Town, ref. no. 270/2014). Manufacturers of all companies marketing AAFs or EHFs in SA were notified of the research and permission was

requested to identify their products by name. Where companies did not give permission for their products to be identified by name, they were referred to as the type of formula followed by a numeral if more than one of the same type of formula remained un-named (Table 1). Where available, feeds were purchased from local pharmacies. Aminomed and Comidagen Plus (Nutr-e-Volution) were obtained directly from the manufacturer as they are sold via web-based ordering, and Neomino (Cipla) was obtained directly from the manufacturer as the feed had not yet been commercially launched. The formulas were reconstituted according to the manufacturer’s specifications under sterile conditions with sterile water ensuring no contamination, then aliquoted and frozen at –20oC until thawed for specific analysis. Chemicals were of reagent grade. Deionised water was used for solutions. The samples were weighed on the same electronic balance and analyses were carried out in solutions according to the manufacturer’s instructions, but were scaled down to practical volumes for use in the laboratory.

Allergen content

Formulas were tested in duplicate by enzyme-linked immunosorbent assay (ELISA) for whole-milk protein (α-, β- and κ-caseins, β-lactoglobulin), and individual β-lactoglobulin, casein, egg albumin, peanut and soy proteins using Ridascreen Fast test kits (R-Biopharm AG, Germany) and for α-lactalbumin (Bethyl Laboratories, USA). These ELISA test kits were used for the quantitative analysis of residual milk allergen content in AAFs and EHFs, and tests were performed according to the manufacturer’s protocol. Whole cow’s milk and human breastmilk served as positive and negative controls, respectively. In addition, all samples were tested for the presence of soy, peanut and egg allergens.

Protein concentration and sizes

Conventional spectrophotometric protein assays are unreliable for small proteins and peptides, and two approaches were therefore used to describe these molecules by size. • Coomassie Blue staining of proteins separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Each sample was reduced and denatured and underwent separation of amino acids, peptides and proteins in a 5 - 20% gradient polyacrylamide gel.[13] Polyacrylamide gel was prepared in the laboratory in a Mini Protean II apparatus (Biorad, USA) according to Laemmli.[14] Before application, 3 μL of the sample were heated with 1% SDS and mercaptoethanol. Bromphenol blue was used with sucrose to load the sample. After running at 130 V until the blue dye approached the end of the gel, the gel was stained in Coomassie Blue solution and destained in methanol-acetic acid. • Size-exclusion chromatography for amino acids and peptides. The reconstituted formula was filtered (0.45 microns) and analysed isocratically on an Agilent 1260 Infinity high-performance liquid chromatography (HPLC) system (Agilent, USA) that detected the absorption at selected wavelengths by diode array. The elution profiles were analysed for area under the curve (AUC) using the Masshunter software acquired with the machine. An Agilent SEC3 size exclusion column (Agilent, USA) was used with a flow rate of 0.35 mL/min using phosphate-buffered saline. This separates molecules between 100 kDa and 0.1 kDa. Calibration was carried out with selected amino acids and proteins. Adequate post-time was used to ensure no carry-over. HPLC employs a flow of molecules in solution through porous material that retards the progress of smaller molecules more than large molecules because the former venture into smaller spaces, increasing their

September 2017, Print edition

RESEARCH

Table 1. AAFs and EHFs tested Product AAFs Aminomed (Nutr-e-Volution) Comidagen Plus (Nutr-e-Volution) Neocate LCP (Nutricia) Neocate Advance (Nutricia) Neomino (Cipla) EHFs Alfare (Nestlé) Pepticate (Nutricia) Casein EHF 1 Similac Alimentum (Abbott)

Intended age

Description

<1 year >1 year <1 year >1 year <1 year

Free amino-acid formula Free amino-acid formula Free amino-acid formula Free amino-acid formula Free amino-acid formula

<1 year <1 year <1 year <1 year

Hydrolysed whey Hydrolysed whey Hydrolysed casein Hydrolysed casein

AAFs = amino acid-based formulas; EHFs = extensively hydrolysed formulas.

travel distance relative to the large molecules that flow through the column with practically no delay. The molecular size markers were gamma-globulin (150 kDa) at the void volume, albumin (66 kDa), oxytocin (1.00 kDa), tryptophan (0.204 kDa) and glycine (0.075 kDa).

Results

Allergen content

All AAF and EHF samples were negative for all milk allergens tested, with values below the detection limit of the assays (milk 2.5 mg/kg, α-lactalbumin 0.78 mg/kg, β-lactoglobulin and casein 0.5 mg/kg). The cow’s milk sample, on the other hand, was positive for all milk allergens with values above the upper detection range of the assay (milk 67.5 mg/kg, α-lactalbumin 50 mg/kg, β-lactoglobulin and casein 13.5 mg/kg), confirming correct performance of the tests. As expected, no cow’s milk allergens were detected in human breastmilk. Furthermore, all samples tested negative for soy, peanut and egg allergens below the detection limit of the assays (peanut and soy 2.5 mg/kg, egg albumin 0.5 mg/kg).

Protein electrophoresis

After electrophoresis, staining with Coomassie Blue did not reveal any protein in the lanes containing reconstituted formulas. Proteins stained readily in cow’s milk (lanes 10 and 12) as well as human milk (lane 11) (Fig. 1). Coomassie Blue stains proteins unreliably below 3 kDA and has a limit of detection at 0.1 μg or even less. No protein was visible in any of the formula samples tested above the limit of detection of Coomassie Blue. The protein profiles differed between the cow’s and human milk. An attempt was made to detect small peptides and amino acids in a similar gel that was modified to 15% acrylamide to favour separation of smaller peptides, by derivatisation of carboxylic acid moieties with the fluorescent dye PDAM (1-pyrenyldiazomethane). This readily demonstrated glycine and tryptophan and conjugated material of identical size in the formulas, but larger peptides were not seen. In contrast, the cow’s milk and breastmilk lanes lacked fluorescence in the range of single amino acids and small peptides, but there was faint fluorescence from the smallest size of protein seen in the Coomassiestained gels as well as in larger proteins (data not shown).

HPLC with size exclusion

HPLC with diode array detection of eluting compounds from a size exclusion column was used to discriminate molecules from amino acids through oligopeptides to proteins.

