SAMJ Vol 108, No 4 (2018) by HMPG

APRIL 2018

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CME Lipidology

IN PRACTICE

Management of late-onset efavirenz neurotoxicity Aetiology of malignant pleural effusion RESEARCH Blood and virus detection on barber clippers Life-threatening hereditary angio-oedema in South Africa Ideal Clinic implementation and patient waiting time

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References 1. Hookey LC, Vanner SJ. Pico-salax plus two-day bisacodyl is superior to pico-salax alone or oral sodium phosphate for colon cleansing before colonoscopy. Am J Gastroenterol 2009;104:703-709. 2. Worthington J, Thyssen M, Chapman G, et al. A randomised controlled trial of a new 2 litre polyethylene glycol solution versus sodium picosulphate + magnesium citrate solution for bowel cleansing prior to colonoscopy. Curr Med Res Opin 2008; 24:(2)481-488. 3. Regev A, Fraser G, Delpre G, et al. Comparison of two bowel preparations for colonoscopy: sodium picosulphate with magnesium citrate versus sulphate-free polyethylene glycol lavage solution. Am J Gastroenterol 1998;93:(9)1478-1482. 4. Parente F, Marino B, Crosta C. Bowel preparation before colonoscopy in the era of mass screening for colo-rectal cancer: A practical approach. Dig Liver Dis 2009;41:87-95.

S3 PICOLAXÂŽ Powder for oral solution. Each sachet contains the following active ingredients: Sodium picosulphate 10,0 mg, Magnesium oxide, light 3,5 g and Citric acid, anhydrous 12,0 g. Reg. No A39/11.5/0058. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: FERRING (Pty) Ltd. Route 21 Corporate Park, 6 Regency Drive, Irene Ext 30. Pretoria, South Africa. Tel: +27 12 345 6358 Fax: +27 12 345 1156. www.ferring.co.za. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 2017/078

APRIL 2018 PRINT EDITION

GUEST EDITORIAL 4

Tuberculin conversion and tuberculosis disease in infants and young children from the Drakenstein Child Health Study: A call to action L Martinez, H J Zar

EDITOR’S CHOICE CORRESPONDENCE

Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki P Zilla, J Brink, T Pennel

Considerations regarding point-of-care testing V Gounden

Pan drug-resistant Serratia marcescens: An emerging threat K Moodley, A K C Peer, C N Govind

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, 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 HMPG

MANAGING EDITORS Claudia Naidu Naadia van der Bergh TECHNICAL EDITORS Emma Buchanan Kirsten Morreira Paula van der Bijl

30 days in medicine B Farham OBITUARY Prof. Alpheus Mabose Segone M Sathekge, S Mutambirwa

PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Clinton Griffin

EDITORIAL 15

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

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

IZINDABA 12

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

Life-threatening hereditary angio-oedema: Challenges of care in South Africa P Potter, J Peter

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za

CONTINUING MEDICAL EDUCATION

SALES MANAGER (CAPE TOWN) Azad Yusuf

GUEST EDITORIAL Dyslipidaemia in South Africa N Ntusi

ARTICLES Elevated triglycerides: A matter of the heart and pancreas D J Blom

JOURNAL ADVERTISING Reneé Hinze Ladine van Heerden Makhadzi Mulaudzi Charmalin Comalie ONLINE SUPPORT Gertrude Fani

Novel approaches to lipid-lowering therapy D Brozin, F J Raal

FINANCE Tshepiso Mokoena

Laboratory investigations in lipidology J A Rusch, C L Hudson, A D Marais

HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Mrs H Kikaya, Dr M Mbokota, Dr G Wolvaardt

IN PRACTICE 32

CLINICAL ALERT A proposed management algorithm for late-onset efavirenz neurotoxicity H M Cross, S Chetty, M T Asukile, H S Hussey, E B Lee Pan, L M Tucker

CLINICAL UPDATE The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa C F N Koegelenberg, S M Bennji, E Boer, P T Schubert, J A Shaw, B W Allwood, E M Irusen

RESEARCH 39

Blood and virus detection on barber clippers Z Spengane, S Korsman, K Mkentane, L M Davids, W Zemanay, M Africa, S Mbhele, M Nicol, F Gumedze, D Ngwanya, N P Khumalo

Hereditary angio-oedema in the Western Cape Province, South Africa* K M Coovadia, M-Y Chothia, S G Baker, J G Peter, P C Potter

April 2018, Print edition

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

Feasibility and acceptability of conducting HIV vaccine trials in adolescents in South Africa: Going beyond willingness to participate towards implementation* M Wallace, K Middelkoop, P Smith, C Pike, T Bennie, J Chandia, G Churchyard, G Gray, M H Latka, M Mathebula, M Nchabeleng, S Roux, C Slack, A Strode, L-G Bekker

Understanding the types of fraud in claims to South African medical schemes* T G Legotlo, A Mutezo

Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa* J Gasson, M Blockman, B Willems

SAMJ SUBSCRIPTION RATES Local subscriptions ZAR1 632.00 p.a. Foreign subscriptions ZAR3 744.00 p.a. Single copies ZAR136.00 local, ZAR312.00 foreign

Impact of ‘Ideal Clinic’ implementation on patient waiting time in primary healthcare clinics in KwaZulu-Natal Province, South Africa: A before-and-after evaluation* B A Egbujie, A Grimwood, E C Mothibi-Wabafor, G Fatti, A M E T Tshabalala, S Allie, G Vilakazi, O Oyebanji

Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit.

Near-real-time tracking of gaps in prevention of mother-to-child transmission of HIV in three districts of KwaZulu-Natal Province, South Africa* F Moyo, A Haeri Mazanderani, S Bhardwaj, O B Mhlongo, T Kufa, K Ng’oma, B A Smith, G G Sherman

Hypertension as the trigger for posterior reversible encephalopathy syndrome in paediatric renal patients: An important diagnosis that should not be missed* J K Strong, K L Petersen, U Kala

Evaluating the effect of ward-based outreach teams on primary healthcare performance in North West Province, South Africa: A plausibility design using routine data* T Assegaai, G Reagon, H Schneider

An investigation of barriers to the use of the World Health Organization Surgical Safety Checklist in theatres* S Verwey, P D Gopalan

The usefulness of routine histological examination of appendicectomy specimens in a South African tertiary centre* O O Jolayemi, N B Moodley, V Y Kong, B Tlou, J L Bruce, D L Clarke

Potential latitudinal variation in orodigestive tract cancers in Africa* H A Adeola, A O Adefuye, S A Jimoh

Seasonal variations in Schistosoma haematobium egg excretion in school-age girls in rural KwaZulu-Natal Province, South Africa* E E Christensen, M Taylor, S G Zulu, K Lillebo, S G Gundersen, S Holmen, E Kleppa, B J Vennervald, P D Ndhlovu, E F Kjetland *Abstract only, full article available online.

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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 Printed by TANDYM PRINT

CAREERS AND CLASSIFIEDS CPD QUESTIONS

APRIL 2018

Background photo: A woman with multidrug-resistant tuberculosis awaits her daily injection from a mobile team in the rural KwaZulu-Natal Midlands | Damien Schumann

PRINT EDITION

CME Lipidology

IN PRACTICE

Management of late-onset efavirenz neurotoxicity Aetiology of malignant pleural effusion

Box photos: Eruptive xanthomata in hypertriglyceridaemia | Blom; Close-shave ‘chiskop’ haircut | Zandile Spengane; Patients queue at a primary healthcare clinic | Bonaventure Egbujie

April 2018, Print edition

RESEARCH Blood and virus detection on barber clippers Life-threatening hereditary angio-oedema in South Africa Ideal Clinic implementation and patient waiting time

Plasmoquine,

for the treatment of rheumatoid arthritis Rheumatoid arthritis is a chronic condition mainly caused by inflammation in the joints of the hand, wrist, elbows, shoulders, hips, knees and feet. These conditions are usually on both sides of the body.

Medchem Pharmaceuticals CC Reg. No. Z/20.2.6/127

Email: medchem3@gmail.com

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

GUEST EDITORIAL

Tuberculin conversion and tuberculosis disease in infants and young children from the Drakenstein Child Health Study: A call to action Although tuberculosis (TB) is widely acknowledged as a major driver of global morbidity and mortality in adults, the disease’s impact on children has been underappreciated. Global estimates of mortality among children aged <5 years, derived largely from vital registration and verbal autopsy records, have excluded paediatric TB as a contributing cause.[1,2] Recent modelling studies, however, have estimated that TB is a leading cause of childhood morbidity and mortality, causing ~1 million new cases and 250 000 deaths per year. [2-5] Approximately 80% of these deaths occur before 5 years of age and many are never diagnosed.[3] Our lack of knowledge regarding paediatric TB is driven by several factors that make diagnosis of children with TB challenging in lowand middle-income countries (LMICs), where most paediatric TB patients reside. Nonspecific symptoms and poor sensitivity of tests or lack of training or capacity for microbiological testing, such as sputum culture and GeneXpert MTB/RIF, hamper diagnosis.[6,7] Most diagnostic procedures, such as chest radiographs and tuberculin skin testing, have reduced value in HIV-infected paediatric populations. [7] In addition, surveillance systems in resource-constrained settings are not equipped to detect paediatric TB owing to lack of laboratory infrastructure or tuberculin shortages. Consequently, much paediatric TB is undiagnosed in LMIC settings, and programmatic estimates (from case notification, vital registration or verbal autopsy) of TB disease in young children are likely to be substantial underestimates of the true community burden. Improving our understanding of the epidemiology of TB in infancy and young childhood in high-burden settings is critical to inform national and global guidelines and devise interventions that target paediatric populations at high risk for TB and subsequent mortality. To fill this knowledge gap, birth cohorts are urgently needed. The Drakenstein Child Health Study is a South African (SA) birth cohort study of 1 137 mother-child pairs investigating the early-life determinants of child health and epidemiology of several important determinants of health, including childhood pneumonia, wheezing, lung function and TB.[8] The study is being conducted in a periurban area of Paarl, outside Cape Town. Pregnant women at 22 - 28 weeks’ gestation were enrolled at two healthcare clinics and followed until childbirth; their offspring have then been followed through childhood. Tuberculin skin tests were administered at 6, 12, 24, 36, 48 and 60 months of age, and also when children presented with a lower respiratory tract infection or pneumonia. Continuous TB and pneumonia surveillance is conducted by trained nurses and clinicians.[9] There is a strong local primary healthcare system in the area where all participants access healthcare. Almost a quarter of pregnant women in the cohort were living with HIV; however, owing to widespread antiretroviral therapy preventing vertical transmission of HIV, only two children (<1%) tested HIV-positive. All children included in the cohort received BCG vaccination at birth. Our objective with this study was to evaluate the incidence and burden of TB infection and disease in the first 5 years of life in this birth cohort. We also wanted to identify prenatal and early childhood risk factors for TB-related outcomes.[10] We defined tuberculin conversion as an induration reaction of ≥ 10 mm, as recommended by national and global guidelines. [11,12]

This induration cut-off is considered conservative and is used to avoid false-positive responses resulting from non-tuberculous mycobacterial infection or BCG vaccination. Boosting of tuberculin results is possible when recurrent skin tests are administered, as was done in our study. To prevent misclassification of boosted reactions, we did not administer additional skin tests to children with a positive test or a reactive skin test between 1 and 9 mm. These children were subsequently censored in further analyses of tuberculin conversion. Children who tested positive were subsequently referred to local TB clinics for preventive therapy; however, study investigators could not enforce prescription and completion. We used three distinct definitions of TB disease: (i) all diagnosed TB disease; (ii) radiographically and microbiologically confirmed TB; and (iii) microbiologically confirmed TB only. We found high rates of tuberculin conversion (11.8 conversions per 100 child-years) and all diagnosed TB disease (2.9 paediatric cases per 100 child-years). These rates equate to an ~11.8% annual risk of infection and 2 900 paediatric cases per 100 000 children, among the highest reported estimates of paediatric TB globally. When we restricted our definition of TB disease to only microbiologically confirmed TB, which has low sensitivity in young children, we found a high rate of 0.7 paediatric cases per 100 child-years (700 paediatric cases per 100 000 children). We also found novel risk factors for TB disease such as lower respiratory tract infection (adjusted hazard ratio (AHR) 2.3, 95% confidence interval (CI) 1.4 - 3.6; p<0.0001) or maternal smoking during pregnancy (AHR 1.7, 95% CI 1.0 - 2.8; p=0.04). Children who received isoniazid (INH) preventive therapy were highly protected against developing disease (AHR 0.2, 95% CI 0.1 - 0.6; p<0.0001), but use of INH prophylaxis among tuberculin converters was disappointingly low, with only 22% completion. Results from the Drakenstein cohort elucidate several characteristics regarding the epidemiology of paediatric TB in SA and other areas of sub-Saharan Africa. First, the high rates of TB infection and disease we observed indicate that delivery of multipronged interventions that prevent disease acquisition and increase TB case detection in young children are urgently needed. Although increased awareness has been given to paediatric TB by national and global guidelines in the past decade,[11-13] strengthening of childhood TB services to under-resourced communities has not followed suit.[14] Second, young children are continuously exposed to TB and probably reinfected several times throughout their first years of life in these settings,[10,15] indicating that interventions must be lasting, sustainable and costeffective. Third, our finding that a relationship exists between lower respiratory tract infection and TB disease confirms prior studies showing high rates of confirmed pulmonary TB in children with severe pneumonia.[16-18] Our study confirms that the association is present, and that these two diseases are strongly interconnected in young children at the community level. The alarming childhood TB burden we see in the Drakenstein cohort, despite a strong primary healthcare system including wide healthcare access, comprehensive antiretroviral therapy and universal BCG vaccination, suggests that paediatric TB control must become a major public health priority in SA and other sub-Saharan African countries. Children rarely present to TB clinics, so integration

April 2018, Print edition

The S-26 brand transitions to

Dear Healthcare Professional

This notice serves to inform you of the S-26 transition. As part of Aspenâ&#x20AC;&#x2122;s S-26 transaction the company is required to rebrand S-26. As a company we have chosen to rebrand S-26 to alula. The transition will take place over a number of years and will involve a number of phases. We are therefore pleased to announce that Aspen Nutritionals will launch the first phase of the S-26 transition program in early 2018. We are excited about the NEW packaging design and would like to assure our trusted partners that there will be no change in formulation. Please be assured that the quality of the S-26 range will not be affected in any way by this design change. Please see pack change below.

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GUEST EDITORIAL

of paediatric TB services with control of other diseases, such as maternal and child health facilities or sick visits for lower respiratory tract infections, is an opportunity to improve detection of paediatric TB.[3] This approach will need to be partnered with a push to improve policy-practice gaps, laboratory infrastructure, use of and adherence to INH prophylaxis, and clinical training to increase paediatric case detection and reduce paediatric mortality in Africa. Such a comprehensive package is essential to reduce the childhood TB burden in Africa and other LMICs. There is great urgency to implement interventions that combine detection, treatment and prevention of TB while maintaining resource efficiency. Acknowledgements. We thank the study staff and the clinical and administrative staff of the Western Cape Government Health Department at Paarl Hospital and at the clinics for support of the study. We also thank members of the study International Advisory Board for their advice, our collaborators, and the families and children who participated in the study. Funding. This study was funded by the Bill & Melinda Gates Foundation (grant number OPP 1017641), the South African Medical Research Council, and the National Research Foundation of SA.

Leonardo Martinez Division of Infectious Diseases and Geographic Medicine, School of Medicine, Stanford University, Calif., USA

Heather J Zar Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and MRC Unit on Child and Adolescent Health, Faculty of Health Sciences, University of Cape Town, South Africa. heather.zar@uct.ac.za

1. Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: An updated systematic analysis for 2010 with time trends since 2000. Lancet 2012;379(9832):2151-2161. https://doi.org/10.1016/S0140-6736(12)60560-1 2. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under-5 mortality in 2000 - 15: An updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2017;388(10063):3027-3035. https://doi.org/10.1016/S0140-6736(16)31593-8 3. Dodd P, Yuen C, Sismanidis C, Seddon J, Jenkins H. The global burden of tuberculosis mortality in children: A mathematical modelling study. Lancet Glob Health 2017;5(9):e898-e906. https://doi. org/10.1016/S2214-109X(17)30289-9 4. Dodd PJ, Gardiner E, Coghlan R, Seddon JA. Burden of childhood tuberculosis in 22 high-burden countries: A mathematical modelling study. Lancet Glob Health 2014;2(8):e453-e459. https://doi. org/10.1016/S2214-109X(14)70245-1 5. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children: Systematic review and global estimates. Lancet 2014;383(9928):1572-1579. https://doi. org/10.1016/S0140-6736(14)60195-1 6. Schumacher SG, van Smeden M, Dendukuri N, et al. Diagnostic test accuracy in childhood pulmonary tuberculosis: A Bayesian latent class analysis. Am J Epidemiol 2016;184(9):690-700. https://doi.org/10.1093/aje/kww094 7. Nicol MP, Zar HJ. New specimens and laboratory diagnostics for childhood pulmonary TB: Progress and prospects. Paediatr Respir Rev 2011;12(1):16-21. https://doi.org/10.1016/j.prrv.2010.09.008 8. Zar H, Barnett W, Myer L, Stein D, Nicol M. Investigating the early-life determinants of illness in Africa: The Drakenstein Child Health Study. Thorax 2014;79(6):592-594. https://doi.org/10.1136/ thoraxjnl-2014-206242 9. Le Roux DM, Myer L, Nicol MP, Zar HJ. Incidence and severity of childhood pneumonia in the first year of life in a South African birth cohort: The Drakenstein Child Health Study. Lancet Glob Health 2015;3(2):e95-e103. https://doi.org/10.1016/S2214-109X(14)70360-2 10. Martinez L, le Roux DM, Barnett W, Stadler A, Nicol MP, Zar HJ. Tuberculin skin test conversion and primary progressive tuberculosis disease in the first 5 years of life: A birth cohort study from Cape Town, South Africa. Lancet Child Adolesc Health 2018;2(1):46-55. https://doi.org/10.1016/ S2352-4642(17)30149-9 11. National Department of Health, South Africa. Guidelines for the Management of Tuberculosis in Children. Pretoria: NDoH, 2013. 12. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva: WHO, 2014. 13. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva: WHO, 2006. 14. Hill PC, Rutherford ME, Audas R, van Crevel R, Graham SM. Closing the policy-practice gap in the management of child contacts of tuberculosis cases in developing countries. PLoS Med 2011;8(10):e1001105. https://doi.org/10.1371/journal.pmed.1001105 15. Martinez L, Shen Y, Handel A, et al. Effectiveness of WHO’s pragmatic screening algorithm for child contacts of tuberculosis cases in resource-constrained settings: A prospective cohort study in Uganda. Lancet Respir Med 2017 (epub 19 December 2018). https://doi.org/10.1016/S22132600(17)30497-6 16. Moore DP, Klugman KP, Madhi SA. Role of Streptococcus pneumoniae in hospitalization for acute community-acquired pneumonia associated with culture-confirmed Mycobacterium tuberculosis in children: A pneumococcal conjugate vaccine probe study. Pediatr Infect Dis J 2010;29(12):10991104. https://doi.org/10.1097/INF.0b013e3181eaefff 17. Zar H, Hanslo D, Tannenbaum E, et al. Aetiology and outcome of pneumonia in human immunodeficiency virus-infected children hospitalized in South Africa. Acta Paediatr 2001;90(2):119-125. https://doi.org/10.1111/j.1651-2227.2001.tb00270.x 18. Oliwa JN, Karumbi JM, Marais BJ, Madhi SA, Graham SM. Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: A systematic review. Lancet Respir Med 2015;3(3):235-243. https://doi.org/10.1016/S2213-2600(15)00028-4

S Afr Med J 2018;108(4):247-248. DOI:10.7196/SAMJ.2018.v108i4.13169

April 2018, Print edition

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EDITORâ&#x20AC;&#x2122;S CHOICE

CME: Lipidology

In this issue of CME, Blom[1] provides an excellent review of an approach to the patient with elevated triglycerides (TGs). Mild-to-moderate hypertriglyceridaemia (TG >1.7 - 10 mmol/L) is an independent cardiovascular risk factor, while severe hypertriglyceridaemia (TG >10.0 mmol/L) can cause acute pancreatitis. Hypertriglyceridaemia is mostly polygenic. Secondary factors, such as uncontrolled diabetes, hypothyroidism, alcohol, renal disease and medications, are important in precipitating or exacerbating hypertriglyceridaemia. Patients with hypertriglyceridaemia require cardiovascular risk assessment and are in the first instance treated with statins if their cardiovascular risk is elevated. Control of secondary factors and lifestyle modifications are important in managing residual hypertriglyceridaemia in statin- treated patients. Severe hypertriglyceridaemia is managed by removing or controlling secondary factors, following a very low-fat diet and prescribing a fibrate. Brozin and Raal[2] provide a state-of-the-art review of novel approaches to lipid-lowering therapy, focusing on new drugs and their mechanisms of action. Statins (with or without ezetimibe) and fibrates are the current first-line therapy in the management of dyslipidaemia. Novel agents include the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (which have shown a reduction in cardiovascular disease (CVD) morbidity), mipomersen, cholesterol ester transfer protein (CETP) inhibitors and bempedoic acid. Drugs such as pemfibrate, angiopoietin-like protein 3 (ANGPTL3) inhibitors, apolipoprotein C3 (apo C3) inhibitors and diacylglycerol acyltransferase-1 (DGAT 1) inhibitors have shown promising results in the management of hypertriglyceridaemia. Finally, Rusch et al.[3] provide an up-to-date, pragmatic and evidence-based approach to the laboratory investigations in lipidology. The conventional lipid profile, comprising fasting TG, total cholesterol, high-density lipoprotein cholesterol and lowdensity lipoprotein, suffices for screening persons at risk for atherosclerosis. Non-fasting samples are gaining in popularity. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell function, as well as genetic investigations, are relevant; important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. It is our hope that the articles in this issue of CME will improve the investigation and management of dyslipidaemia in South Africa, thereby reducing the risk of CVD in our population.

Blood and virus detection on barber clippers

Bleeding from the popular clean-shave chiskop haircut was recently reported as prevalent in SA, a country with 6.9 million HIV-infected people. Spengane et al.[4] investigated the prevalence of barber hair clipper contamination with blood and HIV and hepatitis B viruses. Fifty barbers from three townships in Cape Town, SA, were invited to participate. One clipper from each barber was collected immediately after it had been used for a haircut. The polymerase chain reaction (PCR) was used to identify the blood-specific RNA marker haemoglobin beta (HBB), hepatitis B virus (HBV) and HIV. The clean-shave haircut was the most common haircut requested by clients (78%). Of the clippers, 42% were positive for HBB, confirming detection of blood, none were positive for HIV, and 4 (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR.

This study confirms that there is significant contamination of barber hair clippers with blood and the blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of transmitting infection. Although HIV was not detected in this small study, the risk for transmission should be quantified. Further studies to investigate whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus infections, as well as viral co-infections, are warranted. Public education on individual clipper ownership (as is the case with a toothbrush) should be advocated for clean-shave and blade-fade haircuts.

Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa

Knowledge of antibiotic prescribing practice in primary care in SA is limited. As 80% of human antibiotic use is in primary care, this knowledge is important in view of the global problem of antibiotic resistance. Gasson et al.[5] assessed antibiotic prescribing in primary care facilities in the Cape Town Metro District, and compared it with current national guidelines. A retrospective medical record review was performed in April/ May 2016. Records of all patients seen over 2 days in each of eight representative primary care facilities in the district were reviewed. The treatment of any patient who raised a new complaint on either of those days was recorded. Prophylactic antibiotic courses, tuberculosis treatment and patients with a non-infection diagnosis were excluded. Treatment was compared with the Standard Treatment Guidelines and Essential Medicines List for South Africa, Primary Healthcare Level, 2014 edition. Of 654 records included, 68.7% indicated that an antibiotic had been prescribed. Overall guideline adherence was 45.1%. Adherence differed significantly between facilities and according to the physiological system being treated, whether the prescription was for an adult or paediatric patient, and the antibiotic prescribed. Healthcare professional type and patient gender had no significant effect on adherence. The main reasons for non-adherence were an undocumented diagnosis (30.5%), antibiotic not required (21.6%), incorrect dose (12.9%), incorrect drug (11.5%) and incorrect duration of therapy (9.5%). This study demonstrates poor adherence to guidelines. Irrational use of antibiotics is associated with increased antibiotic resistance. There is an urgent need to improve antibiotic prescribing practice in primary care in the Cape Town Metro District.

