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1. Regeneration of Pancreatic Beta Cells by Modulation of Molecular Targets Using Plant-Derived Compounds: Pharmacological Mechanisms and Clinical Potential

Author: Clare Njoki Kimani, Helmuth Reuter, Sanet Henriët Kotzé, and Christo John Fredrick Muller
Subjects: beta cell, regeneration, plant compounds, plasticity, molecular targets, Biology (General), QH301-705.5
Abstract: Type 2 diabetes (T2D) is characterized by pancreatic beta-cell dysfunction, increased cell death and loss of beta-cell mass despite chronic treatment. Consequently, there has been growing interest in developing beta cell-centered therapies. Beta-cell regeneration is mediated by augmented beta-cell proliferation, transdifferentiation of other islet cell types to functional beta-like cells or the reprograming of beta-cell progenitors into fully differentiated beta cells. This mediation is orchestrated by beta-cell differentiation transcription factors and the regulation of the cell cycle machinery. This review investigates the beta-cell regenerative potential of antidiabetic plant extracts and phytochemicals. Various preclinical studies, including in vitro, in vivo and ex vivo studies, are highlighted. Further, the potential regenerative mechanisms and the intra and extracellular mediators that are of significance are discussed. Also, the potential of phytochemicals to translate into regenerative therapies for T2D patients is highlighted, and some suggestions regarding future perspectives are made.
Published: 2023
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2. Incident tuberculosis disease in patients receiving biologic therapies in the Western Cape, South Africa from 2007 to 2018

Author: Tessa du Toit, Tonya M. Esterhuizen, Nicki Tiffin, Ahmed A. Abulfathi, Helmuth Reuter, and Eric H. Decloedt
Subjects: Tumour necrosis factor-alpha (TNF-α), Biologics, Tuberculosis, South Africa, Infectious and parasitic diseases, RC109-216
Abstract: Abstract Background South Africa has one of the highest tuberculosis incidence rates. Biologic disease-modifying anti-rheumatic drugs are associated with an increased risk of tuberculosis. The objective of this study was to describe the tuberculosis disease incidence rate among public sector patients receiving biologic therapies in the Western Cape Province. Methods A retrospective, descriptive analysis was undertaken using routine health data collated by the Provincial Health Data Centre from January 2007 (first use of biologic therapy in the Western Cape) to September 2018. Results We identified 609 patients treated with tumour necrosis factor-alpha (TNF-α) or non-TNF-α biologic therapies. Thirty-seven (37) patients developed tuberculosis after biologic therapy exposure, of whom the majority (78%) had an immune mediated inflammatory disease and the remainder (22%) a haematologic malignancy. The incidence rate of tuberculosis per 100,000 person-years was 2227 overall [95% confidence interval (CI): 1591, 3037]. Patients treated with TNF-α inhibitors and non-TNF-α inhibitors had estimated incidence rates of 2819 [95% CI: 1669, 4480] and 1825 [95% CI: 1131, 2797], respectively (p = 0.10). Conclusion Patients exposed to both TNF-α and non-TNF-α biologic therapies may have a higher incidence of tuberculosis disease compared to the background risk of 681 cases per 100,000 per year in the Western Cape.
Published: 2020
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3. A retrospective review of calls to the Poisons Information Helpline of the Western Cape during the first 6 months of the COVID-19 pandemic in South Africa