Fig. 1. Milk formula electrophoresis. (Lanes: 1 Alfare, 2 Allernova, 3 Pepticate, 4 Similac Alimentum, 5 Aminomed, 6 Comidagen Plus, 7 Neocate Advance, 8 Neocate LCP, 9 Neomino, 10 full-cream cow’s milk, 11 breastmilk, 12 fat-free milk. M1 molecular mass markers (small to large): 10, 15, 25, 35, 40, 55, 70, 100, 130, 170 kDa; M2 molecular mass markers (small to large): 14.3, 21.5, 30, 46, 69, 97.4, 200 kDa.)

The area of interest was determined by extrapolation from the markers: 13 minutes representing 3.02 kDa, 14 minutes 1.55 kDa and 16 minutes 0.40 kDa. The peaks for the largest amino acid (tryptophan, 0.204 kDa) and the smallest (glycine, 0.075 kDa) were at 16.3 and 16.9 minutes, respectively. The HPLC analysis covers the range of peptides below a molecular size of 3 kDa that could be missed by the SDS-PAGE analysis. The HPLC analysis of very small molecules for sizes up to ~0.4 kDa could include the largest polymer of pentameric glycine and the simplest dimer could be one with tryptophan. Very small (oligo-) peptides can be considered to be in the size range of 0.4 - 1.5 kDa. The polymer with the largest number of amino acids in this range could be the triscidecamer of glycine and the lowest number of amino acids could be the pentamer of tryptophan. The larger peptides from 1.5 to 3 kDa could be a 40-mer of glycine to a 15-mer of tryptophan. The detection of molecules by ultraviolet absorption favours amino acids, but may include other compounds. The elution profiles of the formula samples contain material absorbing at molecular mass equivalents >3 kDa. The SDS-PAGE analysis indicates that these absorbing substances are not proteins. The overlay of all the elution profiles (Fig. 2) illustrates that the region between 3 kDa and 0.4 kDa is relatively clear of molecules absorbing at 214 nm, with very similar patterns in the single aminoacid region between 16 and 18 minutes, indicated by tryptophan

September 2017, Print edition

RESEARCH

and glycine on the control elutions. The cow’s milk and breastmilk samples contained no material at these low-molecular-weight ranges. This indicates that molecules larger than 3 kDa were mostly absent in all formula samples tested. The elution profiles were analysed for AUC in various segments representing 3 - 1.5 kDa and 1.5 - 0.4 kDa, and the ratios were compared for these segments and the whole AUC for the region of <3 kDa. Although little difference was apparent in the molecular mass range between amino acids and 3 kDa, the AUC was analysed to crudely examine for differences between the two formula groups. The different formulations varied approximately four-fold in the 3.0 1.5 kDa peptide range, as well as in the 1.5 - 0.4 kDa peptide range, whereas the variation was seven-fold in the <0.4 kDa (amino-acid) range. Comparison of the EHF group with the AAF group indicated

Concentration (absorbance 214 nm)

0.600

that the EHF preparations had a trend towards a greater AUC for the 0.4 - 1.5 kDa size range than the AAF group (mean (standard deviation (SD)) 1 383 (578) v. 687 (346); p=0.064). In the <0.4 kDa amino-acid region, the AAF group had a trend towards a higher AUC than the EHF group (mean 8 453 (3 226) v. 4 326 (2 442); p=0.064). The proportion of amino acids <0.4 kDa in relation to the total range (peptides plus amino acids) was significantly higher in the AAF group than in the EHF group (mean (SD) 0.850 (0.062) v. 0.631 (0.126); p=0.032). The EHF group also had a higher proportion of (presumed peptide) molecules >0.4 kDa compared with amino acids and small oligopeptides (<0.4 kDa) than the AAF group (mean 0.630 (0.295) v. 0.182 (0.089), respectively; p=0.032). Taken together, these findings suggest that EHFs may have more small oligopeptides than AAFs. According to these indirect criteria, >50% of the EHF molecules were <0.4 kDa, compared with >75% of the AAF formulations. Interestingly, there was no demonstrable material between 1.5 and 0.4 kDa in cow’s milk and human breastmilk, but the latter had demonstrable material between 0.4 and 3 kDa (data not shown).

Discussion 0.400

0.200

0.000 13

3 kDa 1.5 kDa 0.4 kDa

Glycine Tryptophan

Elution time (min) Fig. 2. Milk high-performance liquid chromatography peptide profile. (*Time after injection at which the peak was noted.)

It is extremely important that feeds for the dietary management of individuals with CMPA are free of residual allergenicity. Even trace amounts of native protein can cause significant reactions.[15] The samples analysed in this study were randomly selected and are likely to be representative of the formulas in general. Since the formulas are manufactured according to set methods and with good quality control, it is unlikely that there will be significant differences from time to time. All samples of AAFs and EHFs tested negative for all milk, soy, peanut and egg allergens in quantitative allergen-specific ELISA tests. This supports the conclusion that no protein antigens of a size large enough to bind to antibodies were present in the tested formulas. Polyacrylamide gel analysis showed that none of the formulas tested contained detectable protein >3 kDa, in contrast to the large amounts and variety of proteins in the cow’s milk and breastmilk. The formulas lacked detectable large proteins and can therefore appropriately be termed protein-free, although technically small amounts of oligopeptides may be present. The formulas vary significantly in the range of interest in molecular size, as described in Table 2. The detection of these molecules is not specific to amino acids, but was used to estimate differences in the low concentrations between amino acids and small oligopeptides. The AUC values for the molecular sizes between 3 kDa and 0.4 kDa are

Table 2. AUC for compounds <3 kDa, and their ratios for selected regions detected by spectrophotometry Feed type EHF EHF EHF EHF AAF AAF AAF AAF AAF

Sample Alfare EHF 1 Pepticate Alimentum Aminomed Comidagen Plus Neocate LCP Neocate Advance Neomino Mean SD

3 - 1.5 kDa (peptides) 1 267 503 789 722 285 953 338 1 048 638 727 327

1.5 - 0.4 kDa (peptides) 1 969 1 783 813 968 1 304 496 514 563 558 996 565

0.4 - 0.1 kDa (AAs) 5 870 2 694 1 836 6 904 7 785 12 664 8 682 9 421 3 715 6 619 3 489

AAs divided by (peptides + AAs) 0.645 0.541 0.534 0.803 0.830 0.897 0.911 0.854 0.756 0.752 0.145

AUC = area under the curve; AAs = amino acids; EHF = extensively hydrolysed formula; AAF = amino acid-based formula; SD = standard deviation.