Aetiology of malignant pleural effusion in the Western Cape Province, South Africa

Malignant pleural effusion (MPE) represents a very common cause of pleural exudates and is one of the most challenging pleural disorders to manage. This could be attributed to the paucity of highquality experimental evidence, and inconsistent practice worldwide. SA currently has no data regarding the aetiology of MPE. Koegelenberg et al.[6] identified the most common malignancies causing MPE in a population served by a large tertiary hospital in SA, and specifically the relative contribution of mesothelioma. A secondary objective was to evaluate the efficacy of chemical pleurodesis in a subset of patients. They retrospectively included all known cases of MPE evaluated at their institution over a 3-year period with a tissue diagnosis of MPE. The most common causes of MPE in a total of 274 patients were lung cancer (n=174, 63.5%), breast cancer (n=32, 11.7%), unknown primary

April 2018, Print edition

*P 1 cu C e a P

EDITOR’S CHOICE

(n=22, 11.7%) and mesothelioma (n=27, 9.9%). Talc pleurodesis was performed in 81 of 194 patients (41.8%) referred to the authors’ division, and was radiologically successful in 22 of 25 (88.0%) followed up to 3 months. The main cause of MPE in this setting was lung cancer, followed by breast cancer, unknown primary and mesothelioma. Chemical pleurodesis was a viable palliative measure for MPE in this population. BF

1. Blom DJ. Elevated triglycerides: A matter of the heart and pancreas. S Afr Med J 2018;108(4):258-261. https://doi.org/10.7196/SAMJ.2018.v108i4.13235 2. Brozin D, Raal FJ. Novel approaches to lipid-lowering therapy. S Afr Med J 2018;108(4):262-265. https:// doi.org/10.7196/SAMJ.2018.v108i4.13234 3. Rusch JA, Hudson CL, Marais AD. Laboratory investigations in lipidology. S Afr Med J 2018;108(4):266270. https://doi.org/10.7196/SAMJ.2018.v108i4.13233 4. Spengane Z, Korsman S, Mkentane K, et al. Blood and virus detection on barber clippers in Cape Town, South Africa. S Afr Med 2018;108(4):278-282. https://doi.org/10.7196/SAMJ.2018.v108i4.12830 5. Gasson J, Blockman M, Willems B. Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa. S Afr Med J 2018;108(4):304-310. https:// doi.org/10.7196/SAMJ.2018.v108i4.12564 6. Koegelenberg CFN, Bennji SM, Boer E, et al. The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa. S Afr Med J 2018;108(4):275-277. https://doi.org/10.7196/ SAMJ.2018.v108i4.12936

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* Post-acute patients deined as >48 hours when patients no longer require urgent interventions and intensive monitoring 1. Venketasumbramanian N, et al. CHInese medicine NeuroAiD effi cacy on stroke recovery-Extension study (CHIMES-E) Cerebovascular diseases 2015 DOI: 10.1159/000382082. 2. Young SHY, Zhao Y, Koh A, Singh R, Chan BPL, Chang HM, Venketasubramanian N, Chen C on behalf of the CHIMES investigators. Cerebrovascular Diseases 2010; 30:1-6. 3. Gan R, Lambert C, Lianting J, Chan E, enketasubramanian N, Chen C, Chan BPL, Samama MM, Bousser MG. Danqi Piantan Jiaonang does not modify hemostasis, hema-tology, and biochemistry in normal subjects and stroke patients. Cerebrovascular Diseases 2008; 25: 450-456. 4. NeuroAidTM South Africa Package Insert,Approved 29 November 2012

April 2018, Print edition

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CORRESPONDENCE

Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki

To the Editor: The authors of the guest editorial ‘The world’s first human-to-human heart transplant at Groote Schuur Hospital: 50 years later’[1] wish to acknowledge the letter to the Editor by Mankahla et al.[2] addressing the omission of Mr Hamilton Naki from the invited commentary. This oversight was indeed a missed opportunity to once again honour Mr Naki’s contribution to laboratory research at the University of Cape Town in a local journal. It is with pride that we refer readers of SAMJ to our article published concurrently in the European Heart Journal,[3] which honours Mr Naki’s formidable surgical skills despite a lack of formal training and recognises his contribution in training a future generation of surgeons. Peter Zilla, Johan Brink, Tim Pennel Christiaan Barnard Division of Cardiothoracic Surgery, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa peter.zilla@uct.ac.za 1. Brink J, Pennel T, Seele K, Zilla P. The world’s first human-to-human heart transplant at Groote Schuur Hospital: 50 years later. S Afr Med J 2017;107(12):1035-1036. https://doi.org/10.7196/SAMJ.2017. v107i12.12960 2. Mankahla N, Dlamini S, Taunyane IC, Maqungo S, Cairncross L, Chiliza B. Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. S Afr Med J 2018;108(3):151. https://doi.org/10.7196/SAMJ.2018.v108i3.13114 3. Sliwa K, Zilla P. 50th anniversary of the first human heart transplant – how is it seen today? Eur Heart J 2017;38(46):3402-3404. https://doi.org/10.1093/eurheartj/ehx695

S Afr Med J 2018;108(4):249. DOI:10.7196/SAMJ.2018.v108i4.13242

Considerations regarding point-ofcare testing

To the Editor: I read with interest the article by Abbai et al.[1] regarding the evaluation of a point-of-care (POC) HbA1c analyser, which appeared in a recent issue of SAMJ. In the context of the current medical landscape in southern Africa, there is clearly a place for POC devices, but there are certain important caveats to their use – in particular with HbA1c – that end-users should be aware of and that were not touched on in the article. Firstly, importance of sample type: the Afinion AS100 analyser (Alere, South Africa (SA)) and most other POC devices would utilise finger-prick patient samples (capillary blood) for analysis in most clinical contexts. In the abovementioned article, the authors have not evaluated the diagnostic accuracy of the use of finger-prick samples compared with formal blood collection. Some studies have reported significant differences in composition of capillary v. venous blood. With regard to HbA1c, Schalk et al.[2] found capillary values of Hb to be significantly higher than the corresponding venous values. Incorrect capillary blood sampling can cause significantly inaccurate results. Secondly, importance of location: most POC devices are placed in non-laboratory environments that are not temperature controlled and that do not have sufficient access to refrigeration. Many of the currently available POC devices and reagents have been designed to operate in more temperate climates. Extremes of environment, particularly the high temperatures experienced in SA, may affect the functioning of devices and stability of reagents. In the artice by Gounden and George[3] that evaluated various POC devices in the SA context, a scoring system was developed to evaluate the devices in terms of features, such as ability to be used in extremes of temperature, as well as other important considerations, such as information technology connectivity (to enable transmission of results to electronic medical record/laboratory information systems), water requirements and costs. These need to be considered when choosing a POC device. Thirdly,

importance of interferences: Afinion HbA1c results are reported to be affected by the presence of fetal Hb (HbF).[4] Elevated HbF levels may be found in neonates, hereditary persistence of HbF, thalassaemias and late pregnancy. Fourthly, precision studies: precision performance forms the cornerstone for the assessment of clinical utility of a test or an instrument. Abbai et al.[1] have not presented data with regard to imprecision performance of the POC analyser for the tests evaluated. Shephard et al.[5] have proposed desirable imprecision goals for POC devices for HbA1c (coefficient of variation 3%) and lipid parameters. The American Diabetes Association also provide recommendations for HbA1c precision. Abbai et al.[1] only evaluated performance of Afinion HbA1c with regard to correct categorisation of patients at one medical decision point (HbA1c 6.5%). As one of the primary roles of POC testing (POCT) is the monitoring of diabetic patients receiving treatment in order to allow for a more prompt change in management, evaluation at other important medical decision limits, e.g. HbA1c 7%, would have been clinically relevant. It must be emphasised that POCT also requires implementation of a complete quality management system that includes analysis of internal and external quality assurance samples. V Gounden Department of Chemical Pathology, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban; Inkosi Albert Luthuli Central Hospital, Durban; and National Health Laboratory Service, Durban, South Africa verenagounden@yahoo.com 1. Abbai NS, Nyirenda M, Reddy T, Ramjee G. Good correlation between the Afinion AS100 analyser and the ABX Pentra 400 analyser for the measurement of glycosylated haemoglobin and lipid levels in older adults in Durban, South Africa. S Afr Med J 2018;108(1):50-55. https://doi.org/10.7196/SAMJ.2018. v108i1.12548 2. Schalk E, Heim MU, Koenigsmann M, Jentsch-Ullrich K. Use of capillary blood count parameters in adults. Vox Sang 2007;93:348-353. https://doi.org/10.1111/j.1423-0410.2007.00978.x 3. Gounden V, George J. Multipoint of care instrument evaluation for use in anti-retroviral clinics in South Africa. Clin Lab 2012;58(1-2):27-40. 4. National Glycohemoglobin Standardization Program. HbA1c assay interferences. http://www.ngsp. org/interf.asp (accessed 19 December 2017). 5. Shephard M, Shephard A, Watkinson L, et al. Design, implementation and results of the quality control program for the Australian government’s point of care testing in general practice trial. Ann Clin Biochem 2009;46(5):413-419. https://doi.org/10.1258/acb.2009.009045

S Afr Med J 2018;108(4):250. DOI:10.7196/SAMJ.2018.v108i4.13077

Pan drug-resistant Serratia marcescens: An emerging threat

To the Editor: The five most frequently reported organisms isolated from blood cultures worldwide are Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus species.[1,2] The emergence of carbapenem resistance has seriously compromised treatment options for organisms such as K. pneumoniae, E. coli and other Enterobacteriaceae such as Enterobacter species and Serratia marcescens. Colistin and tigecycline are last-resort therapeutic options for these carbapenem-resistant Enterobacteriaceae.[3] We have observed an increase in the number of carbapenem-resistant S. marcescens isolates in blood cultures in our laboratory in the KwaZuluNatal (KZN) region, South Africa, which is particularly worrisome, given that Serratia species are inherently resistant to colistin. During 2017, S. marcescens was the 6th most common isolate in blood cultures. Of the 572 Enterobacteriaceae isolated from blood cultures, S. marcescens was the 3rd most common after E. coli and K. pneumoniae, accounting for 11% (63/572) of isolates. Ten S. marcescens isolates were carbapenem resistant; 7 of these were also resistant to tigecycline, thus making them pan drug resistant. All the carbapenemresistant S. marcescens isolates carried the New Delhi metallo-betalactamase 1 (NDM-1) gene. Unlike other reports of S. marcescens

April 2018, Print edition

CORRESPONDENCE

bacteraemia, these isolates were from several different hospitals across KZN and were not linked to an outbreak.[4,5] The emergence of pan drug-resistant S. marcescens in blood cultures in this region creates a challenge for the management of patients admitted to hospitals and intensive care units. Implementation of antimicrobial stewardship and strict infection control practices is imperative to prevent further dissemination of this formidable pathogen. K Moodley, A K C Peer, C N Govind

1. Johnson AP. Surveillance of antibiotic resistance. Philos Trans R Soc Lond B Biol Sci 2015;370(1670):20140080. https://doi.org/10.1098/rstb.2014.0080 2. Laupland KB. Incidence of bloodstream infection: A review of population-based studies. Clin Microbiol Infect 2013;19(6):492-500. https://doi.org/10.1111/1469-0691.12144 3. Alhashem F, Tiren-Verbeet NL, Alp E, Doganayt M. Treatment of sepsis: What is the antibiotic choice in bacteremia due to carbapenem resistant Enterobacteriaceae? World J Clin Cases 2017;5(8):324-332. https://doi.org/10.12998/wjcc.v5.i8.324 4. Iosifidis E, Farmaki E, Nedelkopoulou N, et al. Outbreak of bloodstream infections because of Serratia marcescens in a pediatric department. Am J Infect Control 2011;40(1):11-15. https://doi.org/10.1016/j. ajic.2011.03.020 5. Pan A, Dolcetti L, Barosi C, et al. An outbreak of Serratia marcescens bloodstream infections associated with misuse of drug vials in a surgical ward. Infect Control Hosp Epidemiol 2006;27(1):79-82. https:// doi.org/10.1086/500250

Department of Microbiology, Lancet Laboratories, Durban; and Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa S Afr Med J 2018;108(4):251. DOI:10.7196/SAMJ.2018.v108i4.13159

krishnee.moodley@lancet.co.za

April 2018, Print edition

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

IZINDABA

30 days in medicine Opioids no better than other painkillers for osteoarthritis pain

A randomised, controlled 12-month trial involving 240 patients with chronic back pain or hip or knee osteoarthritis pain found that opioid drugs were no better than non-opioids at reducing pain that interfered with activities of daily living. The study, published in JAMA, also found that pain intensity was lower in the non-opioid group and drug-related adverse symptoms were more common in the opioid group. The conclusion is that treatment with opioids was not superior to treatment with non-opioid drugs, and the results do not support starting opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. Krebs EE, Gravely A, Nugent BA, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. JAMA 2018;319(9):872-882. https://doi.org/10.1001/jama.2018.0899

Once-off PSA screening does not reduce deaths from prostate cancer

Results from a trial involving >400 000 men who were invited to a single prostate-specific antigen (PSA) screening test for detecting prostate cancer showed that while more cancer was detected, there was no effect on prostate cancer mortality after 10 years of follow-up. The Cluster Randomized Trial of PSA Testing for Prostate Cancer was conducted at 573 primary care centres in the UK and targeted men aged 50 - 69 years, who were followed up for 10 years. Among practices randomised to a single PSA screening intervention v. standard practice without screening, there was no significant difference in prostate cancer mortality, although the detection of low-risk prostate cancer cases increased. The findings do not support single PSA testing for population-based screening. Martin RM, Donovon JL, Turner EL, et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: The CAP randomized clinical trial. JAMA 2018;319(9):883-895. https://doi. org/10.1001/jama.2018.0154

Cannabis compound may help siezures in drug-resistant epilepsy

A review of pooled data from 17 observational studies shows that seizure frequency in drug-resistant epileptic children fell by at least 50% in just under half of the patients and stopped completely in nearly one in ten (8.5%) in eight of the studies. Half of the patients in 12 studies also reported improved quality of life. The study was published in the Journal of Neurology, Neurosurgery and Psychiatry. Stockings E, Zagic D, Campbell G, et al. Evidence for cannabis and cannabinoids for epilepsy: A systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 2018 (epub 6 March 2018). https://doi.org/10.1136/jnnp-2017-317168

HRT may have positive effect on heart structure

A new study published in PLoS One suggests that hormone replacement therapy (HRT) may have a positive effect on heart structure. The study was carried out using data from UK Biobank, a database of health questionnaire data and physical measurements, including cardiovascular magnetic resonance imaging. Of 1 604 postmenopausal women without known cardiovascular disease, 513 had used HRT for ≥3 years and 1 091 had never used it. Results showed lower left ventricular and higher end-diastolic volume among non-HRT users compared with those who used HRT. There was no significant difference in left ventricular mass between the two groups of women. The study suggests that HRT not only has no adverse effect on heart function but may have some positive effects on heart structure. Sanghvi M, Aung N, Cooper J, et al. The impact of menopausal hormone therapy on cardiac structure and function: Insights from the UK Biobank imaging enhancement study. PLoS One 2018 (epub 8 March 2018). https://doi.org/10.1371/journal.pone.0194015

B Farham Editor ugqirha@iafrica.com

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OBITUARY Prof. Alpheus Mabose Segone

Alpheus Mabose Segone was born on 19 November 1943 and passed away on 20 February 2018. He attended high school at the Diocesan Training College, Pietersburg, and then completed a BSc at the University College of Fort Hare in 1963, with a distinction in chemistry. He went on to the University of Sheffield in the UK, where he completed his MB ChB in 1968. Prof. Segone began his medical career as a houseman and then house officer in surgery at Nottingham City Hospital. He then served as a senior house officer in casualty at Warwick Hospital from 1969 to 1970 and as a senior house officer in surgery at Manchester Royal Infirmary from 1970 to 1971. In 1971 he started his surgical training at Macclesfield Infirmary, and in 1975 began work as a specialist surgeon at Kitwe Hospital in Zambia, where he stayed until 1978. In 1979, Prof. Segone started on the path that he would become well known for, urology. He returned to London to be a registrar in urology at St Peterâ&#x20AC;&#x2122;s Hospital and the Institute of Urology, completing his training at the Central Middlesex Hospital in London in 1985. He then worked as a locum consultant urologist at Halifax General Hospital in Yorkshire and Walton Hospital in Liverpool until March 1986. Our continent was then fortunate enough to regain his expertise, as in April 1986

Prof. Segone began work as a consultant urologist and lecturer in urology at the Harare Central Hospitals, University of Zimbabwe. In 1992, he returned to South Africa and took up the position of senior specialist/senior lecturer in urology at Dr George Mukhari Hospital, Medunsa (now Sefako Makgatho Health Sciences University (SMU)). From 1994 until 2008 he was professor and chief specialist in urology at the same hospital, where he continued to work as a medical specialist until his death. As part of the Interim Council, he played an important role in the establishment of SMU. Prof. Segone was a member of a number of professional societies. He was a Fellow of the Royal College of Surgeons, Edinburgh, and of the College of Surgeons (Urology) South Africa, and a member of the Pan African Urological Surgeons Association, where he served as president from 2004 to 2005 and was a member of the Editorial Board. He was also a member of the British Association of Urological Surgeons, the Zimbabwe Medical Association, the South African Urological Association and the Societe Internationale Dâ&#x20AC;&#x2122;Urologie, which he served as a member of the Executive Committee. He was also a member of a number of university committees, serving on the Board of Surgery at the University of Zimbabwe from 1986 until 1991, and on the Faculty Board of Medunsa from 1993 to 2009, on the Medical Advisory Committee from 1994 to 2009, on the Medical Executive Committee from 1999 until 2009, and on the Joint Medical Personnel Committee for 10 years, 1999 - 2009. He chaired the Dr George Mukhari Hospital Management Committee from 1997 to 2009, was president of the Hospital Board from 1997 to 2008, and served as chair of the Appointments Committee from 1999 to 2009. He was a member of the Education Committee of the South African Urological Association for four years, from 2000 to 2004, and was a member of the Surgical Heads Committee at Medunsa from 1993, a position he held until his death. Prof. Segone chaired a number of congresses and sessions around the world,

April 2018, Print edition

from Zimbabwe to Tunisia, Kenya, Turkey and Nigeria. He also attended and presented at various international conferences, published in a number of journals and was involved in several important clinical trials. All these academic contributions have added significantly to the body of medical knowledge. The Colleges of Medicine of South Africa (CMSA) has been privileged to have Prof. Segone serve it in various capacities. In 2000 he was secretary of the College of Urology, and in 2002 he became a member of the Senate, serving until 2014. From 2012 to 2014 he was a member of the Board of Trustees, and then a member of the Board of Directors from 2013 to 2014. He continued to provide wisdom and counsel to the CMSA by serving in various key positions that ensured that the Colleges are accountable and respond to stakeholders. In 2012, the National Minister of Health, Dr Aaron Motsoaledi, appointed Prof. Segone as a member of the Forum of Statutory Health Councils of South Africa. He was one of two members representing the universities in South Africa. In 2016, he was appointed by the National Minister of Justice and Correctional Services, Adv. Michael Masutha, to chair the Medical Parole Board Committee of the Correctional Services. Despite his busy schedule, Prof. Segone still managed to take time out for himself, enjoying games of squash, tennis and golf. He also listened to music and had a special interest in African art (carvings) and traditional music. In recognition of his outstanding contributions to the CMSA and healthcare in South Africa, Prof. Segone was elected to Honorary Fellowship of the CMSA in 2016, the highest honour the Colleges can bestow. He is survived by his wife Nombulelo and children Tebogo and Yolisa. Mike Sathekge President, Colleges of Medicine of South Africa mike.sathekge@up.ac.za Shingai Mutambirwa Senator, CMSA (urologist)

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

EDITORIAL

Life-threatening hereditary angio-oedema: Challenges of care in South Africa The report and description by Coovadia et al.[1] in this issue of SAMJ of a large cohort of patients in the Western Cape Province of South Africa (SA) suffering from type 1 hereditary angio-oedema (HAE) not only documents for the first time a significant presence of this life-threatening condition on the African continent but highlights the challenges of diagnosis and management in the SA socioeconomic and healthcare context. The diagnosis of HAE is often missed or delayed, as illustrated by diagnosis as late as the fourth decade for some patients in the reported cohort. Failed diagnosis is due to lack of awareness among doctors. The average prevalence of HAE is 1:50 000, so we estimate that >800 individuals in SA may suffer from HAE. However, we estimate that only ~100 of these are actively diagnosed. The good news is that complement C4 levels are an invaluable and easy screening test for type 1 HAE, although availability in more remote settings may vary. C4 is low in most cases of HAE, especially during an attack (sensitivity >90%). Clinicians should perform screening for all patients experiencing non-pruritic episodes of asymmetrical angioedema without urticaria, particularly if there is a family history of swellings and the patient is not on an angiotensinconverting enzyme (ACE) inhibitor. Recurrent episodes of angio-

oedema in the absence of ACE inhibitors should also be reviewed by a specialist, ideally an allergist. A low antigenic C1-esterase level confirms the diagnosis of type 1 HAE and can be accessed in larger National Health Laboratory Service and private laboratories. Since HAE is a Mendelian dominant condition, immediate family members should also be tested. Confirmation of the more unusual type 2 and 3 variants of HAE, which require functional C1-esterase inhibitor assays or genetic testing, respectively, is very difficult. Functional testing is no longer available in SA, while genetic diagnosis of type 3 HAE can only be accessed through certain private laboratories. Patients with HAE should not die from acute attacks. This is the case in most developed countries with good healthcare access and registered effective treatments such as purified C1-inhibitor concentrate or bradykinin-β2-receptor antagonists. Unfortunately, it is not the situation in SA and most other developing-country settings. In our cohort we report two deaths; both were public sector patients with poor access to health facilities, no transport and no available effective medicine to keep at home on standby for attacks.[1] In addition, we were recently saddened by two further HAE deaths that illustrate the role of patient education and

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EDITORIAL

circumstance in affecting the outcome of HAE. The first casualty, a known patientâ&#x20AC;&#x2122;s sister, had refused testing and prophylactic management and died of her first laryngeal attack, out of hospital. The second also died out of hospital, but after repeated admissions for acute attacks, including an admission direct from police custody following arrest for drug dealing; he was a member of a local gang and never adherent to our prescribed prophylaxis. In SA and other developing countries, management of the acute attack is a therapeutic dilemma. Importantly, steroids and antihistamines are completely ineffective for the treatment of acute attacks of angio-oedema in HAE patients, as the oedema is bradykinin-mediated. Intravenous purified C1-inhibitor concentrate, available for many years overseas as Berinert, is firstline treatment in most countries, and is extremely effective in rapidly reducing the oedema. We have imported it on a named-patient basis for several of our patients and have used it both for acute severe attacks and prophylactically for patients undergoing major surgical procedures (e.g. hip replacement). C1-inhibitor concentrate is also safe for use in children. A new highly effective subcutaneous treatment for life-threatening attacks, but not for prophylaxis, is icatibant, the bradykinin receptor antagonist. Icatibant is not registered in SA, although patients in our reported cohort were fortunate to participate in the first global multicentre phase 3 clinical trials;[2] a few continue to access and self-administer this life-saving therapy at home through post-trial access. The response to these two targeted therapies is rapid, potentially allowing hospital discharge in a few hours on the same day, saving the time and cost of intensive care unit or high-care admission. We cannot access either of these targeted therapies for the majority of our public sector patients with acute attacks. Fresh frozen plasma (FFP) has been used in under-resourced areas for life-threatening attacks, as fresh plasma contains some active C1-esterase inhibitor. There has, however, been very little documentation of its effectiveness in blinded or placebo studies,[3,4] although it is widely used empirically. Our experience, referred to by Coovadia et al.[1] suggests that FFP may indeed be helpful, but further studies looking at appropriate doses, timing of administration and treatment outcomes are necessary. FFP may result in anaphylactoid reactions, and like any plasma product carries an infectious transmission risk. Ideally all emergency rooms would have one of these therapies available. However, as highlighted in our reported deaths, even FFP availability is restricted to major centres and may simply be too far away and difficult to access. Home-based targeted therapy would be optimal, but cost and registration are prohibitive. For our patients, effective prophylaxis is imperative.

Berinert and other longer-acting C1-inhibitor concentrates, as well as novel kallikrein inhibitors, are available in many countries as prophylaxis. We are limited to the use of 17Îą-alkylated androgens such as danazol and the antifibrinolytics such as tranexamic acid. Our reported cohort outcomes show danazol to be both well tolerated and effective, and in the absence of more modern and safer prophylactic agents in SA it remains first-line treatment. It can even be used in younger children on a per kilogram adjusted dosage, especially when antifibrinolytics such as tranexamic acid are ineffective. Different patients respond variably to danazol and some develop side-effects, so that the lowest effective dose needs to be determined for each patient and careful monitoring for androgenic side-effects is an ongoing concern. Danazol is contraindicated during pregnancy, and we have successfully motivated for Berinert therapy in these special circumstances. We hope that with the improved awareness associated with the publication of this SA cohort, more doctors will realise the significance of this disease in SA, think to investigate, and refer for treatment. In addition, we hope that state and private sector funders understand the challenges of life-saving treatment and access to services. We continue to support patient and allergy advocacy groups that support and give a voice to these vulnerable patients. Paul Potter Emeritus Professor of Allergology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Jonathan Peter Head of the Division of Allergy and Immunology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa jonny.peter@uct.ac.za 1. Coovadia KM, Chothia M-Y, Baker SG, Peter JG, Potter PC. Hereditary angio-oedema in the Western Cape Province of South Africa. S Afr Med J 2018;108(4):283-290. https://doi.org/10.7196/SAMJ.2018. v108i4.12823 2. Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: The FAST-3 trial. Ann Allergy Asthma Immunol 2011;107(6):529-537. https://doi.org/10.1016/j.anai.2011.08.015 3. Tang R, Chen S, Zhang HY. Fresh frozen plasma for the treatment of hereditary angioedema acute attacks. Chin Med Sci J 2012;27(2):92-95. 4. Prematta M, Gibbs JG, Pratt EL, Stoughton TR, Craig TJ. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007;98(4):383-388. https://doi.org/10.1016/ S1081-1206(10)60886-1

S Afr Med J 2018;108(4):254-255. DOI:10.7196/SAMJ.2018.v108i4.12824

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CME

GUEST EDITORIAL

Dyslipidaemia in South Africa Cardiovascular disease (CVD) is the leading cause of death worldwide, with an estimated 15 million people dying from ischaemic heart disease and stroke in 2015, which represents 26% of all deaths that year.[1] CVD disproportionately impacts low- and middle-income countries, where ~80% of the global CVD mortality occurs.[1] Dyslipidaemia is an important risk factor and a primary driver for CVD, and is defined by the presence of suboptimal serum lipid levels that portend heightened risk of cardiovascular events. There is a paucity of literature on the epidemiology and management of dyslipidaemia in South Africa (SA). The Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI) study[2] was designed to assess the awareness, treatment and control of dyslipidaemia in rural SA, and reported that 67% of rural South Africans met criteria for dyslipidaemia; only 30% of them were aware of their condition and only 0.7% were receiving treatment. In the HAALSI study,[2] being overweight was predictive of dyslipidaemia and dyslipidaemia awareness. These data are particularly concerning when considered against the background of rising levels of obesity, especially among rural women, as well as the increasing vulnerability of rural SA populations, who have limited access to both information and optimal medical therapy. In the Dyslipidemia International Study (DYSIS),[3] a crosssectional, observational study of lipid control in patients receiving statin therapy, the SA participants >45 years old and who had been treated with a stable dose of a statin for 3 years, had lipid goal attainment investigated. DYSIS reported that 50% of the SA patients did not achieve target low-density lipoprotein cholesterol (LDL-C) levels and 74% of these patients were at very high risk of CVD. Furthermore, 34% had low high-density lipoprotein cholesterol (HDL-C) levels and 45% had elevated triglyceride (TG) levels despite statin therapy.[3] Persisting lipid abnormalities in the context of suboptimal therapy place patients at ongoing risk of CVD, particularly many SA public sector patients who receive very low doses of statins, with lipid profiles not followed up after initiation of therapy. A retrospective study performed on black SA patients treated at the Dr George Mukhari Hospital, Gauteng, found a significant burden and high prevalence of dyslipidaemia in black adults in whom a monogenic disorder should have been considered.[4] Severe hypercholesterolaemia (TG >7 mmol/L) was seen in 5% and extreme hypercholesterolaemia (TG >12 mmol/L) in 0.5% of patients. Elevated TG levels were noted in 9% of patients. The authors concluded that the extent and severity of the dyslipidaemia justified a special clinic and laboratory to ensure accurate diagnosis, with effective intervention for patients and their families.[4] Indeed, there are very few dedicated, specialist lipid clinics in the public and private sectors in SA. The association between dyslipidaemia and anthropometric indicators in black and white adolescents (aged 12 - 16 years) residing in the North West Province of SA has been investigated in the Physical Activity and Health Longitudinal (PAHL) study.[5] This study found that waist circumference correlated negatively with HDL-C in both black and white children, and in white children it also correlated positively with LDL-C, total cholesterol (TC)/HDL-C and LDL-C/ HDL-C ratios. In white children, there were greater associations between dyslipidaemia and anthropometric indicators, suggesting

that there might be differences in lipid metabolism or susceptibility to risk factors at this young age.[5] These biological risk factors are further complicated by lack of physical activity and unhealthy diets among young South Africans. In the SA population, diabetes is an important driver of dyslipidaemia. A publication on lipid levels in black South Africans with type 2 diabetes confirmed this association.[6] Diabetes often coexists with other cardiovascular risk factors, such as hypertension, obesity, smoking, gout and hypercoagulability, all of which significantly increase the risk of CVD. SA has the largest population of people living with HIV worldwide, who receive antiretroviral therapy (ART), and also a significant number of treated HIV-infected persons with dyslipidaemia. In a recent publication, Dave et al.[7] reported the prevalence of dyslipidaemia to be 90% in ART-naive and 85% in treated HIV-infected South Africans. The SA Dyslipidaemia Guideline Consensus Statement,[8] based on the European Society of Cardiology and European Atherosclerosis Society guidelines, for the management of dyslipidaemia, was published in 2012, under the auspices of the SA Heart Association and the Lipid and Atherosclerosis Society of Southern Africa. The objective of these simplified guidelines was to promote current best management of dyslipidaemia in SA. In this issue of CME, Blom[9] provides an excellent review on an approach to the patient with elevated TGs. Mild-to-moderate hypertriglyceridaemia (TG >1.7 - 10 mmol/L) is an independent cardiovascular risk factor, while severe hypertriglyceridaemia (TG >10.0 mmol/L) can cause acute pancreatitis. Hypertriglyceridaemia is mostly polygenic. Secondary factors, such as uncontrolled diabetes, hypothyroidism, alcohol, renal disease and medications, are important in precipitating or exacerbating hypertriglyceridaemia. Patients with hypertriglyceridaemia require cardiovascular risk assessment and are in the first instance treated with statins if their cardiovascular risk is elevated. Control of secondary factors and lifestyle modifications are important in managing residual hypertriglyceridaemia in statintreated patients. Severe hypertriglyceridaemia is managed by removing or controlling secondary factors, by following a very low-fat diet and by prescribing a fibrate. Brozin and Raal[10] provide a state-of-the-art review on novel approaches to lipid-lowering therapy, focusing on new drugs and their mechanisms of action. Statins (with or without ezetimibe) and fibrates are the current first-line therapy in the management of dyslipidaemia. Novel agents include the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (that have shown to lead to a reduction in CVD morbidity), mipomersen, cholesterol ester transfer protein (CETP) inhibitors and bempedoic acid. Drugs such as pemfibrate, angiopoietin-like protein 3 (ANGPTL3) inhibitors, apolipoprotein C3 (apo C3) inhibitors and diacylglycerol acyltransferase-1 (DGAT 1) inhibitors have shown promising results in the management of hypertriglyceridaemia. Finally, Rusch et al.[11] provide an up-to-date, pragmatic and evidence-based approach to the laboratory investigations in lipidology. The conventional lipid profile, comprising fasting TG, TC, HDL-C and LDL-C, suffices for screening persons at risk for atherosclerosis. Non-fasting samples are gaining in popularity. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell

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function, as well as genetic investigations, are relevant; important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. It is my hope that the articles in this CME issue will improve the investigation and management of dyslipidaemia in SA, thereby reducing the risk of CVD in our population. Funding. This manuscript is not funded. Prof. N Ntusi gratefully acknowledges support from the National Research Foundation and the Medical Research Council of South Africa, as well as the Harry Crossley Foundation. Conflicts of interest. None.