Author: Catharina E. du Plessis, Farah Mohamed, Cindy R. Stephen, Helmuth Reuter, Gonwayne Voigt, Daniel J. van Hoving, and Carine J. Marks
Subjects: covid-19, poison helpline, poison exposures, pharmaceuticals, antiseptics and disinfectants, Infectious and parasitic diseases, RC109-216
Abstract: Background: Since the start of the coronavirus disease 2019 (COVID-19) pandemic, poison centres worldwide have reported an increase in exposures to chemicals used for infection prevention. Increased availability and use could lead to an increase in exposures. Potential effects on a South African Poison Information Helpline were unknown, therefore a study was performed to describe changes in call volume and profile of poison exposures. Methods: A retrospective analysis was conducted on an observational database of telephone enquiries. All human-related poisoning exposure call data collected from 01 March to 31 August during 2018, 2019 and 2020 were extracted and analysed. Summary statistics were used to describe all variables. Results: The total number of calls were 5137, 5508, and 5181 in 2018, 2019, 2020, respectively. The monthly call number during 2020 was mostly less than in 2019. More calls were received from the public calls (39.4% vs 33.1%) and for accidental exposures (65.6% vs 62.3%) increased during 2020 compared to 2019. Exposures to pharmaceuticals decreased by 14.8% from 2019 to 2020, while exposures to eucalyptus oil more than doubled from 21 in 2019 to 43 during 2020. Exposures to antiseptics and disinfectants increased by 60.4%, mainly due to hand sanitisers exposure which showed a 26-fold increase from 2019 (n = 6) to 2020 (n = 156). Conclusion: A change in the profile of poison exposures was observed during the COVID-19 pandemic. Lockdown regulations and greater availability of antiseptics and disinfectants probably led to the increase in exposures. Although symptoms were mostly mild, the public should be educated on safe storage and proper use of all chemicals.
Published: 2022
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4. Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model

Author: Tracey Ollewagen, Gareth S. Tarr, Kathryn H. Myburgh, Helmuth Reuter, and Carine Smith
Subjects: Pathology, RB1-214
Abstract: Background. The loss of muscle mass in rheumatoid arthritis (RA), termed rheumatoid cachexia, is predicted to result from the complex interactions between different cell types involved in the maintenance of skeletal muscle mass, namely, myoblasts, fibroblasts, and macrophages. The complexity within the muscle is further highlighted by the incidence of nonresponsiveness to current RA treatment strategies. Method. This study aimed at determining differences in the cellular responses in a novel human primary cell triple coculture model exposed to serum collected from nonarthritic controls (NC), RA treatment naïve (RATN), and RA treatment-nonresponding (RATNR) patients. Bone morphogenetic protein-7 (BMP-7) was investigated as a treatment option. Results. Plasma analysis indicated that samples were indeed representative of healthy and RA patients—notably, the RATNR patients additionally exhibited dysregulated IL-6/IL-10 correlations. Coculture exposure to serum from RATNR patients demonstrated increased cellular growth (p
Published: 2022
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5. The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

Author: Ahmed A. Abulfathi, Veronique de Jager, Elana van Brakel, Helmuth Reuter, Nikhil Gupte, Naadira Vanker, Grace L. Barnes, Eric Nuermberger, Susan E. Dorman, Andreas H. Diacon, Kelly E. Dooley, and Elin M. Svensson
Subjects: meropenem, population pharmacokinetic (PK) model, tuberculosis, pharmacokinetics analysis, drug sensitive TB, Therapeutics. Pharmacology, RM1-950
Abstract: Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
Published: 2021
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6. The epidemiology and severity of scorpion envenoming in South Africa as managed by the Tygerberg Poisons Information Centre over a 10 year period