September 2017, Print edition

Peptides/AAs 0.551 0.849 0.873 0.245 0.204 0.114 0.098 0.171 0.322 0.381 0.304

RESEARCH

low relative to the amino-acid range in all samples. There is a trend towards more single amino-acid molecules in the AAFs than in the EHFs and for more oligopeptides in the EHFs than in the AAFs. AAFs had a significantly higher proportion of amino acids in relation to the total range (peptides plus amino acids) than EHFs. Conversely, the EHFs had a higher proportion of oligopeptide molecules compared with amino acids than the AAFs. More than 50% of the EH molecules were <0.4 kDa compared with >75% in the AAFs. The clinical significance of the molecules between 0.4 and 3 kDa is unknown. While it is possible that they may be immunogenic, they are subject to further digestion and modification in the body. It is theoretically possible to examine these molecules as antigens by performing reactions with plasma from patients suspected of allergy. It is unlikely that there is merit in analysing the species of oligomers of amino acids in the range of 3 - 0.1 kDa, unless a specific compound is thought to be particularly immunogenic. It is also possible that oxidatively modified amino acids could be present in the formulas. Such modification could happen during preparation or storage. These data support the opinions expressed by the international Diagnosis and Rationale for Action against Cow’s Milk Allergy[16] food allergy guidelines and the recent South African consensus statement[1] that extensively hydrolysed and amino acid formulas are suitable for the dietary management of cow’s milk protein allergy. It is therefore appropriate that these formulas be labelled accordingly, in line with current legislation. Unintended consumption of allergenic proteins can occur despite excellent labelling, for example due to an allergen’s unlabelled inclusion in a food or cross-contamination during processing or after manufacture.[15] Cross-contamination can be detected with ELISA testing to prove the presence of unintended allergens in both liquid and solid foodstuffs.

Conclusions

All AAFs and EHFs currently available in SA were found to be similar in composition, with an absence of proteins and a prominence of very small molecules. They have no residual allergenicity on ELISA testing for the native cow’s milk protein and major allergenic components. Protein chains, where present, are of sufficiently small length to make it extremely likely that they will comply with the definition of hypoallergenicity as being tolerated by 90% of proven sufferers from cow’s milk allergy, and they should therefore be labelled as suitable for the dietary management of subjects with cow’s milk protein allergy. Acknowledgements. None. Author contributions. MEL conceived the project, sourced hydrolysed cow’s milk formulas and amino-acid formulas, wrote up the article and

reviewed the article; DMB performed chromatography and electrophoresis and contributed to writing and reviewing the article; FK designed the methods for allergen testing, performed allergen testing, wrote up sections of the article and reviewed the article; DK assisted with the performance of protein and amino-acid chromatography and its analysis and reviewed the article; GFvdW performed amino-acid and other analyses on the original formulations and reviewed the article; and ADM designed the methods for protein and amino-acid testing, performed protein and amino-acid testing, wrote up sections of the article and reviewed the article. Funding. Funding for reagents and materials was obtained from Cipla Medpro. Conflicts of interest. None. 1. Levin ME, Gray CL, Goddard E, et al., for the South African Food Allergy Working Group (SAFAWG). South African food allergy consensus document 2014. S Afr Med J 2015;105(1):62-65. https://doi. org/10.7196/SAMJ.9098 2. Basera W, Botha M, Gray CL, et al. The South African Food sensitisation and Food Allergy (SAFFA) population-based study of IgE-mediated food allergy: Validity, safety and acceptability. Ann Allergy Asthma Immunol 2015;115(2):113-119. https://doi.org/10.1016/j.anai.2015.06.003 3. Steinman H, Ruden S. Native and recombinant allergen components. Uppsala, Sweden: X-O Graf Tryckeri AB, 2008. 4. Kleinman RE, Bahna S, Powell GF, Sampson HA. Use of infant formulas in infants with cow milk allergy: A review and recommendations. Pediatr Allergy Immunol 1991;2(4):986-997. https://doi. org/10.1111/j.1399-3038.1991.tb00200.x 5. Motala C, Fiocchi A. Cow’s milk allergy in children. http://www.worldallergy.org/professional/ allergic_diseases_center/cows_milk_allergy_in_children/ (accessed 29 July 2015). 6. Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child 1999;81(1):80-84. 7. Meyer R, Venter C. Food hypersensitivity. In: Shaw V, Lawson M, eds. Clinical Paediatric Dietetics. 4th ed. Oxford: Wiley Blackwell, 2014:308-334. 8. American Academy of Pediatrics: Committee on Nutrition. Hypoallergenic infant formulae. Pediatrics 2000;106(2):346-349. 9. Greer FR, Sicherer SH, Burks AW, and the Committee on Nutrition and Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: The role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods and hydrolyzed formulas. Pediatrics 2008;121(1):183-192. https://doi. org/10.1542/peds.2007-3022 10. Huby RDJ, Dearman RJ, Kimber I. Why are some proteins allergens? Toxicol Sci 2000;55(2):235-246. https://doi.org/10.1093/toxsci/55.2.235 11. South Africa. Foodstuffs, Cosmetics and Disinfectants Act 54 of 1972. Regulations: Relating to foodstuffs for infants and young children (R991). Government Notice 35941, 2012. 12. South Africa. Foodstuffs, Cosmetics and Disinfectants Act 54 of 1972. Regulations: Relating to the labelling and advertising of foodstuffs (R146). Government Notice 32975, 2010. 13. Swank RT, Munkres KD. Molecular weight analysis of oligopeptides by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate. Anal Biochem 1971;39(2):462-477. https://doi. org/10.1016/0003-2697(71)90436-2 14. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970;227(5259):680-685. https://doi.org/10.1038/227680a0 15. Levin ME, Motala C, Lopata AL. Anaphylaxis in a milk-allergic child following ingestion of soy formula cross-contaminated with cow’s milk protein. Pediatrics 2005;116(5):1223-1225. https://doi. org/10.1542/peds.2005-0020 16. Koletzko S, Niggemann B, Arato A, et al.; European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Diagnostic approach and management of cow’s-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr 2012;55(2):221229. https://doi.org/10.1097/MPG.0b013e31825c9482

Accepted 18 April 2017.