Ntobeko Ntusi Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital; Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town; and Hatter Institute of Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa ntobeko.ntusi@uct.ac.za

1. World Health Organization. Global Status Report on Noncommunicable Diseases 2015. Geneva: WHO, 2016. 2. Reiger S, Jardim TV, Abrahams-Gessel S, et al. Awareness, treatment, and control of dyslipidemia in rural South Africa: The HAALSI (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study. PLOS ONE 2017;12(10):e0187347. https://doi.org/10.1371/ journal.pone.0187347 3. Raal FJ, Blom DJ, Naidoo S, Bramlage P, Brudi P. Prevalence of dyslipidaemia in statin-treated patients in South Africa: Results of the Dyslipidaemia International Study (DYSIS). Cardiovasc J Afr 2013;24(8):330-338. https://doi.org/10.5830/CVJA-2013-071 4. Khine AA, Marais DA. High prevalence of primary dyslipidaemia in black South African patients at a tertiary hospital in northern Gauteng, South Africa. S Afr Med J 2016;106(7):724-729. https://doi. org/10.7196/SAMJ.2016.v106i7.10337 5. Mamabolo RL, Sparks M, Moss SJ, Monyeki MA. The association between dyslipidemia and anthropometric indicators in black and white adolescents residing in Tlokwe Municipality, NorthWest Province, South Africa: The PAHL study. Afr Health Sci 2014;14(4):929-938. https://doi. org/10.4314/ahs.v14i4.23 6. Joffe BI, Distiller LA, Kalk WJ. Lipid levels in black South Africans with type 2 diabetes. Diabet Care 2004;27(7):1839-1840. 7. Dave JA, Levitt NS, Ross IL, Lacerda M, Maartens G, Blom D. Antiretroviral therapy increases the prevalence of dyslipidaemia in South African HIV-infected patients. PLOS ONE 2016;11(3):e0151911. https://doi.org/10.1371/journal.pone.0151911 8. Klug E; South African Heart Association (S A Heart); Lipid and Atherosclerosis Society of Southern Africa (LASSA). South African dyslipidaemia guideline consensus statement. S Afr Med J 2012;102(3):178-187. 9. Blom DJ. Elevated triglycerides: A matter of the heart and pancreas. S Afr Med J 2018;108(4):258-261. https://doi.org/10.7196/SAMJ.2018.v108i4.13235 10. Brozin D, Raal FJ. Novel approaches to lipid-lowering therapy. S Afr Med J 2018;108(4):262-265. https://doi.org/10.7196/SAMJ.2018.v108i4.13234 11. Rusch JA, Hudson CL, Marais AD. Laboratory investigations in lipidology. S Afr Med J 2018;108(4):266-270. https://doi.org/10.7196/SAMJ.2018.v108i4.13233

S Afr Med J 2018;108(4):256-257. DOI:10.7196/SAMJ.2018.v108i4.13265

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CME

Elevated triglycerides: A matter of the heart and pancreas D J Blom, MB ChB, MMed, FCP (SA), PhD Division of Lipidology and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: D J Blom (dirk.blom@uct.ac.za)

Mild-to-moderate hypertriglyceridaemia (triglyceride (TG) >1.7 - 10.0 mmol/L) is an independent cardiovascular risk factor, while severe hypertriglyceridaemia (TG >10.0 mmol/L) can cause acute pancreatitis. Hypertriglyceridaemia is polygenic in most patients, and secondary factors, such as uncontrolled diabetes, hypothyroidism, alcohol, renal disease and medication (e.g. corticosteroids, retinoids, oestrogen), often play an important role in precipitating or exacerbating the condition. Patients with mild-to-moderate hypertriglyceridaemia require cardiovascular risk assessment and are in the first instance treated with statins if their cardiovascular risk is high. Control of secondary factors and lifestyle modifications are important in managing residual hypertriglyceridaemia in patients treated with statins. Multiple trials are ongoing to determine whether there is further cardiovascular outcome benefit from adding drugs such as fibrates or omega-3 supplements to the regimen of patients who are receiving statins. Severe hypertriglyceridaemia is managed by removing or controlling secondary factors, following a very low-fat diet and prescribing a fibrate. S Afr Med J 2018;108(4):258-261. DOI:10.7196/SAMJ.2018.v108i4.13235

Of all the lipids routinely measured in clinical practice, serum triglycerides (TGs) are the most variable and can increase more than 50-fold from baseline. Ideally, fasting TGs should be <1.7 mmol/L, but TGs can reach values of >100.0 mmol/L in some patients. The clinical approach to hypertriglyceridaemia varies considerably, depending on the degree of elevation and the clinical context. Although there are multiple classification schemes for hypertriglyceridaemia, a simple and useful scheme is to classify hypertriglyceridaemia of >1.7 <10.0 mmol/L as mild to moderate, while TGs >10.0 mmol/L are classified as severe hypertriglyceridaemia.[1]

What are the potential clinical consequences of hypertriglyceridaemia?

The two most important clinical consequences of hypertriglyceridaemia are acute pancreatitis and atherosclerotic cardiovascular disease (CVD). Severe hypertriglyceridaemia may lead to acute pancreatitis.[2] The mechanisms by which hypertriglyceridaemia causes pancreatitis are not that well understood, but may relate to impairment of capillary perfusion in the pancreas, pancreatic cell necrosis and subsequent release and activation of pancreatic enzymes. When and if pancreatitis will occur in an individual patient is quite unpredictable – some patients may have TGs of >100.0 mmol/L and no symptoms, while others develop pancreatitis at much lower TG levels. Mild-to-moderate hypertriglyceridaemia is an independent cardiovascular risk factor. There is still some debate about the exact mechanisms by which triglyceride-rich lipoproteins (TGRLs) cause atherosclerosis. However, the cholesterol found in these TGRLs is likely a major causative factor.[3] This remnant cholesterol can be approximated by the following calculation: Remnant cholesterol = total cholesterol − high-density lipoprotein (HDL) cholesterol − low-density lipoprotein (LDL) cholesterol[4] The relative risk of CVD from a 1.0 mmol/L increase in TGs ranges from 1.14 to 1.80 (dependent on sex and race) after adjustment for other risk factors such as HDL cholesterol.[5]

What causes hypertriglyceridaemia?

Hypertriglyceridaemia has multiple and complex causes. Most cases are caused by the interaction of multiple genetic factors (polygenic aetiology) with environmental factors. The relative importance of the genetic and environmental contributions can vary between patients, i.e. in some patients environmental factors may be dominant, while in others genetic factors may be more prominent. Genetic investigation of patients with polygenic hypertriglyceridaemia is difficult because of the multitude of genes that may affect TGs. Variants in these genes individually have very little effect on TGs, but accumulation of many TG-raising variants may lead to hypertriglyceridaemia.[1] A score that tallies carrier status for TG-raising alleles at 32 genetic loci has been constructed and is higher in patients with hypertriglyceridaemia than in normal controls.[6] Genetic complexity is further increased by gene variants that lower TGs. From a practical point of view, genetic testing of patients with hypertriglyceridaemia is of limited clinical use unless a monogenic cause is strongly suspected. Monogenic hypertriglyceridaemia is usually severe and manifests in infancy or early childhood. It is usually inherited in an autosomal recessive pattern and is most commonly due to biallelic mutations of the lipoprotein lipase (LPL) gene. LPL deficiency has been described in all South African (SA) population groups, but is most commonly seen in Indians and Afrikaners. Occasionally, patients with dysbetalipoproteinaemia, which results from mutations in apolipoprotein E (apo E), develop severe hypertriglyceridaemia, although the more common phenotype is that of a severe mixed hyperlipidaemia with a total cholesterol to triglyceride ratio of 2:1. Environmental factors that may contribute to the development of hypertriglyceridaemia include lifestyle factors, medical disorders and drugs (Table 1). Identification and treatment of these secondary factors (where possible) are often key to the management of patients with hypertriglyceridaemia. The clinical experience at Groote Schuur Hospital Lipid Clinic, Cape Town, SA, is that uncontrolled or undiagnosed diabetes is by far the most common secondary factor in patients with hypertriglyceridaemia (D J Blom – unpublished observation, 2018).

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What clinical clues can help to identify patients with hypertriglyceridaemia?

Mild-to-moderate hypertriglyceridaemia is generally only identified on laboratory testing, although its presence should be suspected in patients with any of the secondary factors (Table 1). Patients with severe hypertriglyceridaemia may develop eruptive or tuboeruptive xanthomata (Fig. 1A and B). Eruptive xanthomata are most commonly found around the elbows, knees, buttocks and thighs and are usually asymptomatic. Lipaemia retinalis (white to creamy appearance of retinal blood vessels) may be visible on fundoscopy. Severe hypertriglyceridaemia cannot be excluded if these physical signs are absent. Laboratory comments referring to a ‘lipaemic specimen’ (Fig. 1C) should be taken seriously, as this may be the first clue that a patient has elevated TGs. Lipid screening is often commenced with total cholesterol determination only. If the total cholesterol is very high, it should always be followed up with a full lipogram to detect the patients in whom the very high total cholesterol reflects an accumulation of TGRLs rather than LDL particles. Table 1. Secondary causes of hypertriglyceridaemia Medical disorders Type 2 diabetes/metabolic syndrome Hypothyroidism Renal failure Systemic lupus erythematosus Paraproteinaemia (rare) Lifestyle Obesity Increased alcohol consumption Diet (excess energy, high fat, high glycaemic index) Medication Corticosteroids Retinoids Oestrogen (especially when given orally) Tamoxifen Protease inhibitors (the risk is highest with ritonavir) Cholestyramine Leflunomide Second-generation antipsychotics Cyclosporin Sirolimus Thiazides Beta-blockers Other Pregnancy (in susceptible individuals) Auto-immune states

What is the best way to evaluate and investigate patients with hypertriglyceridaemia?

Once hypertriglyceridaemia has been recognised, the evaluation focuses on identifying secondary factors and assessing the risk of acute pancreatitis or CVD. The majority of hypertriglyceridaemic patients seen in routine clinical practice have identifiable secondary factors that might have precipitated new or exacerbated pre-existing hypertriglyceridaemia. A careful dietary history should be taken, focusing particularly on alcohol intake, fat consumption and refined carbohydrate intake. Collateral history may be particularly helpful when assessing alcohol intake. All medication should be reviewed, including over-the-counter drugs. It is particularly important to enquire specifically about oral contraceptives and other hormonal preparations, as many patients do not regard these as ‘medicine’. A family history is also useful and may help to assess the risk of CVD and diabetes. Useful baseline investigations include a fasting glucose, HbA1C (if appropriate), creatinine, urine dipstick and thyroid-stimulating hormone (TSH). Depending on the clinical situation, liver function testing may be useful to screen for non-alcoholic fatty liver disease. Specialised lipid testing may include agarose gel electrophoresis, gradient gel electrophoresis and determination of apo B and apo A1. The latter investigations should generally be performed at the specialist level, as they are not always straightforward to interpret. Genetic testing plays a minor role in the management of most hypertriglyceridaemic patients and should only be done at a specialist lipid clinic. There are no algorithms to formally quantify the risk of acute pancreatitis, which is increased in patients with previous pancreatitis and in alcohol users. The risk also increases with the severity of hypertriglyceridaemia, although the correlation is imperfect. Practically, defining all patients with TGs >10.0 mmol/L as ‘at risk’ for acute pancreatitis, is a good policy to ensure rapid assessment and treatment. Cardiovascular risk is assessed using standard clinical guidelines; patients with diabetes and established CVD are classified as very high risk without needing risk calculation. For other patients, risk is quantified using an algorithm such as the Framingham charts. These charts, unfortunately, do not incorporate TGs and may thus underestimate risk in some patients with hypertriglyceridaemia.

How should patients with hypertriglyceridaemia be managed?

For patients with severe hypertriglyceridaemia, the initial focus is on the prevention of acute pancreatitis, and they should be seen urgently. Any identified secondary factors should be addressed and removed whenever possible. This may include discontinuing and replacing potentially precipitating medications such as corticosteroids,

Fig. 1. Clinical signs in hypertriglyceridaemia. (A) Eruptive xanthomata. (B) Tubo-eruptive xanthomata. (C) Lipaemic plasma.

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retinoids or oestrogen-containing preparations when possible to do so. Patients should be advised not to consume alcohol. Improving glycaemic control is an important intervention and, in many patients, it is best and most rapidly achieved either by starting insulin or by intensifying insulin therapy. Dietary restriction of TG intake is very important in most patients with severe hypertriglyceridaemia because poor clearance of TGRL is usually an important component of the pathophysiology. Reducing dietary TG intake reduces the formation of chylomicrons in the intestine and also results in less TG delivery to the liver for incorporation into very low-density lipoproteins (VLDL). Patients with severe hypertriglyceridaemia are often prescribed a diet that is extremely low in dietary fat (‘rescue diet’: <10.0 g of fat per day). Such a diet is not sustainable in the long term, but can lower TGs relatively acutely over a few days. In the long term most patients are maintained on a very low-fat diet (20 - 30 g of dietary fat per day/~20% of caloric intake from fat), but the diet can be modified later according to the patient’s response and underlying conditions. When referring patients for dietary advice, it is important to specifically request that they not be given a Therapeutic Lifestyle Diet, but that the focus needs to be on reducing dietary fat from all sources. In patients with hypertriglyceridaemia there are no ‘good’ or ‘bad’ dietary fats, as all dietary fats (except for special preparations containing medium-chain TGs) are incorporated into chylomicrons and thus contribute to raising serum TGs. For severe hypertriglyceridaemia, fibrates are the most effective drugs, except for patients with monogenic hypertriglyceridaemia, in whom they are usually not effective. In SA, bezafibrate and fenofibrate are the best-known fibrates. These drugs are generally well tolerated, but because they are renally excreted the dose needs to be adjusted in patients with chronic kidney disease. Fibrates can be combined with statins, but this should be done with caution and specialist review is usually worthwhile when considering a statin and fibrate combination. Gemfibrozil should not be combined with a statin because of the risk of drug-drug interactions. Statins are not effective in patients with severe hypertriglyceridaemia, even if prescribed at maximal doses. Using statins as the primary agent in patients with severe hypertriglyceridaemia is a relatively common mistake, because the very high total cholesterol in cases of severe hypertriglyceridaemia (e.g. a total cholesterol of 30.0 mmol/L in a patient with a TG of 70.0 mmol/L) often becomes a misleading focal point. As the concentration of TGRL falls with treatment, the total cholesterol will decrease. In patients with mild-to-moderate hypertriglyceridaemia, the initial focus is on cardiovascular risk assessment and risk reduction. Very high-risk and high-risk patients require medication in addition to lifestyle modification. Statins are generally the drugs of first choice to reduce cardiovascular risk in patients with mild-tomoderate hypertriglyceridaemia. The statin dose should be adjusted to achieve the guideline-recommended LDL cholesterol target.[7] Non-HDL cholesterol (or apo B) is an important secondary target in patients with hypertriglyceridaemia because it reflects the presence of remnant cholesterol – consider intensifying therapy in patients with LDL cholesterol at target but non-HDL cholesterol above target (the target for non-HDL cholesterol is always 0.8 mmol/L above the relevant LDL cholesterol target). Important lifestyle interventions include reducing body weight, reducing alcohol intake, reducing simple sugar intake, increasing activity, replacing trans and saturated fats with monounsaturated fats and increasing dietary omega-3 fatty acids.

Should additional therapy be added to a statin to reduce cardiovascular risk further in patients with hypertriglyceridaemia?

This is currently the source of much debate, and much confusion ensues from different guidelines giving differing advice. There is clinical equipoise, as demonstrated by the approval of several ongoing double-blind placebo-controlled cardiovascular outcomes studies that are evaluating the addition of omega-3 fatty acids (two studies) or a novel fibrate (one study) to statin-treated patients with residual hypertriglyceridaemia and low HDL cholesterol. Retrospective analyses of fibrate monotherapy studies and a subanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study[8] (in which fenofibrate or placebo was added to the regimen of diabetic patients treated with simvastatin) suggest that fibrates may improve cardiovascular outcomes in patients with TGs >2.3 mmol/L and low HDL cholesterol. Based on the results of the ACCORD study, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines (on which the South African lipid guidelines are based) (https://www.eas-society.org/) state that addition of fenofibrate to statin-based therapy can be considered in high-risk patients with TGs >2.3 mmol/L (class IIB, level C).[7] Once the results of the statin and ‘second agent’ outcome studies are available, the management of hypertriglyceridaemia in high cardiovascular risk patients will hopefully become much clearer and more evidence based. For now, the emphasis remains on prescribing an adequate statin dose, control of other cardiovascular risk factors and intensive lifestyle modifications. Further information on this topic is available at the website of the Residual Risk Reduction Initiative (http://www.r3i.org/) or the National Lipid Association (https://www.lipid.org).

What novel therapies are in the pipeline?

The two most promising and advanced novel strategies focus on the inhibition of proteins that interfere with the action of LPL. Lipoprotein lipase (LPL) is directly inhibited by apo C3. Volanesorsen is an antisense oligonucleotide that reduces apo C3 protein production. Encouraging early results have been seen in patients with LPL deficiency and other forms of hypertriglyceridaemia.[9] Angiopoietinlike 3 (ANGPTL-3) is secreted by the liver and also inhibits LPL, particularly after a meal. Monoclonal antibodies against ANGPTL3 are currently in early-phase clinical trials.[10]

Conclusion

Our understanding of the metabolism and clinical role of TGRLs has improved significantly over the past few years. This research has led to the identification of several new and exciting potential therapeutic targets. However, the major challenge in the next few years remains to define how we should optimally use currently available therapies such as fibrates or omega-3 fatty acids in patients with mild-to-moderate hypertriglyceridaemia and high cardiovascular risk.

Summary

• Severe hypertriglyceridaemia (>10.0 mmol/L) can trigger acute pancreatitis. • A precipitating factor (most commonly uncontrolled or undiagnosed type 2 diabetes mellitus or medication) is present in most patients with severe hypertriglyceridaemia. • Mild-to-moderate hypertriglyceridaemia (1.7 - 10.0 mmol/L) is an independent cardiovascular risk factor.

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â&#x20AC;˘ Currently, it is not clear whether a second agent should be added in high cardiovascular risk patients with mild-to-moderate hypertriglyceridaemia, who are being treated with optimised statin therapy. â&#x20AC;˘ Fibrates are the drugs of choice in patients with severe hypertriglyceridaemia. Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. DJB is the national principal investigator for several trials exploring novel treatments for hypertriglyceridaemia. His institution has received payments for conducting clinical trials, trial supervision and his attendance at advisory board meetings from Akcea Therapeutics, AstraZeneca and Kowa Company Ltd. 1. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: Implications for definition, diagnosis, and management. Lancet Diabet Endocrinol 2014;2(8):655-666. https://doi.org/10.1016/S2213-8587(13)70191-8

2. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med 2006;354(20):2142-2150. https:// doi.org/10.1056/NEJMcp054958 3. Varbo A, Benn M, Tybjaerg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61(4):427-436. https://doi.org/10.1016/j.jacc.2012.08.1026 4. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: New insights from epidemiology, genetics, and biology. Circ Res 2016;118(4):547-563. https://doi. org/10.1161/CIRCRESAHA.115.306249 5. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: Evidence and guidance for management. Eur Heart J 2011;32(11):1345-1361. https://doi.org/10.1093/eurheartj/ehr112 6. Johansen CT, Wang J, McIntyre AD, et al. Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. Circ Cardiovasc Genet 2012;5(1):66-72. https://doi.org/10.1161/CIRCGENETICS.111.960864 7. Catapano AL, Graham I, de Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37(39):2999-3058. https://doi.org/10.1093/eurheartj/ehw272 8. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362(17):1563-1574. https://doi.org/10.1056/NEJMoa1001282 9. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373(5):438-447. https://doi.org/10.1056/NEJMoa1400283 10. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69(16):2054-2063. https://doi.org/10.1016/j.jacc.2017.02.030

Accepted 5 March 2018.

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Novel approaches to lipid-lowering therapy D Brozin,1 MB BCh; F J Raal,2 FRCP, FRCPC, FCP (SA), Cert Endocrinology and Metabolism (SA) Phys, MMed, PhD 1 2

Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Carbohydrate and Lipid Metabolism Research Unit and Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: F J Raal (frederick.raal@wits.ac.za)

Cardiovascular disease (CVD) remains a major cause of death worldwide, with dyslipidaemia playing a significant role in the disease process. It is clinically useful to demarcate hypercholesterolaemia from hypertriglyceridaemia, with an increased serum low-density lipoprotein (LDL) cholesterol being the most powerful predictor of CVD morbidity and mortality, and a significant elevation in triglyceride levels increasing the risk of acute pancreatitis. Statins (with or without ezetimibe) and fibrates are the current first-line therapy in the management of dyslipidaemia. Although these medications have shown effectiveness in reducing CVD complications, there are patients who require a greater modification in lipid profile or are intolerant of first-line therapy. Novel agents are on the horizon, which have shown to lead to a significant decrease in serum LDL cholesterol. These include the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (which have shown a reduction in CVD morbidity), mipomersen, cholesterol ester transfer protein (CETP) inhibitors and bempedoic acid. Further studies of the clinical benefit of these medications are ongoing. Drugs such as pemfibrate, angiopoietin-like protein 3 (ANGPTL3) inhibitors, apolipoprotein C3 (apo C3) inhibitors and diacylglycerol acyltransferase-1 (DGAT 1) inhibitors have shown promising results in the management of hypertriglyceridaemia. It is hoped that these exciting new technological advancements in the future management of dyslipidaemia will result in clinical benefit for patients. S Afr Med J 2018;108(4):262-265. DOI:10.7196/SAMJ.2018.v108i4.13234

Cardiovascular disease (CVD) remains the major cause of death worldwide. In modern medicine, atherosclerotic CVD and its ensuing complications provide a significant challenge to clinicians, from the level of primary care to subspecialty practice. The role of dyslipidaemia in the pathogenesis of atherosclerotic CVD has been extensively researched, and doctors across South Africa (SA) are often tasked with modifying this significant risk factor burden among a wide variety of population groups. When managing dyslipidaemia, it is clinically useful to separate hyperlipidaemia into two main categories, i.e. hypertriglyceridaemia and hypercholesterolaemia, particularly an increase in serum lowdensity lipoprotein (LDL) cholesterol concentrations. As discussed in this article, even though an elevated triglyceride (TG) level may result in an increased risk of CVD, the greatest effect of lowering markedly elevated serum TG (>10 mmol/L) is the reduction in the risk of developing acute pancreatitis, with a reduction of serum LDL cholesterol being a much more powerful predictor of risk reduction with regard to CVD morbidity and mortality.

Management of predominant hypercholesterolaemia Statin therapy

If diet and lifestyle advice does not lower LDL cholesterol sufficiently, the 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors or statins are the current mainstay of treatment of elevated LDL cholesterol. The most efficacious statins at their maximum dose can reduce LDL cholesterol by up to 50%.

Ezetimibe

Ezetimibe prevents intestinal absorption of cholesterol, and is currently the mainstay as a second-line agent in lowering LDL cholesterol. As per the European Society of Cardiology (ESC) guide-

lines, ezetimibe is recommended as an add-on therapy for patients on high-intensity statins, who require further LDL cholesterol reduction, or for patients who are statin intolerant. The IMProvedÂ Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT),[1] which showed a 2% absolute reduction in cardiovascular events compared with placebo over a 6-year follow-up period in patients on background statin therapy, has proven the benefit of the addition of ezetimibe to statin therapy in reducing cardiovascular events. While these medications have been used to excellent effect in lowering the rate of complications secondary to dyslipidaemia, there are still certain groups of the population for whom this combination is insufficient. The two major groups of patients who may require an additional or alternative approach to lipid-lowering therapy, are: (i) individuals with familial hypercholesterolaemia, which is highly prevalent in the Afrikaner, Jewish and Indian populations of SA, as they require a greater percentage reduction in LDL cholesterol to achieve acceptable LDL cholesterol target levels; and (ii) individuals experiencing side-effects from statin therapy, precluding the use of high-intensity statin therapy, i.e. statin-intolerant patients.

New therapies for the treatment of hypercholesterolaemia

Proprotein convertase subtilisin/kexin type 9 inhibitor therapy Currently riding the crest of the wave with regard to lipid-lowering therapy, are the therapies that inhibit the action of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. If PCSK9 binds to the LDL receptor (LDL-R), mainly on the hepatocyte, instead of being recycled to the cell surface, the LDL-R is degraded. By inhibiting the function of this enzyme through the use of monoclonal antibodies (mAbs), the expression of LDL-R on the hepatocyte is increased, thereby enhancing the cellular clearance of serum LDL cholesterol. As of 2018, alirocumab and evolocumab, two

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Table 1. Novel approaches to lipid lowering Class HMG-CoA reductase inhibitors (statins)

Drug Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin* Fibrates: bezafibrate, gemfibrozil, fenofibrate, pemafibrate* Ezetimibe Alirocumab, evolocumab, LY3015014 (mAbs),* inclisiran (reduced synthesis)* Mipomersen* Anacetrapib*

LDL-C

Triglycerides

HDL-C

Apo C3 inhibitors Lp (a) inhibitors

REGN1500* Evinacumab* Volanesorsen* IONIS-APO(a)Rx*

DGAT1 inhibitors Triphosphate citrate lyase inhibitors

Pradigastat* Bempedoic acid*

PPAR alpha modulators Cholesterol absorption inhibitors PCSK9 inhibitors Apo B100 inhibitors CETP inhibitors ANGPTL3 inhibitors

LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; HMG-CoA = 3-hydroxy-3-methyl-glutaryl co-enzyme A; PPAR = protein peroxisome proliferator activated receptor alpha; PCSK9 = proprotein convertase subtilisin/kexin type 9; apo B100 = apolipoprotein B100; CETP = cholesterol ester transfer protein; ANGPTL3 = angiopoietin-like protein 3; apo C3 = apolipoprotein C3; Lp (a) = lipoprotein (a); DGAT1= diacylglycerol acetyltransferase 1; mAbs = monoclonal antibodies. *Not available in South Africa or still undergoing clinical development.

mAbs against PCSK9, i.e. PCSK9 inhibitors, which are administered subcutaneously every 2 - 4 weeks, have received US Food and Drug Administration approval as lipid-lowering agents.[2] Unfortunately, they have not yet been approved for clinical use in SA. These exciting new medications have been shown by numerous clinical trials to produce a significant reduction in serum LDL cholesterol of ~60% when used either as monotherapy or when combined with a statin with or without ezetimibe.[3] The recently published Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial[4] investigated cardiovascular outcomes in high-risk patients on background statin therapy, who were receiving evolocumab v. placebo and showed not only a significant reduction in serum LDL cholesterol concentration, but also a significant reduction in cardiovascular morbidity in those receiving the PCSK9 inhibitor. A similar study with alirocumab, the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes),[5] has recently been completed and the results are eagerly awaited. A third monoclonal against PCSK9, LY3015014, is currently being developed. Current studies show that the reduction of serum LDL cholesterol concentration with the use of LY3015014 is comparable to levels achieved by the mAbs now on the market.[5] The advantage of this mAb, compared with the current medication available, is its prolonged half-life, which enables patients to enter into a regimen requiring subcutaneous administration of the drug at 4 - 8-weekly intervals, as opposed to the current mAb regimen, which is administered at 2 - 4-weekly intervals. Regarding the modulation of PCSK9 function, a fourth drug, inclisiran, is currently undergoing phase 3 clinical trials, and is showing promising results with regard to lowering serum LDL cholesterol concentrations.[6] As opposed to the mAbs, inclisiran reduces the activity of PCSK9 by inhibiting synthesis of the enzyme, acting at the level of protein translation via RNA interference in the liver. Unlike mAbs, inclisiran only needs to be administered once every 3 - 6 months. However, a cardiovascular outcome study with inclisiran will be required to prove that it has similar cardiovascular benefit to PCSK9 mAb therapy.