Author: Carine J. Marks, Gert J. Muller, Dmitrij Sachno, Helmuth Reuter, Cherylynn A. Wium, Catharina E. Du Plessis, and Daniel J. Van Hoving
Subjects: Medicine, Medicine (General), R5-920
Abstract: Introduction: South Africa has a wide distribution of scorpion species, yet limited data are available regarding the incidence and severity of scorpion envenomation. The aim of this study was to analyse South African epidemiological data of scorpion stings and envenomation as reported to the Tygerberg Poisons Information Centre (TPIC). Methods: A retrospective analysis was conducted of scorpion-related telephonic consultations to the TPIC over a ten year period (1 January 2005 to 31 December 2014). Data were entered onto a Microsoft Excel® spreadsheet and descriptive statistics are presented for all variables. Associations with severity of envenomation are presented as odds ratios (OR) with 95% confidence intervals (95%CI). Results: During the study period 52,163 consultations were processed by the TPIC of which 740 (1.4%) cases involved scorpion stings. Of these, 146 (19.7%) cases were deemed serious envenomations. Antivenom was recommended to be administered in 131 (90%) of these cases. Healthcare professionals made most calls (63%), but were less likely to phone for non-serious cases (OR 0.16; 95%CI 0.09 to 0.29). The Western Cape Province had the highest incidence of calls (6.9 scorpion-related calls/100 000 people). Adults (>20 years) were victims in 71.4% of cases, and were more likely to experience less serious stings (OR 0.57; 95%CI 0.37 to 0.86). The TPIC was consulted within six hours of the sting occurring in 356 (48.1%) cases with a significant association to less severity (OR 3.51; 95%CI 1.9 to 6.3). Only 2% (15) of the scorpions were available for identification. Conclusion: The incidence of severe scorpionism to the TPIC was low. Care should be taken when children are involved and when calls are received more than six hours after the sting. TPIC consultants as well as healthcare professionals working in semi-arid regions should be aware of these high risk populations. Keywords: Scorpion sting, Scorpionism, Envenomation, Epidemiology, Poisons centre, South Africa
Published: 2019
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7. Higher SARS-CoV-2 seroprevalence in workers with lower socioeconomic status in Cape Town, South Africa.

Author: Jane Alexandra Shaw, Maynard Meiring, Tracy Cummins, Novel N Chegou, Conita Claassen, Nelita Du Plessis, Marika Flinn, Andriette Hiemstra, Léanie Kleynhans, Vinzeigh Leukes, Andre G Loxton, Candice MacDonald, Nosipho Mtala, Helmuth Reuter, Donald Simon, Kim Stanley, Gerard Tromp, Wolfgang Preiser, Stephanus T Malherbe, and Gerhard Walzl
Subjects: Medicine, Science
Abstract: BackgroundInequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known.MethodsWe tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population.ResultsOf the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls.ConclusionsThere is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.
Published: 2021
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8. Speckle tracking echocardiography in acute lupus myocarditis: comparison to conventional echocardiography

Author: Riëtte Du Toit, Phillip G Herbst, Annari van Rensburg, Hendrik W Snyman, Helmuth Reuter, and Anton F Doubell
Subjects: myocarditis, systemic lupus erythematosus, speckle tracking echocardiography, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Aims: Lupus myocarditis occurs in 5–10% of patients with systemic lupus erythematosus (SLE). No single feature is diagnostic of lupus myocarditis. Speckle tracking echocardiography (STE) can detect subclinical left ventricular dysfunction in SLE patients, with limited research on its utility in clinical lupus myocarditis. We report on STE in comparison to conventional echocardiography in patients with clinical lupus myocarditis. Methods and results: A retrospective study was done at a tertiary referral hospital in South Africa. SLE patients with lupus myocarditis were included and compared to healthy controls. Echocardiographic images were reanalyzed, including global longitudinal strain through STE. A poor echocardiographic outcome was defined as final left ventricular ejection fraction (LVEF)
Published: 2017
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9. An overview of the biological disease modifying drugs available for arthritic conditions in South Africa

Author: Leonie Harmse and Helmuth Reuter
Subjects: tnf-α inhibitors, non-tnf-α biological agents, anti-rheumatic drugs, monoclonal antibodies, fusion proteins, immune modulators, Medicine
Abstract: The past decade has seen a major change in the treatment options and strategies for rheumatoid arthritis (RA) and the other immune-mediated arthritic diseases. The disease modifying antirheumatic drugs (DMARDs) are now used in early stages of the disease in order to preserve joint architecture. There are two groups of DMARDs, the small molecules, like methotrexate, and the biological DMARDs, which are frequently referred to as “magic bullets” since they target specific cytokines and immune cells associated with arthritic conditions. They are monoclonal antibodies or fusion proteins designed to bind and inactivate immune targets. Tumour necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of rheumatoid disorders and is the target of four biological DMARDs, etanercept, infliximab, golimumab and adalimumab. The other biological DMARDs include abatacept, rituximab and tocilizumab and these prevent T-cell costimulation, cause the depletion of mature CD20 positive B cells or prevent the activation of the interleukin-6 receptor molecule, respectively. Ustekinumab, a monoclonal antibody against IL12/IL23 is effective in psoriatic arthritis. Biological agents are indicated when patients do not respond adequately to the traditional DMARDs. Numerous clinical trials have shown that the biological agents reduce joint inflammation and erosive damage, especially when used in combination with methotrexate. Apart from their prohibitive cost, the biological agents are not without potentially serious adverse effects with infections being the main concern. The TNF-α inhibitors increase the risk for tuberculosis and other opportunistic infections, whereas the non-TNF-α immune inhibitors increase the risk for opportunistic viral, fungal and bacterial infections. This review provides an overview of the biological agents currently available in South Africa.
Published: 2016
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10. Review of the safety of nonsteroidal anti-inflammatory drugs and selective cyclo-oxygenase-2 inhibitors