September 2017, Print edition

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

A review of antenatal corticosteroid use in premature neonates in a middle-income country A Laher,1 MB BCh, DCH (SA); D E Ballot,1 MB BCh, FCPaed (SA), PhD; T Ramdin,1 MB BCh, FCPaed (SA), DCH (SA), MMed (Neonatology) (SA); T Chirwa,2 BSc, MSc, PG Dip, PhD 1 2

Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: A Laher (anees.laher@gmail.com) Background. Antenatal corticosteroid (ANS) use in premature neonates has become a standard of practice. However, there is low ANS coverage in low- to middle-income countries (LMICs). Recent studies have questioned the efficacy of ANSs in such countries. Objective. To review the use of ANSs in preterm neonates at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), South Africa. Methods. This was a retrospective observational study of all neonates with a birth weight of 500 - 1 800 g born at CMJAH between 1 January 2013 and 30 June 2016. Neonatal and maternal characteristics of neonates exposed to ANSs were compared with those of neonates who were not exposed. Results. The ANS coverage of the final sample was 930/2 109 (44.1%). The mean (standard deviation (SD)) birth weight was 1 292.4 (323.2) g and the mean gestational age 30.2 (2.9) weeks. Attending antenatal care and maternal hypertension were associated with increased use of ANSs, whereas vaginal delivery was associated with decreased use. In neonates weighing <1 500 g, the use of ANSs was associated with decreased mortality, decreased intraventricular haemorrhage and decreased patent ductus arteriosus. There was no association between ANSs and respiratory distress syndrome, necrotising enterocolitis, sepsis or need for respiratory support in all premature neonates, and no association with improved outcomes in those weighing ≥1 500 g. Conclusion. The benefits of ANSs in terms of neonatal morbidity in this study were not as marked as those published in high-income countries. A randomised controlled trial may be indicated in LMICs. S Afr Med J 2017;107(9):768-772. DOI:10.7196/SAMJ.2017.v107i9.12246

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12246

White blood cell count and C-reactive protein together remain useful for diagnosis and staging of acute appendicitis in children S Monsalve,1,2 MD; A Ellwanger,3 MD; S Montedonico, MD, PhD1,2,4 Department of Pediatric Surgery, Hospital Carlos van Buren, Valparaíso, Chile Clínica Ciudad del Mar, Viña del Mar, Chile 3 Hospital de Contulmo, Arauco, Chile 4 Centro de Investigaciones Biomédicas, Escuela de Medicina, Universidad de Valparaíso, Valparaíso, Chile

Corresponding author: S Montedonico (sandra.montedonico@uv.cl) Background. Acute appendicitis (AA) is the most common acute surgical condition of the abdomen, and the most commonly misdiagnosed. Objective. To analyse the white blood cell count (WBCC) and C-reactive protein (CRP) contribution to the diagnosis of AA in children. Methods. This was a retrospective study of 943 consecutive patients operated on with the preoperative diagnosis of AA, in whom preoperative WBCC and CRP had both been measured. Postoperatively, the patients were divided into three groups: normal appendix (no AA), simple AA and complicated AA. Results. Of the 943 patients, 616 (65.3%) had simple AA. The mean (standard deviation (SD)) age for this group was 9.8 (3.2) years (p<0.01 v. complicated AA), the mean WBCC was 16.5 (5.0) × 109/L (p<0.01 v. complicated AA and no AA), and the mean CRP level was 304.8

September 2017, Print edition

RESEARCH

(409.5) nmol/L (p<0.01 v. complicated AA). The mean age of the patients with complicated AA (283/943, 30.0%) was 7.9 (3.7) years, the mean WBCC was 17.7 (6.2) × 109/L (p<0.01 v. no AA) and the mean CRP level was 1 076.2 (923.8) nmol/L (p<0.01 v. no AA). The mean age of the patients with no AA (44/943, 4.7%) was 8.8 (3.2) years, the mean WBCC was 13.1 (5.3) × 109/L and the mean CRP was 361.9 (447.6) nmol/L. The WBCC was normal in 113/899 patients with appendicitis (12.6%) and CRP in 139 (15.5%). Both the WBCC and CRP were normal in 17 patients with appendicitis (1.9%). The best receiver operating characteristic (ROC) curve was obtained for WBCC when comparing all AA with no AA: cut-off point 15.0 × 109/L, sensitivity 65%, specificity 68%, area under the curve 0.70. The best ROC curve for CRP was obtained when comparing simple AA with complicated AA: cut-off point 361.9 nmol/L, sensitivity 74%, specificity 74%, area under the curve 0.81. Conclusions. The WBCC is helpful in diagnosing simple AA and CRP in diagnosing complicated AA. If both are normal, AA is very unlikely. Together the WBCC and CRP are useful tools in diagnosing and staging AA. S Afr Med J 2017;107(9):773-776. DOI:10.7196/SAMJ.2017.v107i9.12206

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12206

The spectrum and outcome of paediatric traumatic brain injury in KwaZulu-Natal Province, South Africa has not changed over the last two decades J J P Buitendag,1 MB ChB; V Y Kong,1 MB ChB, MSc, PhD, MRCS; J L Bruce,1 MB ChB, FCS (SA); G L Laing,1 MB ChB, MSc, PhD, FCS (SA); D L Clarke,1,2 MB ChB, MPhil, MBA, MSc, PhD; P Brysiewicz,3 BSocSc, MCur, PhD, BA Pietermaritzburg Metropolitan Trauma Service, Department of Surgery, University of KwaZulu-Natal, Durban, South Africa Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 1 2