Mipomersen A major component in the hepatic synthesis of very low-density lipoprotein (VLDL) and hence LDL, is the transcription and translation of apolipoprotein B-100 (apo B100), the carrier protein of LDL. A novel agent, mipomersen, which is not yet available in SA, inhibits the synthesis of apo B100 by ribonucleic acid (RNA) interference at the transcription stage. In doing so, this medication, classed as an antisense oligonucleotide (ASO), can reduce serum LDL cholesterol using an alternate pathway than the statins and PCSK9 inhibitors. Mipomersen is administered as a weekly subcutaneous injection. Studies[7] with mipomersen have shown that this therapy can produce a significant reduction in both serum LDL cholesterol (25 - 39%), as well as lipoprotein (a) [Lp (a)] (21 - 39 %) when added to standard treatment regimens. There are some data to suggest that mipomersen may also result in a reduction in cardiovascular morbidity.[8] The largest barriers with regard to mipomersen are injection site reactions and the propensity for the development of fatty liver (hepatic steatosis), although the long-term morbidity and mortality with regard to hepatic disease with this agent are yet to be studied. Cholesterol ester transfer protein inhibitors Cholesterol ester transfer protein (CETP) is an important mediator protein in the lipid transport cycle owing to its ability to transfer cholesterol esters between lipoproteins. Inhibition of CETP results in a marked increase in serum high-density lipoprotein cholesterol (HDL cholesterol), with a reduction in serum LDL cholesterol. Three medications developed against CETP, i.e. torcetrapib, dalcetrapib and evacetrapib, have been abandoned in the trial stage owing to either adverse events or lack of cardiovascular benefit, with only anacetrapib still undergoing further evaluation. The recently reported Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL)[9] trial showed a modest reduction in cardiovascular events, but the reduction was proportional to the reduction in LDL cholesterol and not related to the marked increase in HDL cholesterol observed with anacetrapib. It is therefore unlikely that CETP inhibitors will undergo further clinical development.

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Management of predominant hypertriglyceridaemia

Apo C3 inhibitors

Dietary change and weight loss in patients who are overweight or obese can effectively reduce serum TG levels. However, if diet and lifestyle do not lower TG levels sufficiently, drug therapy may be required. Statins can modestly reduce serum TG levels and are the agents of choice for mild hypertriglyceridaemia (TG <5 mmol/L), particularly if the LDL cholesterol is also elevated. However, when TG levels are markedly elevated, particularly if >10 mmol/L, there is a risk of developing acute pancreatitis, which is potentially life threatening. In such cases, additional or alternative TG-lowering therapies may be required. The major classes of drugs used for the treatment of hypertriglyceridaemia are the fibrates and niacin (nicotinic acid). However, niacin has been withdrawn in many countries globally, including SA, because of side-effects or lack of cardiovascular benefit.

Fibrates and pemafibrate

Fibrinic acid derivatives, or fibrates, are currently available in SA as first-line treatment for patients with severe hypertriglyceridaemia. These agents are agonists of the nuclear protein peroxisome proliferator activated receptor alpha (PPAR alpha) and therefore stimulate the synthesis of HDL and the activity of lipoprotein lipase, resulting in the increased hydrolysis of TGs, as well as a reduction in synthesis of apo C3. These agents are an important therapy for the prevention of acute pancreatitis and its clinical complications in patients with severe hypertriglyceridaemia (>10 mmol/L). Currently, there are no robust outcome studies that have demonstrated a definitive reduction in CVD morbidity and mortality with fibrate therapy. However, a reduction in CVD events was noted in a subgroup analysis of patients with high TG levels and low HDL cholesterol.[10] Fibrates, particularly fenofibrate and bezafibrate, are well tolerated and can be used in combination with statin therapy in patients requiring a reduction in both serum LDL cholesterol and TG levels. Pemafibrate is a new drug to the fibrate class and reveals a greater selectivity and activity of the PPAR alpha protein. This agent has been shown to produce a significant reduction in serum TG levels and is currently under investigation for its cardiovascular benefit in a large outcome study, the Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT),[11] which is enrolling patients with a combination of a high serum TG and low HDL cholesterol. If significant results are obtained, pemafibrate may be an interesting alternative to currently available fibrate therapy.

Angiopoietin-like protein 3 inhibitors

Other medications belonging to the classes of antisense oligonucleotides are those that inhibit the production of the angiopoietin-like protein 3 (ANGPTL3) enzyme. The enzyme, ANGPTL3, has been shown to inhibit lipoprotein lipase (LPL) and hence its modulation results in a reduction of serum TG. An interesting finding is that the inhibition of ANGPTL3 not only results in the reduction of serum TG, as expected, by reduction of LPL activity, but also in a reduction of serum LDL cholesterol.[12] The mechanism by which this reduction of serum LDL cholesterol is achieved is unknown. A second approach with regard to the inhibition of ANGPTL3 is the development of a monoclonal antibody against the enzyme. This mAb, evinacumab, has been shown to reduce TGs, LDL cholesterol and Lp (a) and is therefore an exciting new avenue for further exploration in the quest to lower lipids and improve cardiovascular outcomes.

Two recently published studies have shown the powerful TG-lowering effect that can be produced by the inhibition of apo C3. These studies, i.e. a Study of Volanesorsen (formerly IONIS-APOCIIIRx) in Patients With Familial Chylomicronemia Syndrome (APPROACH) and the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial,[13] have shown a serum TG reduction of up to 50% with the use of volanesorsen, an apo C3 inhibitor, when used as monotherapy in the management of dyslipidaemia. By inhibiting the apo C3 gene, there is both enhanced activity of LPL, resulting in an increased TG clearance, as well as a reduction in the synthesis of VLDL. The major limiting factor with the use of volanesorsen was the side-effects related to its use, i.e. severe injection site reactions and thrombocytopenia. Further studies investigating the clinical benefit of these medications against the side-effect profile are yet to be conducted.

Lipoprotein (a) inhibitors

Lp (a), a particle with structural similarity to plasminogen, has been shown to be an independent risk factor for CVD, as well as for the development of aortic stenosis. This is probably because Lp (a) is an LDL-like particle, but it is also thought to inhibit the action of plasminogen, resulting in a reduction in fibrinolysis; hence, it is both proatherogenic and prothrombotic. An antisense oligonucleotide, IONIS-APO(a)Rx, is currently undergoing clinical trials, with preliminary results showing a significant reduction in Lp (a) levels with the use of this treatment.[14] The use of this medication in lowering Lp (a) and subsequent CVD is yet to be determined, but it provides an interesting alternate pathway in lowering cardiovascular mortality in patients requiring Lp (a) reduction therapy.

Other novel therapies on the horizon

Pradigastat is an oral inhibitor of the enzyme diacylglycerol acyltransferase 1 (DGAT1), which prevents fat absorption in the small intestine, as well as TG synthesis. This drug is currently undergoing large-scale clinical trials, with small studies revealing a serum TG reduction of up to 70%.[15] Bempedoic acid (ETC-1002) is currently undergoing phase 2 clinical trials, with early results showing a significant reduction in LDL cholesterol, 30% as monotherapy and 50% when added to ezetimibe.[16] This drug inhibits the enzyme adenosine triphosphate citrate lyase, which results in a decreased production of both cholesterol and TGs. In newer studies, the role of modulation of the receptor asialoglycoprotein receptor 1 (ASGR1) is being explored. Individuals with a genetic variant of ASGR1 have been shown to have a lower LDL cholesterol, lower TG and higher HDL cholesterol concentrations. Based on this finding, it may be of interest to explore this receptor, and hence the modulation of its function, to produce a favourable outcome in patients with dyslipidaemia.

Conclusion

Treatment modalities in the management of dyslipidaemia and the complications thereof are making tremendous leaps forward as medical technology advances. These new and novel approaches are now widening the net for individuals who require a greater reduction in serum lipid concentrations, and are also showing promise in patients who were previously unable to partake in first-line therapies owing to side-effects. The end goal that will hopefully be achieved with these exciting new strategies is to lower patientsâ&#x20AC;&#x2122; risk profile, while improving compliance by enhancing dose scheduling and reducing the side-effect profile of these treatments. It is our hope

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that the thirst for knowledge in combating dyslipidaemia will lead to a continued push toward technological advancement in this exciting field of medicine. Acknowledgements. None. Author contributions. Both authors contributed equally to this review. Funding. None. Conflicts of interest. None. 1. Phan BA, Dayspring TD, Toth PP. Ezetimibe therapy: Mechanism of action and clinical update. Vasc Health Manag 2012;2012(8):415-427. https://doi.org/10.2147/VHRM.S33664 2. Stein EA, Raal FJ. New therapies for reducing low density lipoprotein cholesterol. Endocrinol Metab Clin N Am 2014;43(4):1007-1033. https://doi.org/10.1016/j.ecl.2014.08.008 3. Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: A pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. Circulation 2016;134(4):1931-1943. https://doi.org/10.1161/circulationaha.116.024604 4. Navarese EP, Kolodzietjczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systemic review and meta analysis. Ann Intern Med 2015;163(1):40-51. https://doi.org/10.7326/m14-2957 5. Kastelein JJ, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK 9 ): A randomized, placebo controlled phase 2 study. Eur Heart J 2016;37(17):1360-1369. https://doi.org/10.1093/eurheartj/ehv707 6. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376(1):41-51. https://doi.org/10.1056/nejmoa1609243

7. Santos RD, Raal FJ, Catapino Al, et al. Mipomersen, an oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: Results of 4 phase 3 trials. Arterioscler Thromb Vasc Biol 2015;35(3):689-699. https://doi.org/10.1161/atvbaha.114.304549 8. Duell PB, Santos RD, Kirwan B-A, et al. Long term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol 2016;10(4):1011-1021. https://doi.org/10.1016/j.jacl.2016.04.013 9. HPS3/TIMI55-REVEAL Collaborative group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377(13):1217-1227. https://doi.org/10.1056/nejmoa1706444 10. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: A systematic review and meta-analysis. Lancet 2010;375(9729):1875-1884. https://doi.org/10.1016/S0140-6736(10)60656-3 11. Keech AC, Jenkins AJ. Triglyceride lowering therapies. Curr Opin Lipidol 2017;28(6):477-487. https:// doi.org/10.1097/mol.0000000000000465 12. Tikka A, Juahianinen M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 2016;52(2):187-193. https://doi.org/10.1007/s12020-015-0838-9 13. Cupido AJ, Reeskamp LF, Kastelein JP. Novel lipid modifying drugs to lower LDL cholesterol. Curr Opin Lipidol 2017;28(4):367-373. https://doi.org/10.1097/mol.0000000000000428 14. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a); a randomized double blind, placebo controlled phase 1 study. Lancet 2015;386(10002):1472-1483. https://doi.org/10.1016/s01406736(15)61252-1 15. Meyers CD, Tremblay K, Amer A, et al. Effect of DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015;14(1):8. https://doi.org/10.1186/s12944-015-0006-5 16. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol 2016;10(3):556-567. https://doi.org/10.1016/j.jacl.2015.12.025

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Laboratory investigations in lipidology J A Rusch, BSc, MB BCh; C L Hudson, MB ChB, FCPath Chem (SA); A D Marais, MB ChB, FCP (SA) Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa Corresponding author: A D Marais (david.marais@uct.ac.za)

Advances in the causes of disorders of lipid metabolism, and effective intervention in atherosclerosis with medication, have increased the reliance on laboratory investigation in clinical practice. The conventional lipid profile, comprising fasting triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, suffices for screening persons at risk of atherosclerosis. Additionally, lipoprotein (a) measurement enhances risk assessment and could explain atherosclerosis with a desirable lipid profile. Certain rare disorders in sterol and fatty acid metabolism do not alter the conventional lipid profile. Non-fasting samples are gaining popularity, as the triglycerides, although mildly increased, signify atherogenic lipoprotein remnant accumulation. Apoprotein A1 (apo A1) and apo B concentrations parallel HDL cholesterol and LDL cholesterol, respectively, and are of value in disorders of these lipoproteins. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell function, as well as genetic investigations, are relevant. The most important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. Expertise in lipidology is limited in South Africa, but specialist centres can provide clinical and laboratory support to ensure best management of severe disorders. S Afr Med J 2018;108(4):266-270. DOI:10.7196/SAMJ.2018.v108i4.13233

Although laboratory investigation is essential for diagnosis and management, it also introduces advances in science, thereby enhancing patient care. Investigations should not, however, strain limited resources. Modest changes in the lipid profile impact on atherosclerosis risk, and undesirable values, are highly prevalent in both sexes worldwide.[1] More extreme dyslipidaemias identify individuals at higher risk of atherosclerosis. Lipid disorders, including pancreatitis and metabolic disorders, should also be considered in other clinical settings. The purpose of this article is to provide the medical practitioner with an understanding of laboratory investigations in lipidology.

In animals they form fats. In plants they form oils, as unsaturated bonds confer liquid properties. Triglycerides are also synthesised in hepatocytes and adipocytes. During fasting, free FAs mobilise from adipocytes to the liver, which releases triglycerides and ketones as sources of energy.

Lipids

Sterols

Lipids are water-insoluble compounds including sterols (cholesterol) and fatty acids (FAs) (typically esterified as triglycerides and phospholipids). Lipids serve many functions in the cell: membrane formation, steroid hormone and bile acid production, and the provision and storage of energy. Lipids are transported as lipoproteins, but albumin transports non-esterified FAs.

Fatty acids

FAs are carboxylic acids comprising mostly saturated but also mono- or polyunsaturated carbon to carbon bonds. Short-chain (â&#x2030;¤6 C) and medium-chain (8 - 12 C) FAs are generally metabolised intracellularly. Long-chain (14 - 22 C) FAs are found in triglycerides and phospholipids. The latter influences inflammation and thrombosis through prostaglandins. Essential FAs (linoleic acid and alpha-linolenic acid) are sourced from plants. Plants also contain very-long-chain FAs and branch-chain FAs, which are metabolised in peroxisomes. Dietary FAs, as well as those generated in the gut microbiota, significantly influence health.[2]

Triglycerides

Triglycerides consist of three long-chain FAs esterified to glycerol.

Phospholipids

Phospholipids resemble triglycerides, but a terminal FA is substituted by a phosphate and choline, ethanolamine, serine or inositol. Phospholipids are the main structural component of cell membranes, coat lipoproteins and emulsify dietary fat.

Cholesterol is vital to animal cell membranes, functions in signalling during embryogenesis, and is the substrate for steroid hormone and bile acid (BA) synthesis. Cholesterol is absorbed from the diet or synthesised de novo by cells. Beta-hydroxy beta-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in biosynthesis, is upregulated by cholesterol depletion in cells and inhibited by statins. Oxysterols regulate sterol and other metabolic pathways, and may be found in atherosclerotic plaques. Precursor sterols and plant sterols (beta-sitosterol and campesterol), BAs and an intermediate product, cholestanol, occur in trace quantities in plasma. BAs, via signalling pathways, may also regulate glucose and lipid metabolism, and energy homeostasis. The enterohepatic circulation of BAs is disrupted in liver dysfunction, resulting in hypercholanaemia.

Lipoproteins

Lipoproteins are spherical particles comprising a core of triglycerides and cholesterol esters (CEs), and a surface of phospholipid and unesterified cholesterol (UC) in which apoproteins reside. Apoproteins facilitate lipoprotein assembly, modulation and clearance. Lipoproteins are classified by ultracentrifugation into

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five major types, with increasing density and decreasing size: chylomicrons (CMs), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and

high-density lipoprotein (HDL). The density of the particle depends on the lipid (less dense) and protein (denser) content. During fasting, VLDL carries the majority of triglyceride and LDL carries

Fatty acid

the majority of cholesterol. Circulating CMs after a meal raise triglyceride levels. In the circulation, lipoproteins undergo continuous modification in a flux through interconnected pathways (Fig. 1).

Lipoprotein (a) pathway

Exogenous pathway Apo (a)

CM C2

Size remodelling

CM remnant

LDL pathway

VLDL remnants

Reverse transport pathway

Endogenous pathway

Fig. 1. Lipoprotein metabolic pathways. Exogeneous pathway: after the intestinal absorption and assembly on apo B48 of dietary fatty acids and sterols, chylomicrons transport lipids to tissues and finally the liver. Endogeneous pathway: the liver assembles triglycerides and cholesterol on apo B100 in very low-density lipoprotein (VLDL) during fasting, with recycling of remnants. Low-density lipoprotein (LDL) pathway: the endogeneous pathway ends with the supply of cholesterol to tissues on demand through LDL-receptor expression. Reverse cholesterol transport pathway: moves cholesterol from cells to the liver either directly (scavenger receptor) or indirectly (VLDL) by cholesterol ester transfer protein. Apo A4 synthesised in enterocytes, as well as other apoproteins, assimilates in high-density lipoprotein. Lipoprotein (a) pathway: highly variable in humans. Albumin pathway: non-esterified fatty acid complex with albumin in plasma. (A1, A4, B48, B100, E = apoproteins; ABCA1 and ABCG5/G8 = ATP-binding casette transporter proteins; CE = cholesterol ester; CETP = cholesterol ester transfer protein; CM = chylomicron; FA = fatty acid; HSPG = heparan sulphate proteoglycans; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LCAT = lecithin:cholesterol acyl transferase; LPL = lipoprotein lipase; LDL = low-density lipoprotein; LDLR = LDL receptor; LDLRP = LDL receptor-like protein; NEFA = non-esterified fatty acid; SR = scavenger receptor B1; UC = unesterified cholesterol; VLDL = very low-density lipoprotein.)

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In the exogenous pathway, lipoprotein lipase (LPL), held on the vascular endothelium by heparan sulphate proteoglycans (HSPGs), hydrolyses triglycerides (in the presence of apoprotein C2 (apo C2)), releasing FAs and CM-remnants in the process. Excessive phospholipid on shrinking CMs can depart with apo A1, forming HDL. In the endogenous pathway, hepatocytes assemble triglycerides onto apo B100, forming VLDL. Similar to CMs, circulating VLDL undergoes lipolysis, resulting in remnants, while generating some HDL. These remnants, IDL, are cleared by the liver through apo E binding HSPG, LDL receptor-like protein (LRP) and the LDL receptor (LDLR). Some remnants are processed to LDL, on which apo B100, now the sole apoprotein, is in the correct conformation to bind the LDLR (expressed by cells that require cholesterol). HDL transports cholesterol in the reverse pathway, predominantly with apo A1, which assimilates phospholipid, but also apo A4 and apo E. Cells respond to apo A1 by releasing cholesterol and phospholipid through adenosine-binding cassette transporter protein (ABCA1). Lecithin:cholesterol acyl transferase (LCAT) enriches HDL with cholesterol by forming CE that moves to its core. CEs may be exchanged by cholesterol ester transfer protein (CETP) to triglyceride-rich lipoproteins, destined for the liver. HDL can also deliver CEs directly to the liver via scavenger receptor B1 (SR). Lipoprotein (a) (Lp (a)) resembles LDL but contains covalently bound apo (a). Being homologous to plasmin, it may impair thrombolysis, explaining its modest independent impact on atherosclerosis.

Laboratory investigations

Most lipidological investigation assesses cardiovascular disease (CVD) risk and monitors treatment response. Atherosclerosis is associated with increasing LDL and remnants and decreasing HDL concentrations. Hypertriglyceridaemia predicts pancreatitis. Less commonly, genetic disorders with severe dyslipidaemias may occur. Rarely, FAs and sterol disorders may be present without disturbing the conventional lipid profile.

Sampling

Approximately 3 mL of blood for routine analysis is collected in a plain tube (yellow- or red-capped) to analyse the serum lipids. CMs and VLDL scatter light and result in turbidity (triglyceride >2.5 mmol/L). Frank lipaemia indicates severe hypertriglyceridaemia (triglyceride >10 mmol/L). In effusions, cholesterol may differentiate transudates from exudates; triglyceride may indicate chylothorax.[3,4]

Routine investigations

Secondary causes for dyslipidaemias should be excluded or treated before full lipidological work-up (Table 1). Hypercholesterolaemia may be due to nephrotic syndrome or hypothyroidism. Hypertriglyceridaemia may be caused by alcohol or diabetes. The conventional profile comprises triglyceride, total cholesterol (TC) and HDL cholesterol, which are measured by enzymatic colorimetric assays, and LDL cholesterol, which can be calculated in fasting samples or measured directly. Cholesterol esterase ensures that cholesterol oxidase reacts with all cholesterol. In homogenous HDL cholesterol assays, dextran sulphate selectively forms watersoluble complexes with LDL, VLDL and CMs, which resist modified enzymes. Clinically insignificant differences are found in the TC and HDL cholesterol results of fasting or non-fasting individuals. Triglycerides are traditionally measured in the fasting state because the Friedewald equation (Box 1) will approximate the LDL cholesterol

Box 1. Friedewald equation to calculate LDLC (mmol/L) LDLC = TC â&#x2C6;&#x2019; HDLC â&#x2C6;&#x2019; (TG/2.2), where (TG/2.2) is an estimation of VLDLC LDLC = low-density lipoprotein cholesterol; TC = total cholesterol; HDLC = highdensity lipoprotein cholesterol; TG = triglyceride; VLDL = very low-density lipoprotein cholesterol.

when triglyceride values are Ë&#x201A;4.5 mmol/L, provided that remnants, Lp (a) and Lp X are absent. LDL cholesterol can be measured directly by homogenous assays or ultracentrifugation. TC results can vary in an individual by as much as 14% owing to factors such as stress, illness, posture, seasonal variation and interlab variability.[5] More than one TC measurement is advised when decisions are to be made in moderate dyslipidaemias. Even greater variability may be demonstrated by HDL cholesterol measurement.[6]

Extended lipid profile

Apo A1, apo B and Lp (a) are measured immunoturbidimetrically. Apo A1 is the major protein of HDL, whereas apo B is the major protein of LDL, accounting for 95% of plasma apo B. Apo B measurements are a surrogate for lipoprotein particle concentration (number). For the same LDL concentration, small LDL will have a larger particle number.[7] Strong associations between CVD and LDL particle number, or high concentrations of Lp (a), provide a rationale for advanced testing in CVD management.

Special investigations Electrophoresis

Routine ultracentrifugation is impracticable, but electrophoresis can demonstrate lipoprotein fractions in small sample volumes and remains useful for the diagnosis of several dyslipidaemias. The traditional agarose gels can diagnose Fredrickson type 1 (chylomicronaemia), type 3 (dysbetalipoproteinaemia), Lp X and sulphated cholesterol in X-linked ichthyosis. Lp X is an abnormal lipoprotein that is formed in cholestasis or LCAT deficiency. Deficiencies or absences of lipoproteins are also readily demonstrated. This includes abetalipoproteinaemia, hypobetalipoproteinaemia and Tangier disease (analphalipoproteinaemia). Non-denaturing polyacrylamide gel electrophoresis is less well established but discriminates LDL sizes and detects dysbetalipoproteinaemia well.[8] Small and dense LDL is associated with insulin resistance and diabetes, is more susceptible to oxidation and enters arterial walls more readily. CVD risk is increased twoto three-fold.[7,9,10] Nuclear magnetic resonance spectroscopy, density gradient ultracentrifugation and ion mobility analysis also characterise LDL further.

Genetic testing

Genotyping should be used judiciously and only where it impacts management. This includes preconception counselling and identifying carriers of severe recessive disorders. Genetic diagnosis, along with functional fibroblast studies, is warranted if homozygous familial hypercholesterolaemia (FH) is considered. With decreasing costs of sequencing and the future possibility of genome editing, genotyping may become routine.

Sterols

Unlike cholesterol, present in millimolar concentration, its precursors, products and plant analogues are only found at micromolar concentration in plasma. Non-cholesterol sterols are typically detected by gas chromatography-mass spectrometry (GC-MS) or GC-flame ionisation detection (GC-FID). Cholesterol biosynthetic

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CME

Table 1. Dyslipidaemias and dyslipoproteinaemias with their primary and secondary causes Lipid (mmol/L) TG 1.7 - 2.5

Lipoprotein (lipid) involved VLDL

TG 2.5 - 5.0

VLDL Âą IDL

TG 5.0 - 15.0 (often with hypercholesterolaemia)

VLDL, IDL Âą CM

TG >15.0 (usually with hypercholesterolaemia)

CM, VLDL

TC <2.0

LDL, VLDL, CM

TC 2.0 - 5.0 (atherosclerosis setting)

HDL (<0.7 mmol/L) Lp (a)

TC 2.0 - 5.0 (other clinical presentations)

TC 5.0 - 7.5

Unusual lipids VLCFA BCFA Cholesterol sulphate Cholestanol LDL (rarely HDL elevates TC)

TC 7.5 - 15.0

LDL

TC >15.0

LDL

Secondary causes Dysglycaemia Alcohol Obesity Corticosteroids Retinoids Dysglycaemia Alcohol Obesity Corticosteroids Retinoids Dysglycaemia Alcohol Obesity Corticosteroids Retinoids + genetic predisposition Genetic predisposition + metabolic stress

Acute-phase response Malnutrition Malabsorption Acute-phase response

Primary causes Polygenic variants (mild)

Monogenic variants (e.g. LPL deficiency) Polygenic variants (mild) Monogenic variants (e.g. LPL deficiency) Dysbetalipoproteinaemia Polygenic variants (mild) Monogenic variants (e.g. LPL deficiency) Dysbetalipoproteinaemia

Polygenic variants (mild) Monogenic variants (e.g. LPL deficiency), more commonly monogenic (LPL, apo C2 apo Av, LMF-1, GPI-HBP-1) Dysbetalipoproteinaemia Apo B truncations MTTP deficiency ABCA1, LCAT, apo A1 Genetic variants

Not applicable

Diet Hypothyroidism Nephrotic syndrome Lp X Lp X Nephrotic syndrome Hypothyroidism Lp X

Adrenoleukodystrophy Refsum disease X-linked ichthyosis CTX Polygenic Hyperalphalipoproteinaemia: CETP, apo C3, EL and SR-B1 deficiencies FH: LDL >5.0 mmol/L LDL-R, FDB and ARH, PCSK9 gain of function mutations Phytosterolaemia Homozygous FH, ARH Phytosterolaemia

TG = triglyceride; VLDL = very low-density lipoprotein; LPL = lipoprotein lipase; IDL = intermediate-density lipoprotein; CM = chylomicron; apo C2 = apolipoprotein C2; apo Av = apolipoprotein Av; LMF-1 = lipoprotein maturation factor 1; GPI-HBP-1 = glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1; TC = total cholesterol; LDL = lowdensity lipoprotein; apo B = apolipoprotein B; MTTP = microsomal triglyceride transfer protein; HDL = high-density lipoprotein; Lp (a) = lipoprotein (a); VLCFA = very-long-chain fatty acids; BCFA = branched-chain fatty acids; ABCA1 = ATP-binding cassette subfamily A member 1; LCAT = lecithin-cholesterol acyltransferase; apo A1 = apolipoprotein A1; CTX = cerebrotendinous xanthomatosis; Lp X = lipoprotein X; CETP = cholesteryl ester transfer protein; apo C3 = apolipoprotein C3; EL = endothelial lipase; SR-B1 = scavenger receptor class B type 1; FH = familial hypercholesterolaemia; LDLR = low-density lipoprotein receptor; FDB = familial defective apolipoprotein B; ARH = autosomal recessive hypercholesterolaemia; PCSK9 = proprotein convertase subtilisin/kexin type 9.

errors elevating levels of 7-dehydrocholesterol, lathosterol or desmosterol, should be considered in the setting of congenital malformations and impaired development. A spectrophotometric assay for 7-dehydrocholesterol is less expensive to diagnose SmithLemli-Opitz syndrome.[11] Markedly elevated levels of sitosterol and campesterol confirm phytosterolaemia, an autosomal recessive disorder mimicking FH. The adenosine triphosphate (ATP)-binding cassette sub-family G5 or G8 mutations prevent the excretion of plant sterols.