Author: G. S. Tarr and Helmuth Reuter
Subjects: nonsteroidal anti-inflammatory drugs, nsaids, cox-2 inhibitors, Medicine
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most common classes of medication used worldwide, and as the ageing population increases, the prevalence of painful arthritic conditions parallels this, resulting in the increased use of NSAIDs. Selective and nonselective cyclo-oxygenase inhibitors should be avoided, or at best used for short periods at the lowest possible effective dose, in patients with underlying artherosclerotic coronary disease.
Published: 2015
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11. Non-allopathic adjuvant management of osteoarthritis by alkalinisation of the diet

Author: David P. van Velden, Helmuth Reuter, Martin Kidd, and F. Otto Müller
Subjects: Medicine, Public aspects of medicine, RA1-1270
Abstract: Background: Osteoarthritis (OA) is a chronic condition. Nonsteroidal anti-inflammatory drugs recommended for treatment have serious adverse effects. A compelling body of anecdotal evidence alerted the authors to the therapeutic potential of dietary supplementation with Multiforce® (MF) Alkaline Powder for relief of OA symptoms. Aim: The aim of the study was to test the hypothesis that dietary supplementation with MF relieves clinical signs and symptoms of OA of the hands. Setting: The study was done at the MEDSAC hospital in Somerset West, Western Cape, South Africa. Methods: The research was conducted in two stages. An open interventional study (n = 40) confirmed the notion that MF 7.5 g twice daily is likely to be an effective alternative or adjunct for relief of symptoms of OA of the hands. The main study was conducted with 100 eligible, consenting volunteers (aged 47–89 years) according to a randomised, placebo-controlled, crossover design. Study duration was 56 days, 28 days per regimen; crossover to alternate regimens took place on day 28. Results: Compared to placebo, MF intake over 28 days was associated with significant reductions ( p < 0.005) in pain, tenderness and stiffness of interphalangeal and metacarpophalangeal joints of the hand. Confirmation of systemic alkalinisation by MF, which is rich in organic anions in the form of citrate salts, was reflected by a significant and sustained increase in urine pH. Conclusion: A dietary supplement, Multiforce® Alkaline Powder, containing citrate salts which are converted into bicarbonate in vivo, was efficacious and safe as sole therapeutic intervention, significantly attenuating OA-associated signs and symptoms of the hands.
Published: 2015
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12. Sustainability of long-term treatment in a rural district: The Lusikisiki model of decentralised HIV/AIDS care

Author: Nathan Ford, Hermann Reuter, Martha Bedelu, Helen Schneider, and Helmuth Reuter
Subjects: Public aspects of medicine, RA1-1270, Infectious and parasitic diseases, RC109-216
Abstract: No abstract available.
Published: 2006
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13. Psychopathology and coping in recently diagnosed HIV/AIDS patients - the role of gender