Corresponding author: J J P Buitendag (johan_buitendag@yahoo.com) Objectives. This retrospective review of a prospectively entered and maintained hybrid electronic trauma registry was intended to develop a comprehensive overview of traumatic brain injury (TBI) in children and adolescents and to compare it with previous audits from our local environment and from other developing world centres. All TBI patients admitted to hospital were included in this study. We reviewed the age, gender, outcomes, radiological findings and treatment of the patients. Methods. All patients aged ≤18 years old who were admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS) with TBI between December 2012 and December 2016 were included in this audit. Results. During the 4-year period under review, a total of 563 children and adolescents were treated for TBI by the PMTS. The median age was 6.4 years and 29% (n=165) were females. The mechanism of TBI was blunt trauma in 96% (n=544) of cases, with 4% (n=19) suffering penetrating trauma. The penetrating mechanisms included impalement by a cow horn and miscellaneous injuries due to saws, axes, barbed wire, spades, stones and knives. The blunt mechanisms included falls (n=102), assaults (n=108), collapse of a building (n=28), bicyclerelated injury (n=14), falling off a moving vehicle (n=280), motor vehicle accident (MVA; n=59), pedestrian vehicle accident (PVA; n=183) and animal-related injuries (n=8). There were 454 (80%) mild, 67 (12%) moderate and 42 (7%) severe cases of TBI. A total of 48 patients were admitted to the intensive care unit and 23 were admitted to the high care unit. Nine patients died. All the deaths were in the MVA and PVA group. The spectrum of TBI as diagnosed on computed tomography scans was nonspecific cerebral contusion (n=92), depressed skull fracture (n=70), sub-arachnoid haemorrhage (n=60), extradural haemorrhage (n=41), intracerebral haemorrhage (n=19), free air (n=19), subdural haemorrhage (n=13), intraventricular haemorrhage (n=9). A total of 62 (11%) patients required surgery. Conclusion. There is a significant burden of paediatric TBI in Pietermaritzburg. The majority of TBI was related to blunt trauma and assaults were very common. Although the short-term outcomes are good, the long-term consequences are poorly understood. Injury prevention programmes are needed to help reduce this burden of disease and a nationwide trauma registry is long overdue. S Afr Med J 2017;107(9):777-780. DOI:10.7196/SAMJ.2017.v107i9.12394

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12394

September 2017, Print edition

RESEARCH

Concomitant HIV infection in newly diagnosed multiple myeloma patients is hard to recognise and should be tested for routinely in areas of high endemicity J J B de Groot,1,2 MSc; M J Webb,2 MB ChB, MMed; J E Raubenheimer,3 PhD; M C Struwig,4 MMedSc, PhD; V J Louw,2 MB ChB, MMed, FCP (SA), PhD Department of Haematology, VU University Medical Center, Amsterdam, The Netherlands Division of Clinical Haematology, Department of Internal Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 3 Department of Biostatistics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 4 Office of the Dean, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 1 2

Corresponding author: J J B de Groot (jjbdegroot@gmail.com) Background. Over the past three decades much has changed in the treatment and outcomes of patients suffering concurrently from both multiple myeloma (MM) and HIV. While the prevalence of MM appears to be higher in HIV-positive individuals than in those who are uninfected, early recognition of patients suffering from both diseases is difficult and little information is available on their demographics and clinical presentation. Objective. To compare the presenting features of HIV-positive patients diagnosed with MM with those of HIV-negative patients. Methods. A single-centre, retrospective cohort study included 16 HIV-positive and 73 HIV-negative patients diagnosed with MM, in order to compare variables related to the clinical presentation of both conditions. Results. HIV-positive patients presented with MM at a significantly younger age, and had fewer osteolytic lesions, less renal impairment and lower neutrophil counts. Disease stage, gender, pathological fractures, bone marrow plasmacytosis, plasmacytomas and lymphocyte counts were comparable, emphasising the difficulty of identifying these patients. The HIV-positive patients had relatively high CD4 counts and a low prevalence of abnormal Freelite kappa/lambda ratios. All HIV-positive patients presented with paraproteins of the immunoglobulin G (IgG) type, implying a possible relationship between MM and an IgG response to HIV antigens. Conclusions. On the basis of our findings and literature on the treatment of both diseases, we suggest that HIV be tested for routinely in younger MM patients, especially in areas with a high prevalence of HIV. The integration of our results into the sparse knowledge on the role of HIV infection-related MM provides possible new insights into the interaction between these diseases. S Afr Med J 2017;107(9):781-787. DOI:10.7196/SAMJ.2017.v107i9.12360

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12360

A third of patients treated at a tertiary-level surgical service could be treated at a secondary-level facility S van Straten,1 5th-year MB BCh student; C Stannard,1 5th-year MB BCh student; J Bulabula,1 5th-year MB BCh student; K Paul,1 5th-year MB BCh student; J Leong,1 5th-year MB BCh student; M J Klipin,2 FCS (SA) 1 2

School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: M J Klipin (michael.klipin@wits.ac.za) Background. South Africa (SA) has an overburdened public healthcare system. Some patients admitted to Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), SA, may not require tertiary care, but the numbers and details are uncertain. Clinical research in SA is limited by scarce skills and limited access to data. Objective. To determine the proportion of and length of stay for secondary-, tertiary- and quaternary-level patients discharged from the Department of Surgery at CMJAH over 1 year.

September 2017, Print edition

RESEARCH

Methods. This is a retrospective analysis of electronic discharge (ED) summaries from the Department of Surgery at CMJAH between 1 April 2015 and 1 April 2016. An SQL query of the database generated a .csv file of all discharges with the following fields: database reference number, length of stay and level of care. The details of each record were verified by MBBCh V students, using a defined level-ofcare template and the full discharge summary. The data were reviewed by a senior clinician. Results. There were 3 007 discharge summaries – 97 were not classifiable, two were test records and one was a duplicate. These 100 records were excluded. There were no primary-level records. Secondary-level patients represented 29% (854) of those discharged and 19% of total bed days. Tertiary- and quaternary-level patients together represented 71% of the total and 81% of bed days. The average length of stay was 4.31 days for secondary, 6.98 days for tertiary and 9.77 days for quaternary level-of-care allocation. Conclusion. Almost one-third (29%) of patients discharged from CMJAH’s Department of Surgery were deemed suitable for secondarylevel care. These patients had a shorter length of stay and comprised 19% of total bed days. Students and electronic databases represent an important research resource. S Afr Med J 2017;107(9):788-790. DOI:10.7196/SAMJ.2017.v107i9.12090