Cerebrotendinous xanthomatosis is an autosomal recessive disease caused by a deficiency of sterol 27-hydroxylase. Impaired BA synthesis is accompanied by increased formation of cholestanol. There may be massive tendon xanthomata, leukodystrophy and cataracts without significant dyslipidaemia. BA supplements can be of benefit because they suppress BA synthesis.

Fatty acids

Determining the profile of physiologically and nutritionally

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CME

important FAs is of limited use in clinical practice. However, certain rare peroxisomal disorders are diagnosed by identifying abnormal FAs. Very-long-chain FAs impair adrenal and neuronal function in X-linked adrenoleukodystrophy. In Refsum disease, branched-chain FAs accumulate, resulting in neurological, cutaneous and ophthalmic manifestations.

Enzyme analysis

Enzyme analysis is rarely required but can shed light on disease mechanisms and improve management. LPL deficiency is demonstrated in plasma by displacement of LPL from heparan sulphate proteoglycans on endothelial cells after heparin injection. The autosomal recessive disorder, characterised by marked hyperchylomicronaemia and a corresponding hypertriglyceridaemia, can be due to errors in LPL, its cofactors apo C2 and apo A5, or its transporters lipase maturation factor 1 and glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1 (GPI-HBP-1). If apo C2 is deficient, supplementation by fresh-frozen plasma can alleviate severe hypertriglyceridaemia and pancreatitis. Other enzyme studies of interest include LCAT activity in the setting of low HDL cholesterol, and lysosomal acid lipase in Wolman disease and CE storage disease. The latter presents as a mixed hyperlipidaemia with severe liver enzyme derangement, and responds to recombinant lysosomal acid lipase.

Cell culture

Fibroblast cultures are performed at few centres but may be crucial for diagnosis. The neurovisceral storage disorder, Niemann-Pick type C, sequesters cholesterol and glycosphingolipid in lysosomes. Filipin demonstrates the unesterified cholesterol, which cannot be processed, by fluorescence.[12] LDL uptake studies in fibroblasts can reflect LDL receptor function in homozygous FH and can predict the response to proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising monoclonal antibodies.

Discussion

This review addresses dyslipidaemia broadly to ensure recognition of a wide range of disorders. The majority of clinicians, however, will mainly manage persons at risk for atherosclerosis and pancreatitis. Clinical settings, in which specific lipid disorders should be recognised, are also briefly mentioned. The dyslipidaemias and dyslipoproteinaemias and their causes are summarised in Table 1.

Guidelines

Guidelines allow for reasonable practice based on CVD risk when serving the general population, but do not necessarily adequately advise on the management of severe genetic disorders. Every effort must be made to reach a diagnosis in the case of these disorders for best management decisions. This may involve referral to specialist centres.

Cost-effective testing

A full lipogram (TC, HDL cholesterol, LDL cholesterol and triglycerides), costing ~ZAR300, is recommended for the initial diagnosis of dyslipidaemia.[13] LDL cholesterol (ZAR110) or TC (ZAR80) alone can be used in the follow-up of patients with pure hypercholesterolaemia. A full lipogram is advocated for follow-up where increased LDL cholesterol is not the only abnormality in the lipid profile. Despite the proven use of these established tests in CVD risk prediction and management, the burden of CVD events remains high. Additional lipidologic (apo B) and inflammatory markers

(C-reactive protein) may aid in addressing borderline or residual risk. Guidelines differ in their application. Apo B measurement (ZAR130) estimates LDL particle number. Whether it is superior to non-HDL cholesterol or total/HDL cholesterol ratio for CVD risk prediction is controversial. More data are clearly needed on the use of advanced lipoprotein tests, as well as non-HDL cholesterol and total/HDL cholesterol ratio as targets of therapy for common dyslipidaemias.[13]

Referral criteria

Severe dyslipidaemias, unexplained cutaneous or tendon xanthomata, problematic management, premature atherosclerosis and suspected metabolic errors all constitute reasons for referral. Heterozygous FH should be considered if TC concentration is >7.5 mmol/L. Most patients respond to statin therapy, but poorly controlled patients may require additional treatment following specialist work-up. Extreme dyslipidaemias for referral and special investigation include: TC >15 mmol/L, LDL cholesterol >12 mmol/L and triglyceride >10 mmol/L, unusually low TC (<2.0 mmol/L), LDL cholesterol (<1.5 mmol/L) or HDL cholesterol (<0.7 mmol/L).[14] For severe atherogenic dyslipidaemias, or those causing pancreatitis, effective new treatment strategies have been developed. Specialist centres, where clinical and laboratory expertise converge, are important for recognition and accurate diagnosis. Increasing consideration of severe or unusual lipid disorders will drive a relevant diagnostic repertoire, clinical expertise and patient care for South Africa. Acknowledgements. None. Author contributions. All authors confirm that they have contributed to the intellectual content of this article and have met the following three requirements: (i) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (ii) drafting or revising the article for intellectual content; and (iii) final approval of the published article. Funding. None. Conflicts of interest. None. 1. World Health Organization. Global health observatory data. http://www.who.int/gho/ncd/risk_ factors/cholesterol_mean_text/en/ (accessed 3 January 2018). 2. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012;489(7415):242-249. https://doi.org/10.1038/nature11552 3. McGrath EE, Blades Z, Anderson PB. Chylothorax: Aetiology, diagnosis and therapeutic options. Respir Med 2010;104(1):1-8. https://doi.org/10.1016/j.rmed.2009.08.010 4. Heffner JE, Sahn SA, Brown LK. Multilevel likelihood ratios for identifying exudative pleural effusions. Chest 2002;121(6):1916-1920. https://doi.org/10.1378/chest.121.6.1916 5. Cooper GR, Myers GL, Smith SJ, Schlant RC. Blood lipid measurements. Variations and practical utility. JAMA 1992;267(12):1652-1660. https://doi.org/10.1016/0020-7292(92)90669-a 6. Bachorik PS, Cloey TA, Finney CA, Lowry DR, Becker DM. Lipoprotein-cholesterol analysis during screening: Accuracy and reliability. Ann Intern Med 1991;114(9):741-747. https://doi. org/10.7326/0003-4819-114-9-741 7. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation 1997;95(1):69-75. https://doi.org/10.1161/01.cir.95.1.69 8. Blom DJ, Byrnes P, Jones S, Marais AD. Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia. J Lipid Res 2003;44(1):212-217. https://doi.org/10.1194/ jlr.d200013-jlr200 9. Koba S, Hirano T. Small dense low-density lipoprotein in Japanese men with coronary artery disease. Ann Intern Med 2000;132(9):762. https://doi.org/10.7326/0003-4819-132-9-200005020-00024 10. St-Pierre AC, Ruel IL, Cantin B, et al. Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease. Circulation 2001;104(19):22952299. https://doi.org/10.1161/hc4401.098490 11. Solomon GAE, Jones G, de Jong G, Marais AD. Biochemical and genetic diagnosis of Smith-LemliOpitz syndrome in South Africa. S Afr J Child Health 2015;9(1):23-26. https://doi.org/10.7196/ sajch.771 12. Bornig H, Geyer G. Staining of cholesterol with the fluorescent antibiotic ‘filipin’. Acta Histochem 1974;50(1):110-115. 13. Mora S. Advanced lipoprotein testing and subfractionation are not (yet) ready for routine clinical use. Circulation 2009;119(17):2396-2404. https://doi.org/10.1161/circulationaha.108.819359 14. Klug EQ, Raal FJ, Marais AD, et al. South African dyslipidaemia guideline consensus statement. S Afr Fam Pract 2015;57(2):22-31. https://doi.org/10.1080/20786204.2013.10874296

Accepted 5 March 2018.

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

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CLINICAL ALERT

A proposed management algorithm for late-onset efavirenz neurotoxicity H M Cross, MB ChB, MSc, Dip HIV Man (SA), FC Neurol (SA); S Chetty, MB ChB; M T Asukile, BSc, MB ChB; H S Hussey, MB ChB; E B Lee Pan, MB ChB, MMed (Neurol); L M Tucker, MB ChB, MSc, FCP (SA), PhD Division of Neurology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: L M Tucker (lmaskewtucker@gmail.com) A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases. S Afr Med J 2018;108(4):271-274. DOI:10.7196/SAMJ.2018.v108i4.12914

Since September 2016, all individuals in South Africa (SA) who are diagnosed as HIV-positive are immediately eligible for antiretroviral therapy (ART), regardless of CD4+ count. The current preferred first-line regimen is a fixed-dose combination tablet comprising three antiretroviral agents, including efavirenz (EFV).[1] Isoniazid (INH) is being increasingly used as tuberculosis (TB) prophylaxis, especially in HIV-positive individuals. This means that a high proportion of patients in SA are likely to be receiving concomitant EFV and INH therapy. We need to be aware of potential medication-related toxicity syndromes, especially in the context of polypharmacy. EFV is a non-nucleoside reverse transcriptase inhibitor that is metabolised in the liver via the cytochrome p450 system, predominantly via CYP2B6.[2,3] It has a long half-life and is therefore prescribed as a once-daily dose of 600 mg. However, genetic differences in the pharmacokinetics of EFV are increasingly being recognised.[2] EFV is well known to cause neuropsychiatric side-effects. These typically occur (in ~40% of cases) on initiation of the drug, but are usually mild and self-limiting within the first few weeks of exposure.[4] A paediatric case series has described late-onset neurotoxicity associated with toxic EFV levels in the form of subacute ataxia in children treated with EFV-containing antiretroviral regimens for more than a year.[5] A more recent case series from Klerksdorp, SA,[6] described late-onset ataxia and encephalopathy in adult patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. These patients were all female with low body weight. Possible reasons proposed for susceptibility to EFV neurotoxicity included low body weight and polymorphism of the liver enzyme CYP2B6, which is known to result in slowed metabolism of the drug.[7] Two common polymorphisms in CYP2B6 (516G>T and T983C) slow EFV metabolism and have been shown to occur with increased frequency in people with black African genetic

ancestry.[3,8] These polymorphisms probably also play a role in the acute toxicity, and a case of new-onset psychosis following recent initiation of EFV has been described in the context of confirmed CYP2B6 516G>T polymorphism.[9] INH is also metabolised in the liver via the cytochrome p450 system. It inhibits the CYP2A6 enzyme. Although a small proportion of EFV is normally metabolised via this enzyme, this pathway may have a more important role in slow metabolisers with polymorphisms affecting CYP2B6. Concomitant INH use therefore affects plasma levels of EFV, especially in slow metabolisers. This has previously been noted in a pharmacodynamic study.[10,11] INH has also been independently associated with neuropsychiatric effects, occurring a median of 21 days after initiation of treatment.[12,13] We have noted a recent increase in cases of EFV toxicity presenting to our tertiary neurology referral unit in the Western Cape Province, SA, over a relatively short period of time. All the cases occurred in the context of recent initiation of concomitant INH treatment. We therefore conducted a retrospective case record audit to describe these cases of late-onset EFV toxicity. We outline the clinical details (history and examination) and the results of investigations (laboratory results, electroencephalogram (EEG) findings, imaging and neuropsychological assessments), as well as outcomes after EFV was stopped. Comprehensive investigation is often undertaken in HIV-positive patients with impaired cognition and cerebellopathy, because the differential diagnosis is wide and some of these conditions could deteriorate significantly during the period in which EFV is withdrawn. Our main objectives are to highlight the probable role of concomitant use of INH in the development of this syndrome, and to suggest that where a diagnosis of EFV toxicity is strongly suspected, only limited work-up may be warranted. Cases are defined as individuals presenting to the Groote Schuur Hospital neurology services with subacute neurological signs and

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symptoms, confirmed toxic levels of EFV, and no other cause found for their presentation. The study was approved by the University of Cape Town Human Research Ethics Committee (ref. no. 603/2017).

Results

A typical case is that of a 37-year-old woman, originally from Lesotho, known to be HIV-positive (CD4+ count >500 cells/µL, viral load <20 copies/mL) who had been on ART (tenofovir/emtricitabine/ efavirenz) for 5 years. Concomitant INH prophylaxis was initiated 1 month prior to symptom onset. She was admitted after developing subacute, progressive confusion and an unsteady gait over the course of 1 month. On examination she appeared systemically well, but neurological examination confirmed that she was disorientated with psychomotor slowing, poor attention and blunted affect. Primitive reflexes were not elicited. The findings on cranial nerve examination were normal. Motor examination revealed normal tone and reflexes and full power. Sensation was normal. Co-ordination was abnormal, and she had horizontal- and upward-gaze nystagmus with left-sided dysmetria, bilateral intention tremor and abnormal heel-shin tests. Marked truncal ataxia with a broad-based ataxic gait was also noted. On investigation, basic blood work-up including a CD4+/CD8+ ratio, thyroid-stimulating hormone (TSH) and vitamin B12 were normal. Syphilis serology (TPAb) was negative. Liver enzymes, a hepatitis screen, ammonia levels and an abdominal ultrasound scan were normal. Cerebrospinal fluid (CSF) analysis confirmed normal basic parameters, and a cryptococcal latex antigen test, tuberculosis GeneXpert assay and JC virus polymerase chain reaction were negative. Neither computed tomography (CT) nor magnetic resonance imaging (MRI) of the brain revealed significant abnormalities. Two EEGs revealed generalised, high-amplitude, rhythmical, moderate (predominantly theta) slowing consistent with encephalopathy. Plasma EFV levels were toxic (>20 mg/L; normal therapeutic range 1 - 4 mg/L). EFV and INH were immediately withdrawn (and EFV substituted with lopinavir/ritonavir (LPV/r). The patient also initially received highdose parenteral thiamine, with little effect. Initial clinical improvement was noted at the time of discharge (12 days after admission). At follow-up 3 months later she showed marked improvement. She was living independently and seeking employment. Her affect was appropriate without psychomotor slowing. Montreal cognitive assessment screen was normal. Cerebellar examination was normal except for a subtle persisting intention tremor affecting her nondominant hand. A repeat EEG was normal. A total of seven adult women with southern African ancestry presenting with subacute encephalopathy and cerebellar ataxia were identified between May 2017 and August 2017. All had been exposed to INH, either prophylactically or as part of TB treatment. Six of the seven women were HIV-positive with a suppressed viral load. One patient was HIV-negative but was prescribed both EFV-containing ART and INH at a community clinic following what appears to have been a false-positive HIV test.

The clinical picture was similar in all these cases, with marked truncal and gait ataxia and psychomotor slowing, resulting in severe functional impairment and inability to walk unaided. Four patients had nystagmus with abnormal smooth pursuit and saccadic overshoot. Two women exhibited additional mood and psychotic symptoms prior to the encephalopathic, ataxic presentation. One woman initially presented with psychosis and was admitted to the psychiatric ward before being referred for neurological assessment. The other woman initially presented with and was treated for depression as an outpatient (in hindsight this may have been a misdiagnosis of psychomotor slowing). Further characteristics of the included patients are summarised in Tables 1 and 2. All the cases were investigated according to our neurology division practice. Blood tests included TSH, vitamin B12, TPAb, CD8+ count, liver function tests and ammonia levels. All the women had toxic plasma EFV levels (>20 mg/L). CSF was sampled in all cases and found to be normal (including JC virus/FTA-ABS/TB GeneXpert). CT and MRI brain imaging were performed in all cases. Two patients had non-contributory findings (one an old basal ganglia infarct and the other a left parietal FLAIR white-matter hyperintensity of undetermined significance on MRI). EEG, performed in all cases, revealed distinct, moderately high amplitude, rhythmical, generalised (predominantly theta) slowing (except for one case in which the slowing was irregular). Formal neuropsychological assessments were performed in five cases. These yielded uniform findings of predominantly dysexecutive deficits and psychomotor slowing consistent with frontal lobe subcortical dysfunction. All the women showed marked initial improvement in cerebellar and cognitive function a median of 14 days after EFV withdrawal.

Discussion

We have described a series of seven women on EFV-based ART with concomitant INH, who presented with a syndrome of subacute encephalopathy and cerebellopathy with toxic plasma EFV levels. The encephalopathy included disorientation and psychomotor retardation of varying severity, and psychosis in one case. Cerebellar dysfunction ranged from mild truncal ataxia to florid pan-cerebellar Table 2. Characteristics of the patients Characteristics Age (yr), median (IQR) Weight (kg), median (IQR) CD4+ (cells/µL), median (IQR) Duration of ART (mo), median (IQR) Duration of TB treatment before onset of symptoms (mo), median (IQR) Duration of INH prophylaxis before onset of symptoms (mo), median (IQR)

43 (36 - 47) 59 (55 - 62) 353 (324 - 462) 34 (17 - 48) 3.5 (2.75 - 4.25) 6 (2 - 9)

IQR = interquartile range; ART = antiretroviral therapy; TB = tuberculosis; INH = isoniazid.

Table 1. Clinical characteristics of cases Cerebellar signs Neuropsychiatric signs/symptoms EEG generalised rhythmical slowing abnormality Days to initial improvement (median 14)

Case 1 +++ +++ ++ 12

Case 2 ++ +++ ++ 21

Case 3 +++ +++ ++ 21

+ = mild; ++ = moderate; +++ = severe; EEG = electroencephalogram.

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Case 4 + ++ ++ 16

Case 5 +++ +++ ++ (irregular) 10

Case 6 + + ++ 10

Case 7 ++ +++ ++ 10

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dysfunction, including nystagmus. All the patients were virally suppressed with relatively well-preserved CD4+ counts (one patient was HIV-negative) and an otherwise negative diagnostic work-up. The patients all showed improvement within 14 days of EFV withdrawal, strengthening the hypothesis that drug toxicity was responsible. Our patients were all women of southern African genetic ancestry with an age range of 30 - 55 years. Patients described previously in a similar case series were also all women.[6] It is unclear whether the proposed mechanism of EFV toxicity (resulting from slow meta bolism of EFV due to polymorphisms of cytochrome CYP2B6)[2,7,14] may have a sex predilection, as previous studies assessing this have yielded conflicting results.[2,7,14] Some researchers suggest that non-Caucasian females are at high-risk for toxicity even after correcting for age and body weight.[14] Factors such as differences in compliance and healthseeking behaviour between men and women may also play a role. There are almost twice as many women (compared with men) on ART in SA,[15] and women have higher rates of adherence to ART.[15,16] Our patients all had considerable (asymptomatic) exposure to ART prior to presentation (although this varied widely from 5 months to 4 years), qualifying our definition of ‘late-onset’ EFV toxicity. Our patients had all recently been commenced on INH (either in the form of prophylaxis or as part of TB treatment) with an average of 3 months’ INH use prior to symptom onset. This implies a temporal relationship between INH commencement (in the context of EFV use) and onset of symptoms. While we did consider the possibility that INH toxicity might be the cause of the symptoms, we concluded that the EFV was more likely to be causative given the clinical improvement observed in two patients in whom INH was continued after withdrawal of EFV. Furthermore, limited studies of INHinduced cerebral toxicity document earlier onset of symptoms (mean 21 days). [11,13] We were unable to measure INH blood levels in our patients. Unlike a similar case series of EFV toxicity,[6] our patients had an average body weight of 55 kg, with none weighing less than 40 kg. They all received the recommended dose of EFV (600 mg/d). A lower dose of EFV (400 mg/d) has been shown to be non-inferior to 600 mg/d in terms of viral suppression,[17] and it has been suggested that this lower dose may reduce the risk of toxicity in underweight individuals. We are unable to comment on whether toxic EFV levels may be found in asymp

tomatic individuals, as EFV levels are not routinely measured as part of therapeutic drug monitoring.[18] Based on our observations, we have proposed an algorithm (Fig. 1) for the clini cal management of patients presenting with possible EFV-induced late-onset ataxia. It is important that systemic diseases first be excluded. Red flags of older age, low CD4+ count and pyrexia make EFV toxicity less likely, and an alternative diagnosis should be more actively sought. However, once systemic diseases have been excluded, and if both the CSF and CT brain scan are normal, we propose that it could be appropriate to wait for the results of the EFV levels and not investigate the patient further while the levels are pending. This would reduce the costs of investigation and unnecessary transfer of patients to higher-level care facilities. Once there is a suspicion of EFV toxicity, the drug should be discontinued immediately. Alternatives such as nevirapine, LPV/r or dolutegravir can be used, depending on the patient’s viral load and clinical profile, including the presence of comorbid TB. EEG is not required to make the diagnosis, but is useful in cases where it is clinically

History

Clinical examination

Exclude systemic illness

difficult to distinguish encephalopathy from psychiatric disorders. This is a report of only a few cases observed at a single neurology referral centre, and the conclusions that can be drawn are therefore limited. We were not able to determine INH levels or EFV metaboliser genotype. Our observations do, however, corroborate those described in a similar group of patients.[6] We would also like to highlight the likely role of INH in precipitating this syndrome, and in our experience low body weight is not a necessary factor. The findings from this report support consideration of the removal of EFV as first-line treatment for HIV in SA. In the interim, clinicians need to be aware of the potential for the development of this syndrome in patients on EFV, especially those concomitantly managed with INH. Acknowledgements. We thank Prof. Gary Maartens and Dr Isma-eel Ebrahim of the Groote Schuur Hospital Division of Clinical Pharmacology for their advice and input. Author contributions. HMC, SC, MTA, HSH and EBLP designed the study and reviewed all the drafts. HMC, SC, MTA and HSH compiled the patient data and wrote various sections of

• EFV-containing ART ± INH • Sub-acute onset

• Ataxia • Encephalopathy

}

RED FLAGS • Age >60 yr • CD4+ <200 cells/µL • Pyrexia • ?Men*

Consider checking: • TPA, TSH • LFTs and ammonia • Vitamin B12, thiamine

• Contrasted CT brain • LP

No cause for presentation found

CT, LP abnormal

• EFV level • Switch to non-EFV-containing ART

EFV toxicity less likely

Await EFV level; consider down-referral/discharge

Patient clinically improves <2 weeks

EFV level non-toxic

Consider: MRI brain, JCV, CD8+ count, malignancy screen, tertiary hospital referral

Fig. 1. Algorithm for the clinical management of suspected EFV neurotoxicity. (EFV = efavirenz; ART = antiretroviral therapy; INH = isoniazid; TPA = treponemal antibodies; TSH = thyroidstimulating hormone; LFTs = liver function tests; CT = computed tomography; LP = lumbar puncture; MRI = magnetic resonance imaging; JCV = JC virus polymerase chain reaction. *All previously described adult cases are women, although numbers are limited.)

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the paper. LMT assisted with final editing. All authors were involved in the management of the patients. Funding. None. Conflicts of interest. None. 1. Meintjes G, Moorhouse MA, Carmona S, et al. Adult antiretroviral therapy guidelines 2017. South Afr J HIV Med 2017;18(1):2078-6751. https://doi.org/10.4102/sajhivmed.v18i1.776 2. Arab-Alameddine M, di Iulio J, Buclin T, et al. Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. Clin Pharmacol Ther 2009;85(5):485-494. https:// doi.org/10.1038/clpt.2008.271 3. Sinxadi PZ, Leger PD, McIlleron HM, et al. Pharmacogenetics of plasma efavirenz exposure in HIVinfected adults and children in South Africa. Br J Clin Pharmacol 2015;80(1):146-156. https://doi. org/10.1111/bcp.12590 4. Apostolova N, Funes HA, Blas-Garcia A, Galindo MJ, Alvarez A, Esplugues JV. Efavirenz and the CNS: What we already know and questions that need to be answered. J Antimicrob Chemother 2015;70(10):2693-2708. https://doi.org/10.1093/jac/dkv183 5. Hauptfleisch MPK, Moore DP, Rodda JL. Efavirenz as a cause of ataxia in children. S Afr Med J 2015;105(10):876-877. https://doi.org/10.7196/SAMJnew.8780 6. Variava E, Sigauke FR, Norman J, et al. Brief Report: Late efavirenz-induced ataxia and encephalopathy: A case series. J Acquir Immune Defic Syndr 2017;75(5):577-579. https://doi.org/10.1097/ qai.0000000000001451 7. Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G>T polymorphism, increased plasma efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther 2010;7(1):32-41. https://doi.org/10.1186/1742-6405-7-32 8. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: An Adult AIDS Clinical Trials Group study. AIDS 2004;18(18):2391-2400. 9. Hasse B, Günthard HF, Bleiber G, Krause M. Efavirenz intoxication due to slow hepatic metabolism. Clin Infect Dis 2005;40(3):e22-e23. https://doi.org/10.1086/427031

10. McIlleron HM, Schomaker M, Ren Y, et al. Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype. AIDS 2013;27(12):1933-1940. https://doi.org/10.1097/qad.0b013e328360dbb4 11. Court MH, Almutairi FE, Greenblatt DJ, et al. Isoniazid mediates the CYP2B6*6 genotypedependent interaction between efavirenz and antituberculosis drug therapy through mechanismbased inactivation of CYP2A6. Antimicrob Agents Chemother 2014;58(7):4145-4152. https://doi. org/10.1128/aac.02532-14 12. Bhattacharyya S, Darby RR, Raibagkar P, Gonzalez Castro LN, Berkowitz AL. Antibiotic-associated encephalopathy. Neurology 2016;86(10):963-971. https://doi.org/10.1212/wnl.0000000000002455 13. Peter P, John M. Isoniazid-induced cerebellitis: A disguised presentation. Singapore Med J 2014;55(1):e17-e19. https://doi.org/10.11622/smedj.2013188 14. Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: The effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006;61(2):148-154. https://doi.org/10.1111/j.13652125.2005.02536.x 15. Shisana O, Rehle T, Simbayi L, et al. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Cape Town: HSRC Press. 2014. 16. Heestermans T, Browne JL, Aitken SC, Vervoort SC, Klipstein-Grobusch K. Determinants of adherence to antiretroviral therapy among HIV-positive adults in sub-Saharan Africa: A systematic review. BMJ Glob Health 2016;1(4):e00125. https://doi.org/10.1136/bmjgh-2016-000125 17. Puls R, Amin J, Losso M, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebocontrolled, non-inferiority trial. Lancet 2014;383(9927):1474-1482. https://doi.org/10.1016/s01406736(13)62187-x 18. Nettles RE, Kieffer TL, Parsons T, et al. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 2006;42(8):11891196. https://doi.org/10.1086/501458

Accepted 14 November 2017.