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12090

New-onset diabetes after transplant: Incidence, risk factors and outcome S C Alagbe,1 MBBS, MPH, FWACP, MPhil, Cert Nephrology (SA) Phys; A Voster,2 BSc Hons, MSc; R Ramesar,2 BSc Hons, MSc, PhD, Exec MBA; C R Swanepoel,1 MB ChB, MRCP, FRCP (Edin) 1 2

Division of Nephrology and Hypertension, Faculty of Health Sciences, University of Cape Town, South Africa Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: S C Alagbe (salagbe2001@yahoo.com) Background. The outcome of renal transplantation depends on achieving effective immunosuppression while minimising the consequences of such treatment. The occurrence of new-onset diabetes in the post-transplant period has been associated with several risk factors including some immunosuppressive medication. Better understanding of the clinical and genetic risk factors associated with new-onset diabetes after transplant (NODAT) could enable risk stratification of patients in the pre-transplant period, with the goal of applying measures that will reduce the incidence. Objectives. To ascertain the incidence of and clinical and genetic risk factors that predispose to NODAT, and to examine its effect on the outcome of renal transplantation. Methods. We performed a retrospective cohort review of all renal transplants at Groote Schuur Hospital, Cape Town, South Africa, between 2004 and 2008. Patients who were lost to follow-up or had pre-transplant diabetes or primary non-function were excluded. A subset of the cohort who gave informed consent was enlisted for genetic tests. Results. We identified 111 patients who met the inclusion criteria. The incidence of NODAT was 18.0% (n=20 patients). Risk factors for NODAT included age at transplant (p=0.03), body weight (p=0.04), treatment for acute cellular rejection (p=0.02) and polycystic kidney disease as the cause of renal failure (p=0.005). None of the genes investigated (TCF7L2 rs11196205, rs12255372 and rs7903146 and HNF1β rs1800575, rs121918671 and rs121918672) was found to be significantly associated with the risk of NODAT. The genotype frequencies for the single-nucleotide polymorphisms studied were closer (although not identical) to those reported for Caucasians than to those reported for the Yoruba (black) population in West Africa. Overall patient survival was 78% at five years, while graft survival was 72%. There was no significant difference in patient or graft survival between the group with NODAT and the group without. Conclusions. NODAT was common in renal transplant recipients. Some risk factors predate transplant and could be used to risk-stratify patients to determine appropriate risk-reduction strategies. The genetic determinants for NODAT in this population may differ from those reported elsewhere. NODAT had no impact on patient or graft survival in this cohort. S Afr Med J 2017;107(9):791-796. DOI:10.7196/SAMJ.2017.v107i9.12258

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12258

September 2017, Print edition

RESEARCH

Age-group differences in risk perceptions of non-communicable diseases among adults in Diepsloot township, Johannesburg, South Africa: A cross-sectional study based on the Health Belief Model Z Kaba,1 BPH; N Khamisa,1 PhD; N Tshuma,1,2 BSc, MBA 1 2

Department of Public Health, School of Health Sciences, Monash South Africa, Johannesburg, South Africa Community AIDS Response, Johannesburg, South Africa

Corresponding author: Z Kaba (kaba.zahra@gmail.com) Background. Non-communicable diseases (NCDs) in South Africa (SA) occur simultaneously with an ageing HIV-positive population, resulting in premature deaths in persons <70 years of age. Poor risk perception of NCDs results in poor adoption practices of NCD preventive measures. There is a gap in age-related research regarding risk perceptions of NCDs among the SA population. Objective. To investigate age-group differences in risk perceptions of NCDs based on the Health Belief Model. Methods. This cross-sectional design used secondary data obtained from Community AIDS Response (CARe), Johannesburg, SA. Data were collected by means of a cross-sectional survey in Extension 2 (Blocks I, J, K and L) of Diepsloot township, Johannesburg, SA. The Pearson Ď&#x2021;2 test of independence was used to examine the relationship between age groups and risk perceptions of NCDs. A p<0.05 value was considered statistically significant. Results. A total of 2 135 participants were included in the analysis, of whom 71.5% were young adults (18 - 35 years). The mean age of the study participants was 32.1 (standard deviation 9.87) years. Significant associations were found between age groups and risk perceptions of NCDs. More middle-aged adults than young adults and older-aged adults perceived family history (74.00% v. 72.74% v. 62.39%, p=0.045) and smoking (83.80% v. 77.20% v. 74.31%, p=0.004) as risk factors that would increase their risk of NCDs. A higher proportion of older-aged adults than young adults and middle-aged adults perceived effects on life and family (89.91% v. 77.39% v. 75.40%, p=0.004) as risks of NCD morbidities. More middle-aged adults than young adults and older-aged adults perceived the usefulness of not smoking (84.60% v. 81.06% v. 74.31%, p=0.028) as an effective NCD preventive measure. More young adults than middle-aged and older-aged adults considered health check-ups (59.31% v. 58.00% v. 41.28%, p=0.001) as a time-consuming process to prevent risks of NCDs. Conclusion. Young adults had poorer risk perceptions of NCDs than middle-aged and older-aged adults in Diepsloot township, resulting in poor practice of NCD preventive measures among young adults in the area. This may be due to the misunderstanding of the concept of invulnerability, possibly resulting from the limited access and exposure to NCD-related information among young adults compared with middle-aged and older-aged groups. This highlights the need to expand public health education programmes to increase outreach to the young adult population and increase accessibility to information relating to NCD risks, and encourage adoption of NCD preventive measures. S Afr Med J 2017;107(9):797-804. DOI:10.7196/SAMJ.2017.v107i9.12168

Full article available online at https://doi.org/10.7196/SAMJ.2017.v107i9.12168

September 2017, Print edition

CAREERS & CLASSIFIEDS Ladine Van Heerden Tel: 012 481 2121 | E-mail: ladinev@hmpg.co.za Makhadzi Mulaudzi Tel: 012 481 2156 | E-mail: makhadzim@hmpg.co.za We accept credit card payments - Visa or MasterCard.

NEW PSYCHIATRY TEXTBOOK PSYCHIATRY TEXT by Prof. Gangat Recommended for general practitioners, medical officers and medical students (covers psychiatry syllabus). Psychiatric topics explained. Precise treatment guidelines

CALL LADINE OR MAKHADZI FOR ALL YOUR ADVERTISING NEEDS!

ZAR390.00 at all Van Schaik bookshops

SAMF

African Medicines esearched and written ical f the Division of Clin of gy of the University h in collaboration wit care professionals.

SAMF

LADINE, TEL: +27 (12) 481 2121 EMAIL: ladinev@hmpg.co.za

Go to www.samf12.org to download the order form orSocontact uth African

n by the South Africa lary sociation, the formu sts, at doctors, pharmaci cerned tists and others con tive safe and cost-effec ribing of medicines.

Medicines Formulary Tel: 012 481 2069 / Email: dianes@hmpg.co.za Diane Smith

South African ry Medicines Formula

KNOWLEDGE • KNOWLEDGE

Tax invoice to be posted on dispatch of order

Association, South African Medical ing Group, lish lth and Medical Pub Pretoria 0040 ge, Rid 74789, Lynnwood X-X

ISBN 978-1-XXXXXX-X

You can reach over 15 500 Doctors by advertising with us.

OR MAKHADZI, TEL: +27 (12) 481 2156 EMAIL: makhadzim@hmpg.co.za

n EdofitCapio 12of th e Town’s y rsit ive Un the

12th Edition

Postgraduate Programmes in Applied Ethics at Stellenbosch University in 2018 and 2019 the A joint initiative Pharamcology and Division of Clinical ing Group, lish Pub al dic Me Health and Association. th African Medical publishers for the Sou

ESSENTIA L MEDICA L REFERE or every h NCE ealthcare p rofessiona cket-sized design ena l! bles you to nd fo fit it • Postgraduate Diploma in Applied Ethics (NQF 8), leading to

• MPhil in Applied Ethics (Biomedical Ethics, Business Ethics or Environmental Ethics) These programmes, which are offered by the Philosophy Department and the Centre for Applied Ethics (CAE), aim to engage in the challenges of a developing nation by equipping professionals in the medical, business, government, NGO, environmental, development and educational sectors with the knowledge and skills needed to address moral issues in their fields of expertise.

Two one-year programmes are offered. The first is a Postgraduate Diploma (PGD) in Applied Ethics (offered in 2018), followed by an MPhil (Applied Ethics, with specialisations in Biomedical-, Business- or Environmental Ethics), (offered in 2019). The PGD normally grants access to the MPhil (Applied Ethics), but students with other suitable qualifications will also be considered for the MPhil (Applied Ethics), which will be offered in 2019. The MPhil (Applied Ethics) will be more extensively advertised during the course of 2018. Further information regarding these two programmes will also shortly be available on the Centre for Applied Ethic’s website. http://sun025.sun.ac.za/portal/page/portal/Arts/Departments/ comfortab referencphilosophy/cae/programmes. ly into e

r ready . South Afr your hospit Town’s Div anthe al bag or co MePGD contentic for ineApplied Ethics: dicin ision of CCourse at p cket, Ethics; Contemporary Trends in Moral Philosophy; The s FoThinking r li m n u ic la a Introduction to Philosophy and Critical Skills; Introduction so it r l y P (SAMF), a to Ethics andoApplied ha macolo outh Afric jo gyinaApplied an MedicaMethodology of rCase in Studies Ethics t n in d it th ia e tive of the Health and l Associati ng full dru on, protuition edicacombined for 2 two-week M sessions with structured self-study. vides(ineaEnglish) l P g profiles,Structure: On-campus u b li s s y access to hing Grou clinical no Any Bachelor’s degree p, the latest, F is your e Requirements: (or equivalent) tes and spe scientificall ssential refe cial prescr y a ccurate ibe ’s poin rencedate Closing for to th ts. The tho e applications: rational, co30 November r2017 r o u s g th e ly ffecform, For further information and an application updated tivecontact: and safe us e f medic Private Bag Ms J Engelbrecht, Department of Philosophy, University ofoStellenbosch, X1, Matieland 7602. ines. 131522

Tel. 021 808 2418. Fax 021 808 3556. E-mail: jengelb@sun.ac.za

www.ayandambanga.co.za

Drs van Rensburg & Partners acquire the first Toshiba Aquilion ONE Vision (new-generation) in Johannesburg Life Flora Clinic’s radiology department, operated by Drs van Rensburg & Partners, now leads the way in CT imaging in Gauteng, giving patients the most advanced and safest cardiac, neuro- and routine imaging examinations yet seen in this region. This follows the installation and commissioning of the first new-generation Toshiba Aquilion ONE Vision CT scanner in South Africa. Conveniently situated adjacent to the N1 Western bypass, Flora Clinic is within close reach of most north-western Johannesburg suburbs. This X-ray department is the flagship of the Van Rensburg practice. Supplied and installed by Tecmed Africa, this CT scanner, manufactured in Japan, boasts the lowest radiation dose levels of any CT scanner on the world market. The new CT system can produce 640 image slices with 0.5 mm thickness in almost a third of a second, making it the leading and fastest volume CT in the field of clinical imaging. Paediatric imaging now no longer requires that patients be sedated, restrained or have their pulse rates regulated by medication, because this CT system is so fast – it captures the anatomical images almost instantaneously. This also holds true for adult imaging of the heart. In less than half a second, this CT system will produce artefact-free imaging of all regions of the patient without the need to control pulse rates or any other factor that opposition CT systems struggle with to generate perfect and accurate images. All of this with minimal radiation dose levels. Stroke detection time and region identification can now be reduced from the standard of ‘many hours’ to just a few minutes. Full visualisation of blood flow, organ functions and joint movements can be observed, not only in 3D format but on this Aquilion ONE Vision system also in 4D. This means that the specialist can now look at three-dimensional images of the patient with movement (4D movies of the patient’s anatomy). This CT scanner is both a cardiologist and orthopaedic specialist’s dream machine. Flora Clinic’s specialists have long been major supporters of cardiac CT imaging and now have the best system in the world available to further aid them in providing patients with the perfect clinical path to treatment and recovery in the least invasive way. True healthcare professionals strive to provide patients with the least traumatic and safest forms of examination, and the investment by Drs van Rensburg & Partners underlines their commitment to this vision. Along with the cardiologists and other referring specialists in the area, unique, ultra-low-dose, accurate and repeatable CT imaging is now possible for all patients visiting this facility. The X-ray department, located on the 2nd floor of Life Flora Clinic, provides service during normal operating hours, from 08h00 to 18h00 daily. Because of 24-hour trauma requirements, this department is available for all emergency cases. The professional and friendly reception staff will assist you with the making of appointments. Dedicated and highly trained radiographers are in attendance for all investigations required.