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CLINICAL UPDATE

The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD; S M Bennji,1 MD, FCP (SA), MMed (Int); E Boer,1 MB ChB; P T Schubert,2 MB ChB, FCPath (Anat) (SA), MMed (Anat Path), MSc Med Sc (Cytopath), MPhil (Paed Path); J A Shaw,1 MB ChB, FCP (SA), MMed (Int); B W Allwood,1 MB ChB, FCP (SA), MPH, Cert Pulmonology (SA), PhD; E M Irusen,1 MB ChB, FCP (SA), PhD Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 2 Division of Anatomical Pathology, Department of Pathology, Tygerberg Academic Hospital, National Health Laboratory Service and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1

Corresponding author: C F N Koegelenberg (coeniefn@sun.ac.za) Background. Malignant pleural effusion (MPE) represents a very common cause of pleural exudates, and is one of the most challenging pleural disorders to manage. This could be attributed to the paucity of high-quality experimental evidence, and inconsistent practice worldwide. South Africa (SA) currently has no data regarding the aetiology of MPE. Objectives. To identify the most common malignancies causing MPE in a population served by a large tertiary hospital in SA, and specifically the relative contribution of mesothelioma. A secondary objective was to evaluate the efficacy of chemical pleurodesis in a subset of patients. Methods. We retrospectively included all known cases of MPE evaluated at our institution over a 3-year period with a tissue diagnosis of MPE. Results. The most common causes of MPE in a total of 274 patients were lung cancer (n=174, 63.5%), breast cancer (n=32, 11.7%), unknown primary (n=22, 11.7%) and mesothelioma (n=27, 9.9%). Talc pleurodesis was performed in 81 of 194 patients (41.8%) referred to our division, and was radiologically successful in 22 of 25 (88.0%) followed up to 3 months. Conclusions. The main cause of MPE in our setting was lung cancer, followed by breast cancer, unknown primary and mesothelioma. Chemical pleurodesis was a viable palliative measure for MPE in this population. S Afr Med J 2018;108(4):275-277. DOI:10.7196/SAMJ.2018.v108i4.12914

Malignant pleural effusion (MPE) not only represents a very common cause of pleural exudates, but is also one of the most challenging pleural disorders to manage, given the paucity of highquality evidence and the heterogeneity of practice worldwide.[1,2] Between 30% and 50% of all patients with metastatic malignancies will have pleural involvement at autopsy, and approximately half of these will have pleural effusions, which range from insignificant to massive.[2,3] MPE may complicate most malignancies, although lung and breast cancer remain the most common causes.[2] Evidence suggests that MPE is most often caused by haematogenous spread of malignant cells to the visceral pleura with secondary seeding to the parietal pleura.[4] MPE generally signifies incurable disease with a poor prognosis.[2] Median survival is ~3 - 12 months, but can vary significantly according to cell type, performance status of the patient, staging and whether a chemosensitive malignancy is present.[2] The two most common non-surgical interventions are intercostal drainage (ICD) with pleurodesis to obliterate the pleural space, or indwelling pleural catheters (IPCs) that provide continuous drainage of the pleural cavity and may potentially cause autopleurodesis.[2,5] We previously showed that adenocarcinoma had surpassed squamous cell carcinoma as the predominant cell type in lung cancer patients in our setting, which is in keeping with international trends. [6,7] To the best of our knowledge, there are no data regarding the aetiology of MPE for either the Western Cape Province or South Africa (SA).

Objectives

The primary objective of this study was to identify the most common pleural malignancies leading to MPE in the population served by a large tertiary hospital in the Western Cape, and specifically the relative contribution of mesothelioma. The secondary objective was to evaluate the radiological efficacy of chemical pleurodesis, which was offered to selected patients.

Methods

Study design and population

We retrospectively identified and included all known cases of MPE, defined as malignant cells present on pleural fluid analysis or pleural biopsy, that were managed at our institution from January 2014 to December 2016. We identified: (i) cases managed by the Division of Pulmonology at Tygerberg Academic Hospital; and (ii) all other known cases (not referred to our division) with a cytological or histological diagnosis of MPE made by the Division of Anatomical Pathology, Tygerberg Academic Hospital, National Health Laboratory Service (NHLS). Tygerberg Academic Hospital is a 1 380-bed facility in Cape Town, SA. It is one of two referral centres in the city and renders a tertiary service to a population of ~3.0 million people. We used the hospitalâ&#x20AC;&#x2122;s existing lung cancer registry to identify all cases of pleural malignancy presented at the lung cancer board meeting as well as the theatre records to identify any potential patients who underwent pleural procedures related to MPE. We also searched the NHLS records to specifically identify all other cases that

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were not managed by the division. Duplicate entries were removed if encountered.

Ethics approval

The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and local and international good clinical practice guidelines. Ethical approval was obtained from the Health Research Ethics Committee of Stellenbosch University (ref. no. S15/10/233).

Primary diagnoses and further analyses

Primary underlying diagnoses were based on confirmatory cytology/ histology with definitive imaging and/or immunohistochemistry/ immunocytochemistry profiling of malignant cells, or a known history of active extrapleural malignancy (with proven spread to the pleura).

Imaging

We categorised the size of pleural effusion on the chest radiograph into three categories: small (less than one-third of the hemithorax), moderate (one-third to two-thirds of the hemithorax) and large (more than two-thirds of the hemithorax). Computed tomography scans, when available, were reviewed and evaluated for pleural thickening (defined as ≥10 mm) and nodularity of both visceral and parietal layers, diaphragmatic thickening (defined as a diaphragmatic diameter >7 mm), and liver metastasis. Table 1. The causes of malignant pleural effusion (N=274) Causes Primary

Tissue type Mesothelioma Other

n (%) 27 (9.9) 0

Secondary

Lung Adenocarcinoma Squamous cell NSCLC – non-specified Undifferentiated/large cell SCLC Breast Unknown primary Gynaecological Gastrointestinal Lymphoma Other*

174 (63.5) 115 (66.1) 15 (8.6) 20 (11.5) 3 (1.7) 21 (12.1) 32 (11.7) 22 (8.0) 9 (3.3) 3 (1.1) 3 (1.1) 4 (1.5)

NSCLC = non-small-cell lung cancer; SCLC = small-cell lung cancer. *Skin cancer (n=1), prostate cancer (n=1), sarcoma (n=1), renal cell carcinoma (n=1).

Pleurodesis

Pleurodesis was routinely offered to patients with symptomatic MPE, provided they experienced relief of dyspnoea after thoracentesis, had no trapped lung and had a predicted life expectancy of >3 months. Patients who underwent chemical pleurodesis using talc slurry were identified from the division’s records, and the radiological success rate at 3-month follow-up was documented. Successful pleurodesis was defined as lack of reaccumulation of pleural fluid collection.

Statistical analysis

Descriptive statistics and χ2 comparisons of proportional data were performed. A p-value <0.05 in a two-tailed test of proportions (χ2) was considered significant. The data were presented as means (standard deviation (SD)).

Results

A total of 274 cases (mean age 59.3 (SD 12.5) years, 123 males) of MPE were identified: 194 from the division’s records (an average of 65 per year) and a further 80 from the NHLS database. The primary underlying diagnoses are summarised in Table 1, with the most common being lung cancer (n=174, 63.5%), breast cancer (n=32, 11.7%, malignant mesothelioma (n=27, 9.9%) and unknown primary (n=22, 11.7%). Table 2 provides a summary of the radiological findings. The size of pleural effusion in patients with mesothelioma was mainly large (n=11, 52.3% of all mesothelioma patients), followed by moderate (n=7, 33.3%) and small (n=3, 14.2%). In lung cancer, the size was approximately equally spread from small to large. In breast cancer, moderate-sized effusions (n=12, 46.1%) were the most common. Pleural thickening and nodularity in mesothelioma were parietal (n=11, 52.3%) and visceral (n=9, 42.8%). Chemical pleurodesis was performed in 81 of 194 cases (41.8%) managed by our division, and was successful in 22 (88.0%) of 25 patients followed up at 3 months.

Discussion

In our patient population, the most common causes of MPE were lung cancer (63.5%), breast cancer (11.7%), unknown primary (11.7%) and mesothelioma (9.9%). In patients who were offered chemical pleurodesis and followed up for at least 3 months, pleurodesis was successful in nearly 90%. Our findings are in line with international trends, with the one exception being the relatively small proportion of lymphomas.[2] This is surprising, given the relatively high prevalence of HIV infection in our population and the known association between HIV and lymphomas.[8] Possible explanations may include lack of referral

Table 2. Radiological features of malignant pleural effusion (N=194), %

Mesothelioma Lung Adenocarcinoma Squamous cell Undifferentiated SCLC Breast Other

Size of pleural effusion <1/3 1/3 - 2/3 >2/3 14.2 33.3 52.3

Pleural thickening or nodularity Visceral Parietal 42.8 52.3

Diaphragmatic thickening >7 mm 28.5

Liver metastasis 9.5

25.0 33.3 27.7 27.7 23.0 12.5

11.3 6.6 11.1 22.2 3.8 12.5

2.2 6.0 0 0 3.8 12.5

29.1 26.6 16.6 27.7 26.9 12.5

38.6 33.3 44.4 61.1 46.1 50.0

36.3 33.3 27.7 11.1 30.7 37.5

11.3 20.0 11.1 0 11.5 12.5

SCLC = small-cell lung cancer.

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from outside doctors, owing to misdiagnoses as pleural tuberculosis or presumptive diagnoses of pleural involvement in patients known to have lymphoma and imaging compatible with pleural spread (e.g. positive positron emission tomography-computed tomography). We also did not observe a female predominance as is sometimes reported,[9] arguably because in our cohort breast cancer was only responsible for just over 10% of MPEs. The fact that 1 in 10 MPEs were in patients with malignant mesothelioma, almost a decade after asbestos was finally banned in SA, remains a significant finding.[10] The latency period after exposure to asbestos is known to be very prolonged, with almost all cases seen ≥15 years after exposure.[11] Moreover, the estimated median latent period is at least 30 years after the initial exposure.[11] The incidence of mesothelioma peaked around 2015 in the UK, but in contrast may continue to increase in resource-limited settings secondary to poor regulation of industrial and household utilisation of asbestos.[12] Mesothelioma is therefore expected to continue to account for a significant proportion of MPE in our setting for at least another two to three decades. The two most common approaches to MPE are IPCs or chemical pleurodesis via rigid or semirigid thoracoscopy or ICD.[2] IPCs were only introduced to our service in the latter half of 2015, and pleurodesis was therefore the most common form of palliation offered for dyspnoea during the study period. The proportion of patients offered pleurodesis (41.8%) as well as the 3-month radiological success rate of 88.0% are on par with reported figures, which generally range from 30% to 50% and from 75% to 90%, respectively.[9]

Study strengths and limitations

One of the strengths of our study is the fact that we did not limit our cohort to patients referred to our unit. We anticipated that a significant proportion of patients would be managed by other disciplines, which proved to be the case in 80 of 274 cases. An obvious limitation is the retrospective nature of the study and possible selection bias, as patients with advanced malignancy may have been referred directly for palliative care, without further investigations. Further, loss to follow-up in the pleurodesis group limits the conclusions with regard to the apparent high success rate of chemical pleurodesis. Our sample size was restricted to cases seen over a 3-year period, which could limit the general applicability of our findings to the greater SA context.

Conclusions

We identified that the main cause of MPE was lung cancer, followed by breast cancer, unknown primary and mesothelioma. The proportion of mesothelioma cases was both surprising and concerning. Chemical pleurodesis appears to be a viable palliative measure for MPE in our population. Acknowledgements. We thank Ms Greta Neethling, who aided in identifying all cases of MPE from the NHLS database. Author contributions. CFNK initiated the study, analysed the data and wrote the manuscript. SMB, EB, PTS, JAS and BWA assisted with the study design and data collection, and edited the manuscript. EMI critically reviewed the data analysis and edited the final draft of the manuscript. Funding. None. Conflicts of interest. None.

1. Heffner J, Klein J. Recent advances in the diagnosis and management of malignant pleural effusions. Mayo Clin Proc 2008;83(2):235. https://doi.org/10.4065/83.2.235 2. Azzopardi M, Porcel MJM, Koegelenberg CFN, Lee YCG, Fysh ETH. Current controversies in the management of malignant pleural effusions. Semin Respir Crit Care Med 2014;35(6):723-731. https://doi.org/10.1586/17476348.2015.1098535 3. Fitzgerald DB, Koegelenberg CFN, Yasufuku K, Lee YCG. Surgical and non-surgical management of malignant pleural effusions. Expert Rev Respir Med. 2018;12(1):15-26. https://doi.org/10.1080/ 17476348.2018.1398085 4. Antony V, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J 2001;18(2):402-419. https://doi.org/10.1183/09031936.01.00225601 5. Fortin M, Tremblay A. Pleural controversies: Indwelling pleural catheter vs. pleurodesis for malignant pleural effusions. J Thorac Dis 2015;7(6):1052-1057. https://doi.org/10.3978/j.issn.20721439.2015.01.51 6. Koegelenberg CFN, Aubeelack K, Nanguzgambo AB, et al. Adenocarcinoma the most common cell type in patients presenting with primary lung cancer in the Western Cape. S Afr Med J 2011;101(5):2011. 7. Nanguzgambo AB, Aubeelack K, von Groote-Bidlingmaier F, et al. Radiologic features, staging, and operability of primary lung cancer in the Western Cape, South Africa. J Thorac Oncol 2011;6(2):343350. https://doi.org/10.1097/JTO.0b013e3181fd40ec 8. Sissolak G, Seftel M, Uldrick T, Esterhuizen T, Mohamed N, Kotze D. Burkitt’s lymphoma and B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma in patients with HIV: Outcomes in a South African public hospital. J Glob Oncol 2016;3(3):218-226. https://doi.org/10.1200/JGO.2015.002378 9. Dresler C, Olak J, Herndon J 2nd, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 2005;127(3):909-915. https://doi.org/10.1378/ chest.127.3.909 10. National Institute for Occupational Health (division of the National Health Laboratory Service). Asbestos. 2017. http://www.nioh.ac.za/?page=asbetos&id=26 (accessed 8 November 2017). 11. Lanphear B, Buncher C. Latent period for malignant mesothelioma of occupational origin. J Occup Med 1992;34(7):718-721. 12. Hodgson J, McElvenny D, Darnton A, Price M, Peto J. The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer 2005;92(3):587-593. https://doi. org/10.1038/sj.bjc.6602307

Accepted 10 November 2017.

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RESEARCH

Blood and virus detection on barber clippers Z Spengane,1 MB ChB, MPhil; S Korsman,2 FC Path; K Mkentane,1 MSc, PhD; L M Davids,3 PhD (Med); W Zemanay,3 BSc Hons, PhD; M Africa,3 BTech; S Mbhele,3 MSc; M Nicol,3 FCPath, PhD; F Gumedze,4 MSc, PhD; D Ngwanya,1 FC Derm; N P Khumalo,1 FC Derm, PhD Division of Dermatology, Faculty of Health Sciences, University of Cape Town, South Africa Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa 3 Division of Medical Microbiology and Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 4 Department of Statistical Sciences, Faculty of Science, University of Cape Town, South Africa 1 2

Corresponding author: N P Khumalo (n.khumalo@uct.ac.za) Background. Bleeding from the popular clean-shave ‘chiskop’ haircut was recently reported as prevalent in South Africa (SA), a country with 6.9 million HIV-infected people. Objectives. To investigate the prevalence of barber hair clipper contamination with blood and HIV and hepatitis B viruses. Methods. Fifty barbers from three townships in Cape Town, SA, were invited to participate. One clipper from each barber was collected immediately after it had been used for a clean-shave haircut. Each clipper was rinsed with phosphate-buffered saline and then submerged in viral medium. The polymerase chain reaction (PCR) was used to identify the blood-specific RNA marker haemoglobin beta (HBB), hepatitis B virus (HBV) and HIV. Results. The clean-shave haircut was the most common haircut requested by clients (78%). Of the clippers collected, 42% were positive for HBB, confirming detection of blood, none were positive for HIV, and 4 (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR. HBV DNA from clipper 16 clustered with genotype A sequences from SA, India, Brazil and Martinique, while clipper 20 clustered with SA genotype D sequences. The clipper 20 sequence was identical to a subtype D sequence (GenBank accession AY233291) from Gauteng, SA. Conclusion. This study confirms that there is significant contamination of barber hair clippers with blood and blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of transmitting infection. Although HIV was not detected in this small study, the risk of transmission should be quantified. Further studies to investigate barber clipper sterilisation practices and whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus infections are warranted. Public education on individual clipper ownership (as is the case with a toothbrush) should be advocated for clean-shave and blade-fade haircuts. S Afr Med J 2018;108(4):278-282. DOI:10.7196/SAMJ.2018.v108i4.12830

Human scalp hair varies significantly in curvature, and individuals of African ancestry have hair with the tightest curl.[1,2] Population data suggest that hair follicles with this texture are prone to specific forms of alopecia (hair loss) that predominantly affect women (traction alopecia[3] and central centrifugal cicatricial alopecia[4]) and men (folliculitis keloidalis nuchea[4]). Hairstyle trends for men have changed over the years, from the ‘big afros’ of the 1960s and 1970s to the ‘blade-fade’ haircut or German cut (originally worn by working class men in the 1920s and popular among Hitler’s Wehrmacht soldiers in Germany, hence the name) that became popular in the 1990s and the current clean-shave or ‘chiskop’ that became fashionable at the turn of the last century and is worn by 70% of black men in Cape Town townships. [4] The chiskop is worn by the majority of black men in South Africa (SA) and the African diaspora. Besides being a trend, this haircut is part of certain cultural rituals in various African and Indian (tonsure) tribes. The haircut is achieved either by using a razor blade or by pressing the metal shears of an electric clipper directly onto the scalp without using the manufacturer-supplied plastic stages (combs). This gives a clean-shave haircut similar to that achieved using a razor blade. Shaving pimples, more commonly seen in the beard area, also occur on the scalp as transient papules and pustules. However, when these pimples evolve into permanent keloids on the back (nucheal)

scalp they are characteristic of folliculitis keloidalis nuchea (FKN), also commonly and incorrectly called acne keloidalis nuchea, which has a prevalence of 10.5% in males and 0.1% females aged >18 years.[4] The prevalence of FKN was found to be highest in individuals whose hair had been cut with razors (10.7%), followed by clippers (5.9%), while no case was seen in those who used depilatory creams.[5] A history of haircut-associated bleeding as a result of clean-shave haircuts was an unexpected finding in 32% of male participants from a population study[4] in which HIV status was unknown. This was later confirmed in a later study where a history of bleeding was reported in 24.8% of HIV-positive men.[5,6] Invisible bleeding was recently detected from scalp swabs after professional clean-shave haircuts (with no visible injury on the scalp when examined by a dermatologist) in 37% of participants using genetic testing for bloodspecific RNA markers (albumin and haemoglobin beta (HBB)).[7] The potential transmission of blood-borne viruses such as hepatitis B (HBV) and HIV is most concerning. A study in Ethiopia reported that sharing shaving equipment in barber shops is common practice,[8] and an accidental scratch by sharp equipment in barber shops may create an opportunity for HIV and other blood-borne pathogens to enter the body.[8] Currently there is no study in the literature that has looked at informal barber practices in SA townships. The prevalence of contamination of haircut clippers or razors with blood and bloodborne viruses in our setting is unknown. Methods of sterilisation

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RESEARCH

or disinfection of barber instruments in our townships have been speculated on but not verified.

Objectives

The primary objective was to test clippers that had just been used for a haircut for blood and viruses. Our intention was to detect the prevalence of clipper contamination with blood, HIV and HBV, to ascertain whether barbers who mainly cut clean-shave chiskop haircuts caused more or less haircut-associated bleeding than barbers who did longer haircuts, i.e. at a distance from the scalp, and to investigate the cleaning methods used by barbers.

Methods

This was a prospective cross-sectional study. Aerial maps were used to sample 50 barber shops from three townships, the populations of which reflect the racial (apartheid) segregation of the previous SA government. Langa and Gugulethu townships have a population of predominantly black African ancestry and Bonteheuwel a population of predominantly mixed-race ancestry. The maps of Gugulethu and Langa, the two larger townships, were divided into four, then five barbers were selected from each section. The smaller Bonteheuwel township was divided into two, and five barbers were selected from each section. Basic demographic data were collected. Consenting barbers then performed one haircut, immediately after which they gave their clipper to the investigator; in exchange they received a new clipper. Methods used by the barbers to clean the clippers after use on each client were documented. Each clipper was placed into a ziplock bag at room temperature, after which the bag was sealed and taken to a laboratory for virological sampling of the clipper. At the laboratory the clipper was submerged in a petri dish with 1.5 mL of viral medium, plugged into an electrical port and switched on to allow maximum wash through the teeth. The viral medium was then aspirated using a pipette and the residue was placed into a tube and stored at –80oC until viral analysis. Total nucleic acid was extracted from 800 µL of wash using the EasyMag system (bioMérieux, Netherlands). For HIV testing, qualitative nested reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect HIV RNA present, as follows. A 160 bp region of gag (nucleotide position 1494 - 1653 on the reference HIV HXB2 genome) was amplified by onestep RT-PCR using the SuperScript One-Step RT-PCR System with Platinum Taq (Invitrogen, Thermo Fisher Scientific, USA) in 50 µL final volume reaction with primers GAG A (forward, 5'-AGAGAACCAAGGGGAAGTGA-3') and GAG B (reverse, 5'-TCTCTAAAGGGTTCCTTTGG-3’) each at 0.6 µM, and 10 µL nucleic acid eluate. Reverse transcription was carried out at 50°C for 30 minutes and PCR at 94°C for 2 minutes, followed by 40 cycles at 94°C for 25 seconds, 40°C for 30 seconds and 68°C for 45 seconds, with a final extension step of 68°C for 7 minutes. Nested PCR was performed using SuperTherm Taq DNA polymerase (Separation Scientific, SA) in a 50 µL final reaction volume with primers GAG C (forward, 5'-CATAGCAGGAACTACTAGTA-3') and GAG D (reverse, 5'-TCCTTGTCTTATGTCCAGAA-3'), each at 1 µM, with 2 µL prenested PCR product. PCR cycling conditions were the same as described above. PCR products were analysed under ultraviolet (UV) light after 2% agarose gel electrophoresis.[6,9] For HBV testing, 600 µL of wash was tested with the quantitative Roche COBAS AmplPrep/COBAS TaqMan HBV Test, version 2 (Roche Diagnostics, Germany). Samples with detectable HBV DNA were then tested on a qualitative nested PCR[11] to obtain products for sequencing, as follows. A 189 bp region of the HBV pre-S1 gene was

amplified by nested PCR using SuperTherm Taq DNA polymerase (Separation Scientific) in a 50 µL final reaction volume. First-round primers were as follows: HBV1 (forward) TGGGAACAAGAKCTAC; HBV2 (reverse) GAACTGGAGCCACCAG; the final primer concentration was 0.4 µM. Nested PCR primers were as follows: HBV3 (forward) AATCCMGATTGGGACYTCAA; HBV4 (reverse) TCCTRACTGSCGATTGGT; final primer concentration 1 µM. Cyc ling conditions were identical for both rounds, and were as follows: 94°C for 2 minutes, followed by 35 cycles of 94°C for 20 seconds, 50°C for 30 seconds and 72°C for 45 seconds, with a final extension step of 72°C for 7 minutes. PCR products were analysed under UV light after 2% agarose gel electrophoresis. Both qualitative HIV and HBV PCRs were performed on the Applied Biosystems GeneAmp PCR System 9700 (Applied Biosystems, USA). HBV PCR products obtained were sent to Inqaba Biotechnical Industries (SA) for bidirectional Sanger sequencing. Chromatograms were edited in FinchTV (Geospiza, USA). Sequences were aligned using ClustalX[12] and manipulated in BioEdit.[13] The maximumlikelihood tree was drawn from an alignment of 188 nucleotide positions in MEGA6[14] using the Tamura-Nei evolutionary model.[15] Bootstrap support was calculated with 1 000 replicates. For comparison, HBV sequences representing most genotypes were selected from GenBank, including sequences from SA. The following sequences, with GenBank accession numbers listed by genotype, were chosen to represent the different genotypes: genotype A: AY576430, AY576434, GQ355536, GQ355565, GQ355572, GQ355575, HE974375, HE974376, HQ646554, HQ646556, JF784220, KC752150, KF476003, KF476015, KF476018 and X51970; genotype B: AB033554, AF100309 and D00329_JP; genotype C: AB644284, AB644286 and GQ184326; genotype D: AF280817, AY233291, AY233295, AY576433, EU594430, FJ904447, GQ184322, GQ205389, HE974377, JX898722, KC012652, KF170740 and KF476030; genotype E: AP007262, DQ060824 and HE974380; genotype F: AB116654 and AF223965; genotype G: AP007264 and GU565217; genotype H: AB298362 and AY090454; genotype I: FJ023674 and FJ882615. Orangutan HBV, AF193864, was used to root the tree. For the blood-specific markers, hair clippers were rinsed with phosphate-buffered saline (PBS) and RNA was extracted from the PBS using the QIAgen RNeasy kit (Qiagen, SA). Briefly, total RNA was extracted according to the manufacturer’s instructions. The eluted RNA was used for cDNA synthesis with a reverse-transcription enzyme (Fermentas, SA) and random hexamer primers. Conventional PCR was performed using primer sets for the blood-specific marker, with HBB RNA primer sequences as follows: (forward) CAC CTG GAC AAC CTC AAG; (reverse) AAT TCAC CCC ACC AGT GCA. PCR products were detected with a 3130xl Genetic Analyzer (Applied Biosystems). Briefly, a 1 μL aliquot of neat PCR product was added to 8 μL Hi-Di Formamide and 0.2 μL of GeneScan 500 Rox size standard (Applied Biosystems). The samples were heated to 95°C before being loaded onto the analyser. The conditions used for capillary electrophoresis were as follows: samples were injected through a 36 cm capillary filled with pop7 polymer, (ThermoFisher Scientific, USA) at a temperature of 60°C. Samples were injected for 3 seconds using an injection voltage of 1.2 kV and electrophoresed for ~20 minutes. The raw data were analysed using GeneMapper Software v4.0 (ThermoFisher Scientific).

Ethics clearance

Ethics approval for this study was obtained from the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town (ref. no. 208/2013).

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RESEARCH

Results

All invited barbers agreed to participate, and a total of 50 clippers were collected. Twenty-one (42%) of all clippers were positive for the blood RNA marker HBB (5/20, 7/10 and 9/20 from townships 1, 2 and 3, respectively). Clippers from township 2 had a significantly higher prevalence of blood contamination at 72%, compared with 33% of those from townships 1 and 3 (p=0.023). Table 1 shows the characteristics of the study participants according to hairstyle. No clippers were positive for HIV. Four clippers (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR. HBV DNA from clipper 16 clustered with genotype A sequences from SA, India, Brazil, and Martinique, while clipper 20 clustered with SA genotype D sequences. The clipper 20 sequence was identical to a subtype D sequence (GenBank accession AY233291) from Gauteng, SA[15] (Fig. 1). In the communities with a predominantly black African population, townships 1 and 3, the chiskop haircut was the style most commonly requested by clients. In township 2, the population of which is predominantly of mixed-race ancestry, no client requested a chiskop; instead 6 had a brush cut, 3 a blade-fade and 1 a German cut (the scalp margins are shaved with a blade in the blade-fade and with a clipper in the German cut; however, the result is the same). All the barbers cleaned the clippers after each client, but the cleaning agents varied. Most barbers (82%) used disinfection with methylated spirits after using a brush to remove hair, and 8% used an open flame. All the barbers who used an open flame to clean their clippers (8% of the total sample) were from township 2 and usually cut the blade-fade style (p=0.013).

Discussion

Four clippers were contaminated with HBV. The HBV sequences identified are in keeping with other sequences from SA, where the

main hepatitis B genotypes are A and D.[15,16] The use of only 188 nucleotide positions for phylogenetic analysis limits the conclusions that can be reached, but is adequate to show that our sequences cluster with sequences obtained from our region by other researchers. We found concentrations of HBV DNA of between <20 and 45 IU/ mL in clipper wash. Welzel et al.[17] calculated a ratio of 1 IU:10 DNA copies in their laboratory. The 2009 chronic hepatitis B practice guidelines[18] indicate a ratio of 1 IU:5 DNA copies. This amounts to approximately 300 DNA copies washed from clipper 16. Levels of HBV DNA in blood vary considerably, depending on the stage of infection, whether infection is acute or chronic, e-antigen positivity or negativity, and other factors. Viral loads are reported to reach as high as 10 log10 IU/mL serum/plasma,[19-22] and in our diagnostic laboratory we have seen occasional samples with an estimated viral load of up to 15 log10 IU/mL plasma. Viral loads (log copies/ mL) of 4.3, 5.9, 6.2 and 5.2 have been reported in urine, saliva, tears and sweat, respectively.[23] Hepatitis B transmission has been linked to body fluids other than blood,[23,24] as well as to the sharing of toothbrushes and razors.[25] The risk of transmission between healthcare workers and patients has been well documented. [24,26] There is therefore a risk of clipper contamination from minor bleeding on the scalp. The infectious dose of hepatitis B has been estimated at 10 - 100 viruses. A study in chimpanzees determined the ID50 of HBV (the minimum infectious dose of HBV, or the dose at which 50% of chimpanzees would be infected[27]) in five chimpanzees to be ~10 DNA copies for both genotypes A and C.[27] In a subsequent study, the same team found that a dose of 2.6 - 4.6 DNA copies from pre-acute-phase chimpanzee serum caused infection in 3/3 chimeric mice with transplanted human hepatocytes, while a dose of 200 - 350 DNA copies from late acute-phase serum caused infection in only 1/3 mice,[28] suggesting that virus during early acute infection is more able

Table 1. Characteristics of study participants according to hairstyle Characteristic Site Township 1 (Langa) Township 2 (Bonteheuwel) Township 3 (Gugulethu) Total Age group of clients serviced (years) 5 - 17 18 - 60 Total Cleaning methods Brush and spirit Spirit only Open flame Total Hepatitis B virus Positive Negative Total Blood marker (HBB) Positive Negative Total

Total, N (%)

Clean-shave haircut barbers, n (%)

Other haircut barbers, n (%)

20 (40.0) 10 (20.0) 20 (40.0) 50

19 (48.7) 0 20 (51.3) 39

1 (9.1) 10† (90.9) 0 11

6 (12.0) 44 (88.0) 50

6 (15.4) 33 (84.6) 39

0 11 (100) 11

41 (82.0) 5 (10.0) 4 (8.0) 50

35 (89.8) 3 (7.7) 1 (2.5) 39

6 (54.5) 2 (18.2) 3 (27.3) 11

4 (8.0) 46 (92.0) 50

3 (7.7) 36 (92.3) 39

1 (9.1) 10 (90.9) 11

21 (42.0) 29 (58.0) 50

13 (33.3) 26 (66.7) 39

8 (72.7) 3 (27.3) 11

p-value* <0.0001

0.317

0.013

0.643

0.023

HBB = haemoglobin beta. *p-value based on χ2 test of association for difference between clean-shave and other hairstyles. † 6 brush-cut, 3 blade-fade, 1 German cut.

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RESEARCH Figure 1 Clipper 20

D AY233291 ZA

D AY576433 ZA

D AY233295 ZA

D HE974377 MQ D JX898722 SE

D KC012652 AR

Genotype D

D FJ904447 TN

D KF476030 ZA

D GQ205389 IN

D AF280817 CN

98 97

D GQ184322 ZA

D EU594430 RU

D KF170740 SD

100

G AP007264 JP

E DQ060824 NA

E HE974380 MQ

C AB644284 ID

100

C GQ184326 ZA C AB644286 ID

I FJ023674 LA

F AB116654 JP

F AF223965 AR

93 H AB298362 JP

H AY090454 NI

Genotype E

Genotype F

Genotype H Genotype C

Genotype I

I FJ882615 CA

A KF476003 ZA A KF476015 ZA

A HE974376 MQ

A X51970 DE

A HQ646556 ZA

A KF476018 ZA

Genotype G

G GU565217 NL

E AP007262 JP

A HQ646554 ZA

A GQ355572 ZA

A GQ355575 ZA

A AY576434 ZA

A GQ355536 ZA

A GQ355565 ZA

A AY576430 ZA

Genotype A

A HE974375 MQ 100

0.02

Orang AF193864

A JF784220 BR

A KC752150 IN

Clipper 16

B D00329 JP

B AB033554 ID

Genotype B

B AF100309 CN

Legend: Fig. 1.Figure A maximum-likelihood tree constructed in MEGA6 using an alignment of 188 nucleotide sequences. bootstrap support above 60%inisMEGA6 shown.using Studyansamples areofshown in red. The tree is Fig X.Selected A maximum likelihood tree constructed alignment 188nt sequences. bootstrap support 60% is shown. Study samples are shown in red. starting The tree is rooted rootedSelected on an orangutan HBV above sequence. Sequences for comparison have names with genotype, on an orangutan HBV sequence. Sequences for comparison have names start with genotype, followed by Genbank accession number, ending ending with country 3166-1ISO abbreviation (AR, Argentina;(AR BR, Brazil; followed by Genbank accession number, withISO country 3166-1 abbreviation = Argentina; C BR = Brazil; CA = Canada; CN = China; DE = Germany; ID = Indonesia; IN = India; LA = Laos; Canada; CN, DE, Germany; Indonesia; IN, LA, Laos; Martinique; NA,Sweden; MQ =+.A, Martinique; NAChina; = Namibia; NI =ID,Nicaragua; RUIndia; = Russia; SD MQ, = Sudan; SE = Namibia; NI, Nicaragua;RU, Russia; SD, Sudan; SE, Sweden; TN, Tunisia; ZA, South Africa). TN = Tunisia; ZA = South Africa; scale bar = number of substitutions per site.)

to initiate a new infection when transmitted, possibly because in later infection virus in serum may be bound to antibodies. Commercial methylated spirit contains ethyl alcohol (95%) and methyl alcohol (5%), and our findings indicate that it is commonly used to decontaminate barber equipment. Ethyl alcohol and methyl alcohol are not virucidal. The use of open flames for sterilisation has been reported from African countries,[29] but there are no data on efficacy or adequate exposure time. UV light is reported to kill bacteria and viruses effectively.[30] Application of UV radiation in biological safety cabinets destroys organisms on the surface of instruments. This microbicidal activity is highly dependent on the wavelength of UV radiation. Modern UV light sterilisation units as well as specific

antiviral sprays are used internationally in hair salons. Quaternary ammonium disinfectant cleaners have virucidal activity effective enough to kill herpes simplex virus (HSV) in the presence of blood.[31] HSV has similar properties to HIV, and quaternary ammonium disinfectants could therefore be used to decontaminate surfaces or tools with blood spills.[31] The new generation of accelerated hydrogen peroxide-based environmental surface disinfectants are bactericidal, virucidal, mycobactericidal and fungicidal.[32] The formulation is safe to use and has a high compatibility profile for various materials in addition to being a fastacting intermediate-level disinfectant. [32] In the USA, disinfectant must be approved by the Environmental Protection Agency (EPA), which certifies the efficacy of

April 2018, Print edition

products for infection control. The SA counterpart is the South African Bureau of Standards (SABS). Barbers are encouraged to use EPA- or SABS-approved disinfectants for their equipment. In our study, the low levels of HBV DNA copies on the clippers represent a possible public healthcare risk. We are not aware of cases of HBV or HIV infection resulting from clipper use in our setting. We are unable to identify when each clipper became contaminated with virus, and we do not know how virus levels on clippers decline as the clippers move through hair when they are used on subsequent clients. It is unlikely that the HBV levels detected on the clippers would pose a risk to a client, but closer to the time of the source contamination there may have been levels that did pose such a risk. We are also unable to determine whether the viral DNA levels detected represent infectious virus, or damaged virus no longer able to cause infection. HIV viral loads are typically lower than HBV viral loads, and with similar clipper use this may explain why we did not detect HIV RNA on any clippers. However, closer in time to the source contamination, clippers may have had levels of infectious HIV that could have posed a risk to clients. The results show that clippers used to mostly cut the longer blade-fade hairstyle were associated with more bleeding markers, although one would expect that the clippers used to cut the clean-shave chiskop would have had more blood markers as a result of the close contact of the blade with the scalp. Our results showed that 72% of the clippers used to cut the longer blade-shade were positive for HBB, compared with 33% of the clippers used for the chiskop cut. One plausible explanation could be the small sample size in township 2. There was a statistically significant difference in cleaning methods used by the barbers cutting the chiskop and blade-fade hairstyles. Of the barbers using clippers to cut the bladefade, only 54% used a brush and spirit, while 27% used other methods such as open flames to clean clippers. While it has been reported that an open flame is used to clean clippers in other African countries, there are no data on the efficacy of this method for disinfection or sterilisation.[29] Many developing countries lack regulating bodies that monitor health practices at barber shops. In developed countries, activities of barbers are regulated through comprehensive training, licensing and monitoring programmes.[8] Lack of knowledge about correct methods of sterilisation and disinfection may be directly

RESEARCH

associated with the lack of formal trade training of the barbers. Barbers’ level of education may be a contributory factor.

Study limitations

The hepatitis B and HIV status of clients was unknown. There are some confounding factors that could have contributed to our results, such as the skill of the barbers in the different townships and the methods they used to cut the hairstyles. The small sample size of township 2 could also have skewed our results. The amount of time spent cleaning the clippers with the different methods was not measured. This is also a possible confounding factor and could have contributed to the results. A study with a bigger sample size could obtain results of better quality.

Conclusions

This study confirmed that there is significant contamination of barber hair clippers with blood and blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of infection. Although HIV was not detected, the clinical significance of contamination of clippers with blood, especially with regard to the transmission of blood-borne infections, warrants further study. Further scientific scrutiny is required to quantify infection risk and investigate whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus (HCV) infections as well as HIV/HBV and HIV/HCV co-infections. Finally, barber hygiene practices may require upscaling and access to sterilisation facilities. In the meantime, public education recommending individual clipper ownership for close-shave chiskop and blade-fade haircuts should be advocated. Acknowledgements. Simphiwe Khondlo assisted with data collection in the communities. Author contributions. Conception and design of the work: NPK, ZS; data collection: ZS, SK ; laboratory data analysis: SK, KM, LMD, WZ, MA, MN; data capturing: SM; data analysis and interpretation: FG, NPK, ZS, MN ; drafting the article: ZS, NPK, SK, MN; critical revision of the article: ZS, NPK, SK, MN, MN; final approval of the version to be published: NPK. Funding. South African Medical Research Council. Conflicts of interest. None. 1. Khumalo NP, Doe PT, Dawber RP, Ferguson DJ. What is normal black African hair? A light and scanning electron-microscopic study. J Am Acad Dermatol 2000;43(5 Pt 1):814-820. https://doi. org/10.1067/mjd.2000.107958 2. Loussouarn G, Garcel AL, Lozano I, et al. Worldwide diversity of hair curliness: A new method of assessment. Int J Dermatol 2007;46(Suppl 1):2-6. https://doi.org/10.1111/j.1365-4632.2007.03453.x 3. Khumalo NP, Jessop S, Gumedze F, Ehrlich R. Hairdressing is associated with scalp disease in African schoolchildren. Br J Dermatol 2007;157(1):106-110. https://doi.org/10.1111/j.1365-2133.2007.07987.x 4. Khumalo NP, Jessop S, Gumedze F, Ehrlich R. Hairdressing and the prevalence of scalp disease in African adults. Br J Dermatol 2007;157(5):981-988. https://doi.org/10.1111/j.1365-2133.2007.08146.x 5. Khumalo NP, Gumedze F, Lehloenya R. Folliculitis keloidalis nuchae is associated with the risk for bleeding from haircuts. Int J Dermatol 2011;50(10):1212-1216. https://doi.org/10.1111/j.13654632.2010.04655.x 6. Khumalo NP, Gantsho N, Gumedze F, Mthebe T. Health risks of the clean-shave chiskop haircut. S Afr Med J 2013;103(7):489-490. https://doi.org/10.7196/SAMJ.6675

7. Khumalo NP, Muthukarapan C, Hardy D, et al. Invisible bleeding from clean-shave haircuts, detection with blood specific RNA markers. Dermatology 2013;227(3):197-201. https://doi. org/10.1159/000353529 8. Biadgelegn F, Belyhun Y, Anagaw B, et al. Potential risk of HIV transmission in barbering practice in Ethiopia: From public health and microbiological perspectives. BMC Public Health 2012;12:707. https://doi.org/10.1186/1471-2458-12-707 9. Engelbrecht S, van Rensburg EJ. Detection of southern African human immunodeficiency virus type 1 subtypes by polymerase chain reaction: Evaluation of different primer pairs and conditions. J Virol Methods 1995;55(3):391-400. https://doi.org/10.1016/0166-0934(95)00088-7 10. Hardie DR, Kannemeyer J, Stannard LM. DNA single strand conformation polymorphism identifies five defined strains of hepatitis B virus (HBV) during an outbreak of HBV infection in an oncology unit. J Med Virol 1996;49(1):49-54. https://doi.org/10.1002/(SICI)1096-9071(199605)49:1<49::AIDJMV8>3.0.CO;2-K 11. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994;22(22):4673-4680. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC308517/ (accessed 12 March 2018). 12. Hall TA. BioEdit: A user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 1999:41:95-98. http://brownlab.mbio.ncsu.edu/JWB/ papers/1999Hall1.pdf (accessed 2 March 2018). 13. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol 2013;30(12):2725-2729. https://doi.org/10.1093/molbev/mst197 14. Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of <span class=”cvyg601” id=”cvyg601_3”>mitochondrial DNA</span> in humans and chimpanzees. Mol Biol Evol 1993;10(3):512-526. https://doi.org/10.1093/oxfordjournals.molbev.a040023 15. Kimbi GC, Kramvis A, Kew MC. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol 2004;85(Pt 5):1211-1220. https://doi.org/10.1099/ vir.0.19749-0 16. Andersson MI, Maponga TG, Ijaz S, et al. The epidemiology of hepatitis B virus infection in HIV-infected and HIV-uninfected pregnant women in the Western Cape, South Africa. Vaccine 2013;31(47):5579-5584. https://doi.org/10.1016/j.vaccine.2013.08.028 17. Welzel TM, Miley WJ, Parks TL, Goedert JJ, Whitby D, Ortiz-Conde BA. Real-time PCR assay for detection and quantification of hepatitis B virus genotypes A to G. J Clin Microbiol 2006;44(9):33253333. https://doi.org/10.1128/JCM.00024-06 18. Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50(3):661-662. https:// doi.org/10.1002/hep.23190 19. Ciupe SM, Ribeiro RM, Nelson PW, Perelson AS. Modeling the mechanisms of acute hepatitis B virus infection. J Theor Biol 2007;247(1):23-35. https://doi.org/10.1016/j.jtbi.2007.02.017 20. Ganem D, Prince AM. Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 2004;350(11):1118-1129. https://doi.org/10.1056/NEJMra031087 21. Ribeiro RM, Lo A, Perelson AS. Dynamics of hepatitis B virus infection. Microbes Infect 2002;4(8):829-835. https://doi.org/S1286457902016039 22. Whalley SA, Murray JM, Brown D, et al. Kinetics of acute hepatitis B virus infection in humans. J Exp Med 2001;193(7):847-854. https://doi.org/10.1084/jem.193.7.847 23. Komatsu H, Inui A, Sogo T, Tateno A, Shimokawa R, Fujisawa T. Tears from children with chronic hepatitis B virus (HBV) infection are infectious vehicles of HBV transmission: Experimental transmission of HBV by tears, using mice with chimeric human livers. J Infect Dis 2012;206(4):478485. https://doi.org/10.1093/infdis/jis293 24. Hu DJ, Kane MA, Heymann DL. Transmission of HIV, hepatitis B virus, and other bloodborne pathogens in health care settings: A review of risk factors and guidelines for prevention. Bull World Health Organ 1991;69(5):623-630. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2393247/ (accessed 12 March 2018). 25. Goh KT, Ding JL, Monteiro EH, Oon CJ. Hepatitis B infection in households of acute cases. J Epidemiol Community Health 1985;39(2):123-128. https://doi.org/10.1136/jech.39.2.123 26. Corden S, Ballard AL, Ijaz S, et al. HBV DNA levels and transmission of hepatitis B by health care workers. J Clin Virol 2003;27(1):52-58. https://doi.org/S1386653202001270 27. Komiya Y, Katayama K, Yugi H, et al. Minimum infectious dose of hepatitis B virus in chimpanzees and difference in the dynamics of viremia between genotype A and genotype C. Transfusion 2008;48(2):286-294. https://doi.org/10.1111/j.1537-2995.2007.01522.x 28. Tabuchi A, Tanaka J, Katayama K, et al. Titration of hepatitis B virus infectivity in the sera of pre-acute and late acute phases of HBV infection: Transmission experiments to chimeric mice with human liver repopulated hepatocytes. J Med Virol 2008;80(12):2064-2068. https://doi.org/10.1002/jmv.21320 29. Arulogun OS, Adesoro MO. Potential risk of HIV transmission in barbering practice among professional barbers in Ibadan, Nigeria. Afr Health Sci 2009;9(1):19-25. https://www.ncbi.nlm.nih. gov/pmc/articles/PMC2932524/ (accessed 12 March 2018). 30. Russell AD, Hugo WB, Ayliffe GAJ. Principles and Practices of Disinfection, Preservation and Sterilization. Oxford: Blackwell Science, 1999. 31. Weber DJ, Barbee SL, Sobsey MD, Rutala WA. The effect of blood on the antiviral activity of sodium hypochlorite, a phenolic, and a quaternary ammonium compound. Infect Control Hosp Epidemiol 1999;20(12):821-827. https://doi.org/10.1086/501591 32. Omidbakhsh N, Sattar SA. Broad-spectrum microbicidal activity, toxicologic assessment, and materials compatibility of a new generation of accelerated hydrogen peroxide-based environmental surface disinfectant. Am J Infect Control 2006;34(5):251-257. https://doi.org/10.1016/j. ajic.2005.06.002

Accepted 24 August 2017.

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RESEARCH

Hereditary angio-oedema in the Western Cape Province, South Africa K M Coovadia,1 MB ChB, FCP (SA), MMed, Dip Allerg (SA); M-Y Chothia,1 MB ChB, FCP (SA), MMed, Cert Nephrology (SA); S G Baker,2 BSc (Nursing), MSc (Medicine), Dip Asthma (UK); J G Peter,2,3 MB ChB, MMed, FCP (SA), PhD; P C Potter,2,3 MB ChB, DCH (SA), FCP (SA), BSc Hons Immunology, MD, FAAAAI, FACAAI epartment of Internal Medicine, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa D Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, Cape Town, South Africa 3 Division of Allergology and Clinical Immunology, Department of Internal Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: K M Coovadia (kcoovadia@gmail.com) Background. Hereditary angio-oedema (HAE) is an autosomal dominant condition caused by a deficiency in the C1-esterase inhibitor protein, resulting in increased bradykinin release. It presents clinically with recurrent attacks of angio-oedema, commonly affecting the limbs, face, upper airway and gastrointestinal tract. Little is known about this condition in sub-Saharan Africa. Objectives. To analyse and report on the clinical presentation and treatment of patients with HAE in the Western Cape Province, South Africa. Methods. A retrospective analysis was conducted on a series of 60 cases of HAE seen between 2010 and 2015 at the Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, and the Allergy Clinic at Groote Schuur Hospital, Cape Town. The findings in 43 cases of type 1 HAE are described. Parameters assessed included age, gender, age of diagnosis, duration of illness, family history, identifiable triggers, average duration of attack, number of attacks per year and type of attack. Results. A total of 43 patients were included in this study. Of these, 65.1% (28/43) were female. The median age at diagnosis was 20 years (interquartile range (IQR) 10 - 27) and the median duration of illness 10.5 years (IQR 6 - 22). Of the patients, 62.8% (27/43), 32.6% (14/43) and 4.7% (2/43) were of mixed ancestry, white and black African, respectively; 51.2% (22/43) were index cases, with the remaining 48.8% (21/43) diagnoses via family member screening, 12 families making up the majority of the cohort. The mean (standard deviation) duration of an acute attack was 49 (25.8) hours, and 64.3% (27/42), 71.4% (30/42), 14.3% (6/42) and 88.1% (37/42) of patients experienced facial or upper airway, abdominal, external genitalia and limb attacks, respectively. Danazol for long-term prophylaxis was used in 21 patients, while C1-inhibitor concentrate (Berinert) was accessed for short-term prophylaxis in only four patients. Acute life-threating attacks were treated with fresh frozen plasma in 11 patients, and only four accessed icatibant. The mortality rate for the period 2010 - 2015 was 4.5% (2/43). The prevalence of HAE in the Western Cape was estimated to be 1:140 000. Conclusions. HAE occurs in South Africans of all ethnicities, and life-threatening attacks occur in almost two-thirds of patients. Despite limited therapeutic options and very limited access to gold-standard therapies available in the developed world, our mortality rate is very low, with both the deaths related to inability to access emergency treatment rapidly. S Afr Med J 2018;108(4):283-290. DOI:10.7196/SAMJ.2018.v108i4.12823

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12823

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Feasibility and acceptability of conducting HIV vaccine trials in adolescents in South Africa: Going beyond willingness to participate towards implementation M Wallace,1 BSocSci Hons, MSc, PhD; K Middelkoop,2 MD, PhD; P Smith,2 MSocSci; C Pike,2 BSc Hons, MSc; T Bennie,3 MA; J Chandia,4 MB ChB, DTM&H, DPH, DIPHC, MPraxMed, FCFP, PhD; G Churchyard,5 MB BCh, FCPaed; G Gray,6,7 MB BCh, FCPaed, DSc; M H Latka,5 PhD, MPH; M Mathebula,8 MB ChB; M Nchabeleng,8 MB ChB, MMed (Micro); S Roux,9 MB ChB, MPH; C Slack,10 MA (Clin Psych), PhD; A Strode,11 BA, LLB, LLM; L-G Bekker,2 MB ChB, DCH, DTM&H, FCP (SA), PhD Cancer Association of South Africa, Cape Town, South Africa Desmond Tutu HIV Centre, Faculty of Health Sciences, University of Cape Town, South Africa 3 International Partnership for Microbicides, Paarl, South Africa 4 HIV Vaccine Research Unit, Faculty of Health Sciences, Walter Sisulu University, Mthatha, South Africa 5 The Aurum Institute, Johannesburg, South Africa 6 Perinatal HIV Research Unit, Chris HaniÂ Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 7 South African Medical Research Council, Johannesburg, South Africa 8 MeCRU Clinical Research Unit, Department of Microbiological Pathology, School of Healthcare Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa 9 Synexus Clinical Research SA (Pty) Ltd, Somerset West, South Africa 10 Vaccines Ethics Group, Discipline of Psychology, College of Humanities, University of KwaZulu-Natal, Pietermaritzburg, South Africa 11 Centre for Socio-Legal Studies, School of Law, University of KwaZulu-Natal, Pietermaritzburg, South Africa 1

Corresponding author: C Pike (carey.pike@hiv-research.org.za) Background. HIV/AIDS remains a leading cause of death in adolescents (aged 15 - 25 years), and in sub-Saharan Africa HIV-related deaths continue to rise in this age group despite a decline in both adult and paediatric populations. This is attributable in part to high adolescent infection rates and supports the urgent need for more efficacious prevention strategies. In particular, an even partially effective HIV vaccine, given prior to sexual debut, is predicted to significantly curb adolescent infection rates. While adolescents have indicated willingness to participate in HIV vaccine trials, there are concerns around safety, uptake, adherence, and ethical and logistic issues. Objectives. To initiate a national, multisite project with the aim of identifying obstacles to conducting adolescent HIV vaccine trials in South Africa (SA). Method. A simulated HIV vaccine trial was conducted in adolescents aged 12 - 17 years across five SA research sites, using the already licensed Merck human papillomavirus vaccine Gardasil as a proxy for an HIV vaccine. Adolescents were recruited at community venues and, following a vaccine discussion group, invited to participate in the trial. Consent for trial enrolment was obtained from a parent or legal guardian, and participants aged 16 - 17 years were eligible only if sexually active. Typical vaccine trial procedures were applied during the five study visits, including the administration of vaccination injections at study visits 2, 3 and 4. Results. The median age of participants was 14 years (interquartile range 13 - 15), with 81% between the ages of 12 and 15 years at enrolment. Overall, 98% of screened participants opted to receive the vaccine, 588 participants enrolled, and 524 (89%) attended the final visit. Conclusions. This trial showed that adolescents can be recruited, enrolled and retained in clinical prevention trials with parental support. While promising, these results were tempered by the coupling of sexual-risk eligibility criteria and the requirement for parental/guardian consent, which was probably a barrier to the enrolment of high-risk older adolescents. Further debate around appropriate consent approaches for such adolescents in HIV prevention studies is required. S Afr Med J 2018;108(4):291-298. DOI:10.7196/SAMJ.2018.v108i4.12909

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12909

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Understanding the types of fraud in claims to South African medical schemes T G Legotlo, BNSC, BCom, BCom Hons, MCom; A Mutezo, BCom, BCom Hons, MCom, DCom Department of Finance, Risk Management and Banking, School of Economic and Financial Sciences, College of Economic and Management Sciences, University of South Africa, Pretoria, South Africa Corresponding author: T G Legotlo (legottg@unisa.ac.za) Background. Medical schemes play a significant role in funding private healthcare in South Africa (SA). However, the sector is negatively affected by the high rate of fraudulent claims. Objectives. To identify the types of fraudulent activities committed in SA medical scheme claims. Methods. A cross-sectional qualitative study was conducted, adopting a case study strategy. A sample of 15 employees was purposively selected from a single medical scheme administration company in SA. Semi-structured interviews were conducted to collect data from study participants. A thematic analysis of the data was done using ATLAS.ti software (ATLAS.ti Scientific Software Development, Germany). Results. The study population comprised the 17 companies that administer medical schemes in SA. Data were collected from 15 study participants, who were selected from the medical scheme administrator chosen as a case study. The study found that medical schemes were defrauded in numerous ways. The perpetrators of this type of fraud include healthcare service providers, medical scheme members, employees, brokers and syndicates. Medical schemes are mostly defrauded by the submission of false claims by service providers and syndicates. Fraud committed by medical scheme members encompasses the sharing of medical scheme benefits with non-members (card farming) and non-disclosure of pre-existing conditions at the application stage. Conclusions. The study concluded that perpetrators of fraud have found several ways of defrauding SA medical schemes regarding claims. Understanding and identifying the types of fraud events facing medical schemes is the initial step towards establishing methods to mitigate this risk. Future studies should examine strategies to manage fraudulent medical scheme claims. S Afr Med J 2018;108(4):299-303. DOI:10.7196/SAMJ.2018.v108i4.12758

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12758

Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa J Gasson,1 BMBS, BMedSci; M Blockman,2 MB ChB, BPharm, PG Dip (Health Research Ethics), MMed; B Willems,3 MB ChB, DA (SA), FCPHM I mproving Global Health Fellow, Health Impact Assessment, Western Cape Department of Health, South Africa; NHS Thames Valley and Wessex Leadership Academy, UK; THET/UK Aid in association with Health Education England, UK 2 Department of Internal Medicine, Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa 3 Division of Health Systems and Public Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1