Other services that the department provides with excellence are: • general and emergency radiographs • MRI • CT • ultrasound • nuclear medicine • angiography • fluoroscopy. The women’s health section provides personal and private attention and services include: • bone densitometry • digital mammography • specialised ultrasound. Drs van Rensburg & Partners is an organisation striving to provide patient service excellence by investing in world-leading technology, highly trained specialists and professional staff.

Their contact details are as follows:

Drs van Rensburg & Partners SA Inc. Life Flora Clinic (2nd floor) William Nicol Drive Floracliffe, Florida Gauteng Tel: (011) 475-1364

CPD

SEPTEMBER 2017

The CPD programme for SAMJ is administered by Medical Practice Consulting. CPD questionnaires must be completed online at www.mpconsulting.co.za.

True (A) or false (B): SAMJ Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test 1. The only plants or plant-related compounds on the official list of the World Anti-Doping Agency are cannabis, cocaine and ephedra, and they are listed as stimulants. Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria 2. Duodenal ulcer is more common than gastric ulcer. 3. Duodenal ulcer and gastric ulcer can easily be distinguished on clinical presentation alone. Central-line-associated bloodstream infections in a resourcelimited South African (SA) neonatal intensive care unit 4. Meta-analysis of healthcare-associated infection in low- and middle-income countries reported infection rates double those of developed countries, with these rates tripling in intensive care units. 5. Hospitalised neonates are at particular risk of healthcareassociated infection because of prematurity, poor skin integrity and prolonged hospitalisation. Residual allergenicity of amino acid-based and extensively hydrolysed cow’s milk formulas 6. Modified cow’s milk formulas are the most common breastmilk replacement formula, but are not always tolerated by infants with lactose intolerance or cow’s milk protein allergy. 7. Cow’s milk formulas are categorised according to the degree of hydrolysis into intact milk protein formulas, partially hydrolysed formulas or extensively hydrolysed formulas (EHFs). A review of antenatal corticosteroid (ANS) use in premature neonates in a middle-income country 8. Preterm birth is the most common cause of neonatal mortality, accounting for 28% of neonatal deaths. 9. A Cochrane review of 21 articles evaluating the effect of ANSs on preterm neonates showed that ANSs reduced the risk of respira-

tory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis and early-onset sepsis, reduced mortality and the need for respiratory support, and resulted in a trend towards reduced need for surfactant therapy. Age-group differences in risk perceptions of non-communicable diseases among adults in Diepsloot township, Johannesburg, SA: A cross-sectional study based on the Health Belief Model 10. According to the World Health Organization, non-communicable diseases resulted in 38 million deaths globally in 2010 - 2012, with low- and middle-income countries accounting for 28 million deaths. CME Recent important strategies in the management of chronic kidney disease 11. Chronic renal failure was the fifth most common cause of death in SA in 2006. 12. Fewer than 10% of the calculated potential sufferers from endstage renal failure in SA are able to receive renal replacement therapy. 13. Patients with chronic kidney disease at stage 4 or 5 or those on dialysis commonly exhibit widely fluctuating glucose levels. 14. Autosomal-dominant polycystic kidney disease can manifest in utero as well as in childhood. 15. Even small changes in blood acidity can cause harm in patients with only mild renal dysfunction. 16. Elevated uric acid may have a role in initiating hypertension, nephrosclerosis and insulin resistance. 17. Exercise plays no role in patients with chronic kidney disease who are not on dialysis. 18. Gut bacterial byproducts have been linked to chronic kidney disease progression and associated cardiovascular disease. 19. One to two small saltspoons of baking powder three times a day with meals are recommended for acidosis in chronic kidney disease. 20. Reducing consumption of red meat and pork may significantly slow renal function decline.

Readers please note: Articles may appear in summary/abstract form in the print edition of the Journal, with the full article available online at 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, in print or online. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB015/047/01/2017

September 2017, Print edition

Transpharm is a complete Healthcare provider offering services to: 3 Pharmacies 3 Hospitals 3 Doctors 3 Veterinarians 3 Dentists 3 Homeopaths 3 Allied Healthcare Professionals DONâ&#x20AC;&#x2122;T HAVE AN ACCOUNT WITH TRANSPHARM? Open a COD or 30 day account now & start placing orders today. Visit our website or contact our call centre for more information.

GAUTENG:

Tel: 012 377 9000 Email: clientservice@transpharm.co.za Email: orders@transpharm.co.za

WESTERN CAPE:

Tel: 021 929 2120 Email: infowc@transpharm.co.za

www.transpharm.co.za

JAGUAR XF

DYNAMIC, EVEN WHEN STILL.

One glimpse of the Jaguar XF and there’s no mistaking it for anything but a performance car. With its taut, athletic exterior made more pronounced by its beautiful curves and F-TYPE inspired design cues, the XF truly stands apart. Once you step inside, you’ll experience the contemporary style, exquisite craftsmanship and exceptional comfort that make XF so seductive. Distinctive lines. Dramatic beauty. No wonder XF turns heads, even when it’s stationary.

LOWER EMISSIONS From 114g/km CO 2 HIGHER FUEL ECONOMY Up to 4.3l/100km LOWER TOTAL COST OF OWNERSHIP 2 years or 34,000km

Contact your nearest Fleet & Business centre to arrange a test drive: Jaguar Centurion: Jaguar Bedfordview: Jaguar Umhlanga: Jaguar N1 City:

(012) 678 0044 (011) 621 6300 (013) 571 2620 (021) 595 7100

jaguar.co.za/fleet-and-business

Jaguar Sandton: Jaguar The Glen: Jaguar Constantiaberg:

(011) 548 0500 (011) 682 5400 (021) 710 0900