Corresponding author: J Gasson (julia.gasson@gmail.com) Background. Knowledge of antibiotic prescribing practice in primary care in South Africa is limited. As 80% of human antibiotic use is in primary care, this knowledge is important in view of the global problem of antibiotic resistance. Objectives. To assess antibiotic prescribing in primary care facilities in the Cape Town Metro District and compare it with current national guidelines, and to assess the reasons why prescriptions were not adherent to guidelines. Methods. A retrospective medical record review was performed in April/May 2016. Records of all patients seen over 2 days in each of eight representative primary care facilities in the Cape Town Metro District were reviewed. The treatment of any patient who raised a new

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complaint on either of those days was recorded. Prophylactic antibiotic courses, tuberculosis treatment and patients with a non-infection diagnosis were excluded. Treatment was compared with the Standard Treatment Guidelines and Essential Medicines List for South Africa, Primary Healthcare Level, 2014 edition. Results. Of 654 records included, 68.7% indicated that an antibiotic had been prescribed. Overall guideline adherence was 45.1%. Adherence differed significantly between facilities and according to the physiological system being treated, whether the prescription was for an adult or paediatric patient, and the antibiotic prescribed. Healthcare professional type and patient gender had no significant effect on adherence. The main reasons for non-adherence were an undocumented diagnosis (30.5%), antibiotic not required (21.6%), incorrect dose (12.9%), incorrect drug (11.5%), and incorrect duration of therapy (9.5%). Conclusions. This study demonstrates poor adherence to guidelines. Irrational use of antibiotics is associated with increased antibiotic resistance. There is an urgent need to improve antibiotic prescribing practice in primary care in the Cape Town Metro District. S Afr Med J 2018;108(4):304-310. DOI:10.7196/SAMJ.2018.v108i4.12564

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12564

Impact of ‘Ideal Clinic’ implementation on patient waiting time in primary healthcare clinics in KwaZulu-Natal Province, South Africa: A before-and-after evaluation B A Egbujie,1 MBBS, MPH; A Grimwood,1 MB ChB, MPH; E C Mothibi-Wabafor,1 MB ChB, FRCP; G Fatti,1 MB ChB, MPH; A M E T Tshabalala,2 BA Cur Hons, MBA, PhD; S Allie,1 MB ChB, MSc; G Vilakazi,1 MB ChB; O Oyebanji,1 MBBS, MPH 1 2

Kheth’Impilo AIDS Free Living, South Africa Department of Health, Amajuba District, KwaZulu-Natal, South Africa

Corresponding author: B A Egbujie (greatdabon@yahoo.com) Background. Long waiting times are a major source of dissatisfaction for patients attending public healthcare facilities in South Africa (SA). The National Department of Health has identified this as one of six priority areas for improvement. Health system-strengthening (HSS) interventions to improve patient waiting time are being implemented in public health facilities across SA as part of the ‘Ideal Clinic’ model. The effect of these interventions on patient waiting time needs to be assessed and evidence generated for system improvement. Objectives. To determine the effect of Ideal Clinic HSS intervention on patient waiting time in public health facilities in Amajuba District, KwaZulu-Natal Province, SA. Methods. We implemented 12 months of HSS activity, including facility reorganisation and patient appointment scheduling. The major outcome of interest was the total time spent by patients in a facility during a visit. This was calculated as the median time spent, obtained through a ‘before-and-after’ intervention survey. Univariate and multivariate factors associated with waiting time were determined. Results. A total of 1 763 patients from nine clinics were surveyed before and after the intervention (n=860 at baseline and n=903 at follow-up). The median overall waiting time after the intervention was 122 minutes (interquartile range (IQR) 81 - 204), compared with 116 minutes (IQR 66 - 168) before (p<0.05). Individual facility results after the intervention were mixed. Two facilities recorded statistically significant reductions in patient waiting time, while three recorded significant increases (p<0.05). Patient load per nurse, type of service received and time of arrival in facilities were all independently associated with waiting time. Patients’ arrival patterns, which were determined by appointment scheduling, played a significant role in the results obtained. Conclusions. Implementation of the Ideal Clinic model in the selected facilities led to changes in patient waiting time. Observed changes were positive when a clinic appointment system was successfully implemented and negative when this was unsuccessful. We recommend strengthening of the appointment system component of the Ideal Clinic model to improve patient waiting time. Assessing facility waiting time performance in terms of average time spent by patients during a clinic visit was shown to be inadequate, and we suggest the inclusion of ‘proportion of clients who spent above the national waiting time threshold during their visit’ as a sensitive measure of performance. S Afr Med J 2018;108(4):311-318. DOI:10.7196/SAMJ.2018.v108i4.12583

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12583

April 2018, Print edition

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Near-real-time tracking of gaps in prevention of mother-to-child transmission of HIV in three districts of KwaZulu-Natal Province, South Africa F Moyo,1,2,6 MSc; A Haeri Mazanderani,2,3 MB ChB; S Bhardwaj,4 MB BS, MD, MPH; O B Mhlongo,5 B Cur; T Kufa,2,6 MB ChB, MPH, PhD; K Ng’oma,4 MB BS, MSc; B A Smith,4 B Tech; G G Sherman,1,2,7 MB BCh, MMed, PhD Paediatric HIV Diagnostics, Wits Health Consortium, Johannesburg, South Africa Centre for HIV and STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa 3 Department of Medical Virology, Faculty of Health Sciences, University of Pretoria, South Africa 4 United Nations Children’s Fund (UNICEF), Pretoria, South Africa 5 National Department of Health, KwaZulu-Natal Province, South Africa 6 School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 7 Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: F Moyo (faithmo@nicd.ac.za) Background. Identifying and addressing gaps in the prevention of mother-to-child transmission of HIV (PMTCT) is required if South Africa (SA) is to achieve targets for eliminating MTCT (eMTCT). Potential PMTCT gaps that increase MTCT risk include late maternal HIV diagnosis, lack of or delayed antiretroviral therapy (ART) during pregnancy and breastfeeding, and lack of effective prophylaxis for HIV-exposed infants. Objectives. To investigate, in near real time, PMTCT gaps among HIV-infected infants in three districts of KwaZulu-Natal Province, SA. Methods. Between May and September 2016, PMTCT co-ordinators from eThekwini, uMgungundlovu and uMkhanyakude districts received daily email notification of all HIV polymerase chain reaction (PCR)-positive results. Co-ordinators reviewed facility records for each infant to identify gaps in PMTCT care, including maternal age, timing of maternal HIV diagnosis, maternal treatment history and maternal viral load (VL) monitoring. Data were submitted via the mobile phone SMS (text message) service using Rapid Pro technology and analysed in Stata 14. Results. Data on PMTCT gaps were received for 367 (91.8%) of 400 infants with HIV PCR-positive results, within a median time of 12.5 days (interquartile range (IQR) 6 - 23). The median maternal age was 25 years (IQR 22 - 30), with 48 teenage mothers (15 - 19 years). The sample size was too small to determine whether there were significant differences in PMTCT gaps between the 48 teenage mothers and 293 older (20 - 34 years) mothers. Of the mothers, 220 (60.0%) were first diagnosed prior to conception or at their first antenatal care (ANC) visit, and 127 (34.6%) at or after delivery; 137 (37.3%) transmitted HIV to their infants despite receiving >12 weeks of ART. VL results were unavailable for 70.0% of women. Only 41 (17.5%) of women known to be HIV-positive during ANC had confirmed virological suppression. No statistically significant differences in PMTCT gaps were observed between districts, owing to small sample sizes in uMgungundlovu and uMkhanyakude. Conclusions. The findings highlight the need to improve services during ANC, in particular prioritising maternal VL monitoring. We intend to use improved technology to streamline data collection and reporting towards eMTCT. S Afr Med J 2018;108(4):319-324. DOI:10.7196/SAMJ.2018.v108i4.12630

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12630

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Hypertension as the trigger for posterior reversible encephalopathy syndrome in paediatric renal patients: An important diagnosis that should not be missed J K Strong, MB ChB; K L Petersen, MB ChB; U Kala, MB ChB Department of Paediatrics, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: J K Strong (jessie.rule@gmail.com) Background. Posterior reversible encephalopathy syndrome (PRES) is a reversible neurological condition presenting with seizures and visual disturbances and diagnosed on magnetic resonance imaging (MRI). Little is understood about its pathogenesis, particularly in children, but it is thought to be related to hypertension. Objectives. To review the presentation, diagnosis and outcome of PRES in paediatric renal patients at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, between 1 January 2000 and 31 January 2017 and compare these with published case reports to date. Methods. This was a retrospective analysis of five new cases and a review of the existing literature. Results. The five reported patients were all hypertensive at the time of diagnosis and presented with seizures. Most (91%) of the 64 reviewed patients were also hypertensive at initial presentation. All five of the reported and 91% of the reviewed patients presented with seizures. The most common pattern of change on MRI occurred in the parietal and occipital regions. Complete neurological recovery occurred in four of the five reported and 87.5% of the reviewed patients. Conclusion. All patients presented clinically with hypertensive crises and radiological evidence of PRES. Seizures were the most common presenting symptom. The prognosis for paediatric patients with PRES is favourable, so it is important to confirm the diagnosis in lowresource settings where intensive care is limited. S Afr Med J 2018;108(4):325-328. DOI:10.7196/SAMJ.2018.v108i4.12816

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12816

Evaluating the effect of ward-based outreach teams on primary healthcare performance in North West Province, South Africa: A plausibility design using routine data T Assegaai,1 BCom, MPH; G Reagon,1 MB ChB, FCPHM; H Schneider,1,2 MB ChB, MMed, PhD 1 2

School of Public Health, University of the Western Cape, Cape Town, South Africa niversity of the Western Cape/South African Medical Research Council Health Services to Systems Unit, University of the Western Cape, U Cape Town, South Africa

Corresponding author: T Assegaai (mampetumelo@yahoo.com) Background. North West Province (NWP), South Africa, was an early adopter of the primary healthcare (PHC) ward-based outreach team (WBOT) strategy and has made considerable progress in implementing it. Given the interest in and expectations of greater investment in WBOTs, assessing their impact on and contribution to PHC outputs and health outcomes is becoming increasingly important. Objectives. To describe the application of a plausibility evaluation design for assessing the contribution of WBOTs to PHC performance in NWP, comparing changes in coverage, utilisation and outcome indicators in facilities with and without WBOTs. Methods. Routine data from the District Health Information System on both WBOTs and PHC facilities for the period 2011/12 (prior to implementation) to 2014/15 (3 years after implementation began) were extracted. Analysis involved the following three steps: (i) selection of

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indicators sensitive to community-based action; (ii) data cleaning; and (iii) comparison of the degree of change in median indicator values between 2011/12 and 2014/15 in facilities with and without WBOTs (a difference-in-differences analysis). Results. Changes in indicator values in facilities were grouped into four categories: (i) indicators where there was greater (statistically significant) improvement in facilities with WBOTs (couple year protection rate, measles immunisation coverage in children aged <1 year, incidence of children aged <5 years with severe diarrhoea with dehydration); (ii) indicators that declined or worsened, but less so in facilities with WBOTs at statistically significant levels (antenatal first visits as a percentage of children born in that year, PHC utilisation rate of children aged <5 years); (iii) indicators that improved in all facilities with no significant difference between facilities with and without WBOTs (antenatal attendance before 20 weeks, prophylactic vitamin A coverage to children aged 12 - 59 months); and (iv) indicators that remained unchanged in all facilities (immunisation coverage in children aged <1 year, postnatal mother visits at 6 days, cervical cancer screening coverage in women aged ≥30 years, PHC utilisation rate of children aged ≥5 years). Conclusion. Notwithstanding the limitations of routine data and the need to approach the findings with caution, this analysis suggests that WBOTs plausibly had some positive effects on the overall performance of the PHC system. We propose a methodology to monitor the performance of WBOTs using routine PHC indicators that programme managers could apply elsewhere. S Afr Med J 2018;108(4):329-335. DOI:10.7196/SAMJ.2018.v108i4.12755

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12755

An investigation of barriers to the use of the World Health Organization Surgical Safety Checklist in theatres S Verwey, MB ChB, DA (SA), FCA (SA); P D Gopalan, MB ChB, DA (SA), FCA (SA), Crit Care (Anaesthetics) Department of Anaesthesiology and Critical Care, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Corresponding author: S Verwey (stefneventer@hotmail.com) Background. The World Health Organization (WHO) has implemented the Surgical Safety Checklist (SSCL) as part of the Safe Surgery Saves Lives campaign. This is aimed at improving surgical safety worldwide. Despite many perceived benefits of the SSCL, compliance and acceptance in many areas remain poor. Objectives. To investigate perceptions of theatre staff regarding the checklist and to identify reasons and barriers for poor compliance and implementation. Methods. Questionnaires were handed out to theatre teams across all surgical disciplines at two large hospitals in Durban, South Africa, over a 2-week period. Data collected included role in theatre, intention of the SSCL, training received, as well as questions regarding previously identified barriers and staff perceptions. Results. Questionnaires were distributed to 225 practitioners, with a response rate of 81.7% from 51 nurses, 54 anaesthetists and 79 surgeons. Rank of medical staff included 52 seniors (consultants) and 81 juniors (registrars and medical officers). The majority (95%) of respondents perceived the SSCL as intended to improve safety, prevent errors or reduce morbidity and mortality. A total of 146 respondents (79.3%) received no SSCL training. No new barriers were identified, but previously identified barriers were confirmed. Our key factors were time-related issues and lack of buy-in from team members. Surgeons were perceived as being supportive by 45.1% of respondents, in contrast to nurses (62.5%), anaesthetists (70.1%) and management (68.5%). When compared with junior staff, senior staff were 5-fold more likely to feel that staff did not need to be trained and 8-fold more likely to indicate that the checklist did not improve patient safety. Conclusions. The WHO SSCL is an important tool in the operating room environment. The barriers in our setting are similar to those identified in other settings. There needs to be widespread training in the use of the SSCL, including adaptation of the checklist to make it fit for purpose in our setting. Improving use of the checklist will allow theatre staff to work together towards ensuring a safer theatre environment for both patients and staff. S Afr Med J 2018;108(4):336-340. DOI:10.7196/SAMJ.2018.v108i4.12780

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12780

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RESEARCH

The usefulness of routine histological examination of appendicectomy specimens in a South African tertiary centre O O Jolayemi,1 FCS (SA); N B Moodley,2 FCS (SA); V Y Kong,2 MSc, PhD, MRCS; B Tlou,3 PhD; J L Bruce,2 FCS (SA); D L Clarke,1,2,4 MPhil, MBA, PhD, FCS (SA) epartment of Surgery, Ngwelezane Hospital and Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZuluD Natal, Durban, South Africa 2 Department of Surgery, Pietermaritzburg Hospital Complex and Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 3 Department of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 4 Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: O O Jolayemi (funsozn@hotmail.com) Background. It is accepted surgical practice to send all appendicectomy specimens for histological examination, but the usefulness and cost associated with this practice have not been established in our setting, a tertiary hospital in KwaZulu-Natal Province, South Africa (SA). Objectives. To determine the histological diagnoses of appendicectomy specimens in our centre, and the cost of identifying an alternative histological diagnosis requiring further treatment. Methods. Clinical data on patients undergoing appendicectomy for suspected acute appendicitis during the study period December 2012Â August 2015 were retrospectively retrieved from the hybrid electronic medical registry. Histological data were then extracted from the National Health Laboratory Service database. The cost of an appendicitis histology report was sourced from a private laboratory service. Results. A total of 290 patients were identified during the study period. Males had a significantly higher risk (p<0.0001) than females of histologically confirmed appendicitis (odds ratio 3.2, 95% confidence interval 1.7 - 5.8). The negative appendicectomy rate was 22.4% (n=65/290). In 5.9% of specimens (n=17/290) an alternative diagnosis was made on histological examination, which influenced the management plan. These were parasitic co-infections in 13 cases (4.5%), premalignant conditions in 2 and tuberculosis in 2. The average cost of processing each appendicectomy specimen was ZAR871. The cost of identifying each patient with an alternative diagnosis that required treatment was ZAR14 858 ([290 Ă&#x2014; ZAR871]/17). Conclusions. This audit correlates with other SA studies showing that the aetiological differential for appendicitis is broad. Histological examination therefore remains critical in the management of patients with suspected acute appendicitis in our clinical setting. S Afr Med J 2018;108(4):342-346. DOI:10.7196/SAMJ.2018.v108i4.12759

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12759

April 2018, Print edition

RESEARCH

Potential latitudinal variation in orodigestive tract cancers in Africa H A Adeola,1,2 BDS, PhD (Med); A O Adefuye,3 MB ChB, PhD (Med); S A Jimoh,4 BSc, PhD (Med) epartment of Oral and Maxillofacial Pathology, Faculty of Dentistry, University of the Western Cape and Tygerberg Hospital, Cape Town, South Africa D Division of Dermatology, Department of Medicine, Faculty of Health Sciences and Groote Schuur Hospital, University of Cape Town, South Africa 3 Division Health Sciences Education, Office of the Dean, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 4 Department of Anatomical Sciences, Faculty of Health Sciences, Walter Sisulu University, Mthatha, Eastern Cape, South Africa 1 2

Corresponding author: H A Adeola (henry.adeola@uct.ac.za) Background. Previous studies have alluded to a causal relationship between pathological entities and geographical variations, but there is a paucity of studies from Africa discussing the effect of latitudinal variation on orodigestive cancers in this region. It seems plausible that the burden of orodigestive cancer would differ as a result of variations in diet, cultural habits, climate and environmental conditions down the length of Africa. Objectives. To analyse regional variations in prevalence, incidence and mortality data in the global cancer statistics database (GLOBOCAN 2012) curated by the World Health Organization and the International Agency for Research on Cancer. Basic descriptive statistical tools were used to depict regional variations in cancer morbidity and mortality. Methods. Data on 13 African countries between longitude 20⁰ and 30⁰ east and latitude 35⁰ north and 35⁰ south were examined for variation in age-standardised orodigestive cancer prevalence, incidence and mortality. Possible regional causes for orodigestive tract cancer development were investigated. Data on lip and oral cavity, oesophageal, gastric, colorectal, liver, gallbladder and pancreatic cancers in the 13 countries were compared. Results. Our empirical findings from this preliminary study support the notion that the incidence and prevalence of orodigestive cancers vary within Africa. This effect may be due to environmental, economic, political and possibly genetic factors. Conclusions. Considering the heterogeneity of the above factors across Africa, disbursement of funding for cancer research and therapy in Africa should be focused in terms of regional variations to make best use of the fiscal allocation by African governments, non-governmental organisations and international agencies. S Afr Med J 2018;108(4):347-351. DOI:10.7196/SAMJ.2018.v108i4.12908

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12908

April 2018, Print edition

RESEARCH

Seasonal variations in Schistosoma haematobium egg excretion in school-age girls in rural KwaZulu-Natal Province, South Africa E E Christensen,1,2 MD; M Taylor,3 PhD; S G Zulu,3 MSc; K Lillebo,1,2 MD; S G Gundersen,4,5 MD, PhD; S Holmen,1,2 MD, PhD; E Kleppa,1,2 MD, PhD; B J Vennervald,6 MD, MSA, PhD; P D Ndhlovu,7 MSc, PhD; E F Kjetland,1,3 MD, PhD Norwegian Centre for Imported and Tropical Diseases, Department of Infectious Diseases Ullevaal, Oslo University Hospital, Norway Faculty of Medicine, University of Oslo, Norway 3 Discipline of Public Health Medicine, Nelson R Mandela School of Medicine, School of Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 4 Department of Global Development and Planning, Faculty of Social Sciences, University of Agder, Kristiansand, Norway 5 Research Department, SĂ¸rlandet Hospital HF, Kristiansand, Norway 6 Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 7 Imperial College London, UK 1 2

Corresponding author: E E Christensen (erikegelandchristensen@gmail.com) Background. A predominant feature of Schistosoma haematobium infection is urinary egg excretion, and microscopic egg detection remains the accepted standard field diagnostic tool. Praziquantel is the drug of choice for schistosomiasis, and the World Health Organization recommends that it should be administered to all children >4 years of age living in schistosomiasis-endemic areas. The frequency of mass drug administration depends on the prevalence rate in the community. Urinary schistosome egg output has a day-to-day and hour-to-hour intrasubject variation. Therefore, it is important to assess possible seasonal variations in egg excretion to improve the planning of drug treatment. Objectives. To assess the influence of seasonality on urinary schistosome egg excretion in South Africa (SA). Methods. We performed a prospective cohort study, exploring seasonal variations of S. haematobium egg excretion in 184 girls aged 10 - 12 years from randomly selected schools in a rural area of KwaZulu-Natal Province, SA. The area has a subtropical climate characterised by a cool dry season and a hot humid season. For children, water contact is higher in the latter season. At baseline, 108 girls were examined in the hot season, and 76 in the cold season. In the next yearâ&#x20AC;&#x2122;s cold season the untreated patients were re-investigated before treatment. Results. There was a decrease in infection in the group initially tested in the hot season compared with the group tested in the cold season at both time points when adjusted for age and water contact (adjusted odds ratio 3.61 (95% confidence interval 1.14 - 11.44); p=0.03). Conclusions. This unique study shows that schistosomiasis prevalence determined by microscopy exhibits seasonal variation, with a higher prevalence in the hot rainy season. Precise community prevalence estimations are key in decisions to treat communities. There was significantly lower egg output in the cold season, and sampling in that season may therefore underestimate the prevalence of urinary schistosomiasis. The study indicates that sampling in SA should be done in the hot season. S Afr Med J 2018;108(4):352-355. DOI:10.7196/SAMJ.2018.v108i4.12775

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i4.12775

April 2018, 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

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PATHOLOGIST POSITION IN WESTERN CAPE Lancet Laboratories is one of the leading Pathology laboratories providing vital diagnostic and monitoring pathology services throughout Africa. We are seeking to employ a Clinical Pathologist in the Somerset West / Helderberg basin area in the Western Cape. We are looking for a passionate professional, with high levels of ethics and integrity, who adopts a patient and customercentric approach. The incumbent will be responsible for diagnostic testing and to promote and deliver professional, commercially viable, quality results. Knowledge of quality processes will be a valuable attribute for this position.

Requirements • MMed or FCPath (Clinpath) • Current registration with the HPCSA as a Pathologist

Interested applicants should email required documents to amalia.vwyk@lancet.co.za by the 30th of April 2018. • CV • Qualifications • Certified ID Copy • Proof of SARS & HPCSA registration

Pathologist position in Western Cape *Lancet Laboratories shall apply the principles as set out in its Employment Equity, Recruitment and all other associated policies and procedure.

Lancet Laboratories, is one of the leading Pathology laboratories providing vital diagnostic and monitoring pathology services throughout Africa. We are seeking to employ a Clinical Pathologist in the Somerset West / Helderberg basin area in the Western Cape.

Pathologist position in Weste

We are looking for a passionate professional, with high levels of ethics and integrity, who adopts a patient and customer-centric approach. The incumbent will be responsible for diagnostic testing and to promote and deliver professional, commercially viable, quality Lancet Laboratories, is one of the leadin results. Knowledge of quality processes will be a valuable attribute for this position. and monitoring pathology services throu

Pathologist in the Somerset West / Held

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

CONSULTANT BREAST RADIOLOGIST • Opportunity to grow your career • Excellent remuneration package • Relocation assistance • Innovative practice • Positive, supportive, dedicated team St Marks Group in Auckland, New Zealand seeks a Consultant Breast Radiologist to join our well-established practice and multi-disciplinary team of breast specialists. You will have experience in all forms of breast imaging, including digital and analogue mammography, breast ultrasounds, as well as ultrasound-guided biopsies, sentinel node injections and preoperative localisations. You should also possess outstanding clinical and interpersonal skills. Full- or part-time (minimum 0.4 FTE) option considered, with assistance offered to obtain further sessions in general radiology. This is an exciting opportunity to deliver a high-quality customer-centred service in both the private St Marks Breast Centre and the public Breastscreen Auckland clinics. You will be part of a progressive and exciting business and a warm and professional team. This is an excellent place to forge your specialist career and contribute to the very best in patient care. We offer an excellent remuneration package, a sign-on bonus for a Radiologist working a minimum of 0.4FTE and relocation assistance. Please direct applications to: Debbie van Ryswyk, Group General Manager St Marks Group d.vanryswyk@smwh.co.nz | Phone: (64)-9-5223871 | ‘smwh.co.nz’

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• Registration with the HPCSA • Accredited training where applicable • Malpractice indemnity Contact details Email CV, ID/passport, proof of HPCSA registration, accreditation certificates and malpractice indemnity to: DrMaphisa@listerclinic.com; mobile: 083-527-7913

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April 2018

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True (A) or false (B): SAMJ A proposed management algorithm for late-onset efavirenz neurotoxicity 1. Since September 2016, all individuals in South Africa (SA) who are diagnosed as HIV-positive are immediately eligible for antiretroviral therapy (ART), regardless of CD4+ count. The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa 2. Malignant pleural effusion may complicate most malignancies. 3. Lung and breast cancer are uncommon causes of malignant pleural effusions. Blood and virus detection on barber clippers 4. Human scalp hair varies significantly in curvature, and individuals of African ancestry have hair with the tightest curl.

CME Elevated triglycerides: A matter of the heart and pancreas 11. Mild-to-moderate hypertriglyceridaemia (triglyceride (TG) >1.7 - 10.0 mmol/L) is an independent cardiovascular risk factor, while severe hypertriglyceridaemia (TG >10.0 mmol/L) can cause acute pancreatitis. 12. The two most important clinical consequences of hypertriglyceridaemia are acute pancreatitis and atherosclerotic cardiovascular disease (CVD). 13. When and if pancreatitis will occur in an individual patient is quite unpredictable â&#x20AC;&#x201C; some patients may have TG levels of >100.0Â mmol/L and no symptoms, while others develop pancreatitis at much lower TG levels. 14. Mild-to-moderate hypertriglyceridaemia is generally only identified on laboratory testing.

The usefulness of routine histological examination of appendicectomy specimens in a South African tertiary centre 8. The lifetime risk of developing appendicitis is 8.6% and 6.7% in males and females, respectively.

Novel approaches to lipid-lowering therapy 15. It is clinically useful to demarcate hypercholesterolaemia from hypertriglyceridaemia, with an increased serum low-density lipoprotein (LDL) cholesterol being the most powerful predictor of CVD morbidity and mortality, and a significant elevation in TG levels, increasing the risk of acute pancreatitis. 16. When managing dyslipidaemia, it is clinically useful to separate hyperlipidaemia into two main categories, i.e. hypertriglyceridaemia and hypercholesterolaemia, particularly an increase in serum LDL cholesterol concentrations. 17. If diet and lifestyle advice does not lower LDL cholesterol sufficiently, the current mainstay of treatment of elevated LDL cholesterol are the 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors or statins

Potential latitudinal variation in orodigestive tract cancers in Africa 9. Cancer mortality is relatively high in blacks owing to factors such as population-specific high incidences of cancer, late stage at diagnosis and poor survival profiles. 10. A latitudinal relationship has been found between the typical diet in the Mediterranean region (high olive oil consumption) and a low risk of development of myocardial infarction.

Laboratory investigations in lipidology 18. Lipids are transported as lipoproteins. 19. Cholesterol is vital to animal cell membranes, functions in signalling during embryogenesis, and is the substrate for steroid hormone and bile acid synthesis. 20. Most lipidological investigation assesses CVD risk and monitors treatment response.

Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa 5. Globally 700 000 people currently die each year from drugresistant infections. 6. Antibiotic resistance in an individual patient is evident for 1 month following an antibiotic course and can last for up to 12 months. 7. Eighty percent of antibiotics prescribed for human use are in primary care.

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April 2018, Print edition

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