Author: Benjamin O Olley, Faniswa Gxamza, Soraya Seedat, Hugo Theron, Dan J Stein, Jantjie Taljaard, Emile Reid, and Helmuth Reuter
Subjects: Psychiatry, RC435-571
Abstract: Background. Although there is growing literature on the psy- chological responses to and the psychopathology associated with HIV/AIDS, few investigations have focused on the role of gender. This study compared psychiatric morbidity, coping responses, and disability in male and female outpatients recently diagnosed with HIV/AIDS. Method. One hundred and forty-nine patients (44 male, 105 female) with HIV/AIDS (mean ± standard deviation (SD) months since diagnosis 5.8 ± 4.1) attending an infectious dis- eases clinic at Tygerberg Hospital, Cape Town, were evaluat- ed. Subjects were assessed using the MINI International Neuropsychiatric Interview (MINI), the Carver Brief COPE, and the Sheehan Disability Scale. In addition, negative life events and risk behaviours were evaluated. Results. Fifty-six per cent of patients were diagnosed with a psy- chiatric disorder, most commonly major depression (34.9%), dysthymic disorder (21.5%), post-traumatic stress disorder (14.8%), and alcohol dependence (10.1%). There were no significant gender differences in the prevalence of mood disor- ders in the sample. Men, however, were more likely than women to meet diagnostic criteria for alcohol abuse or depen- dence, and to engage in certain risky sexual behaviours. Women were more likely to suffer from post-traumatic stress dis- order, and to use coping strategies of planning and religion to deal with the illness. There were no significant gender differ- ences in disability. Conclusion. Psychiatric disorders are common in recently diag- nosed HIV/AIDS patients in South Africa. Clinicians should be aware of the high prevalence of mood disorders in both men and women, and of gender-different responses such as increased alcohol and substance use and more risky sexual behaviour in men.
Published: 2004
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14. Lupus myocarditis: review of current diagnostic modalities and their application in clinical practice

Author: Riette, du Toit, Sumanth, Karamchand, Anton F, Doubell, Helmuth, Reuter, and Phillip G, Herbst
Subjects: Rheumatology, Pharmacology (medical)
Abstract: Lupus myocarditis (LM) is a potentially fatal manifestation of SLE, occurring in 5–10% of patients. Clinical manifestations may vary from an unexplained tachycardia to fulminant congestive cardiac failure (CCF). With no single clinical or imaging modality being diagnostic, a rational and practical approach to the patient presenting with possible LM is essential. Markers of myocyte injury (including troponin I and creatine kinase) may be unelevated and do not exclude a diagnosis of LM. Findings on ECG are non-specific but remain essential to exclude other causes of CCF such as an acute coronary syndrome or conduction disorders. Echocardiographic modalities including wall motion abnormalities and speckle tracking echocardiography may demonstrate regional and/or global left ventricular dysfunction and is more sensitive than conventional echocardiography, especially early in the course of LM. Cardiac magnetic resonance imaging (CMRI) is regarded as the non-invasive diagnostic modality of choice in myocarditis. While more sensitive and specific than echocardiography, CMRI has certain limitations in the context of SLE, including technical challenges in acutely unwell and uncooperative patients, contraindications to gadolinium use in the context of renal impairment (including lupus nephritis) and limited literature regarding the application of recommended diagnostic CMRI criteria in SLE. Both echocardiography as well as CMRI may detect subclinical myocardial dysfunction and/or injury of which the clinical significance remains uncertain. Considering these challenges, a combined decision-making approach by rheumatologists and cardiologists interpreting diagnostic test results within the clinical context of the patient is essential to ensure an accurate, early diagnosis of LM.
Published: 2022

15. Ivermectin for COVID-19: Promising but not yet conclusive

Author: Neshaad Schrueder, Eric H Decloedt, Sa'ad Lahri, Helmuth Reuter, R Van Rensburg, and Arifa Parker
Subjects: 2019-20 coronavirus outbreak, Ivermectin, Drug development, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine, MEDLINE, General Medicine, Medical journal, business, Virology, medicine.drug
Abstract: CITATION: Van Rensburg, R. et al. 2021. Ivermectin for COVID-19 : promising but not yet conclusive. South African Medical Journal, 111(3):188, doi:10.7196/SAMJ.2021.v111i3.15522.
Published: 2022

16. Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab

Author: Emil Hagström, P. Gabriel Steg, Michael Szarek, Deepak L. Bhatt, Vera A. Bittner, Nicolas Danchin, Rafael Diaz, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Evangelos Liberopoulos, Nikolaus Marx, Jennifer McGinniss, Garen Manvelian, Robert Pordy, Michel Scemama, Harvey D. White, Andreas M. Zeiher, Gregory G. Schwartz, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, William J. Sasiela, Jean-François Tamby, Philip E Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N Gotcheva, Juan-Carlos Prieto, Huo Yong, Patricio López-Jaramillo, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Steen Hvitfeldt Poulsen, Margus Viigimaa, Markku S Nieminen, Vakhtang Chumburidze, Pablo Carlos, Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M Correa Flores, Rody G. Sy, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J Dalby, José Tuñón, H. Asita de Silva, Ulf Landmesser, Christian Müller, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean F.P. van Diepen, Matthew D. Wilson, Andrew Tze-Kay Yan, Lilia B Schiavi, Marcelo Garrido, Andrés F Alvarisqueta, Sonia A Sassone, Anselmo P Bordonava, Alberto E Alves De Lima, Jorge M Schmidberg, Ernesto A Duronto, Orlando C Caruso, Leonardo P Novaretto, Miguel Angel Hominal, Oscar R Montaña, Alberto Caccavo, Oscar A Gomez Vilamajo, Alberto J Lorenzatti, Luis R Cartasegna, Gustavo A Paterlini, Ignacio J Mackinnon, Guillermo D Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R Codutti, Horacio O Jure, Julio OE Bono, Adrian D Hrabar, Julio A Vallejos, Rodolfo A Ahuad Guerrero, Federico Novoa, Cristian A Patocchi, Cesar J Zaidman, Maria E Giuliano, Ricardo D Dran, Marisa L Vico, Gabriela S Carnero, Pablo N Guzman, Juan C Medrano Allende, Daniela F Garcia Brasca, Miguel H Bustamante Labarta, Sebastian Nani, Eduardo DS Blumberg, Hugo R Colombo, Alberto Liberman, Victorino Fuentealba, Hector L Luciardi, Gabriel D Waisman, Mario A Berli, Ruben O Garcia Duran, Horacio G Cestari, Hugo A Luquez, Jorge A Giordano, Silvia S Saavedra, Gerardo Zapata, Osvaldo Costamagna, Susana Llois, Jonathon H Waites, Nicholas Collins, Allan Soward, Chris LS Hii, James Shaw, Margaret A Arstall, John Horowitz, Daniel Ninio, James F Rogers, David Colquhoun, Romulo E Oqueli Flores, Philip Roberts-Thomson, Owen Raffel, Sam J Lehman, Constantine Aroney, Steven GM Coverdale, Paul J Garrahy, Gregory Starmer, Mark Sader, Patrick A Carroll, Ronald Dick, Robert Zweiker, Uta Hoppe, Kurt Huber, Rudolf Berger, Georg Delle-Karth, Bernhard Frey, Franz Weidinger, Dirk Faes, Kurt Hermans, Bruno Pirenne, Attilio Leone, Etienne Hoffer, Mathias CM Vrolix, Luc De Wolf, Bart Wollaert, Marc Castadot, Karl Dujardin, Christophe Beauloye, Geert Vervoort, Harry Striekwold, Carl Convens, John Roosen, Emanuele Barbato, Marc Claeys, Frank Cools, Ibrahim Terzic, Fahir Barakovic, Zlatko Midzic, Belma Pojskic, Emir Fazlibegovic, Azra Durak-Nalbantic, Mehmed Kulić, Dusko Vulic, Adis Muslibegovic, Boris Goronja, Gilmar Reis, Luciano Sousa, Jose C Nicolau, Flavio E Giorgeto, Ricardo P Silva, Lilia Nigro Maia, Rafael Rech, Paulo RF Rossi, Maria José AG Cerqueira, Norberto Duda, Renato Kalil, Adrian Kormann, José Antonio M Abrantes, Pedro Pimentel Filho, Ana Priscila Soggia, Mayler ON de Santos, Fernando Neuenschwander, Luiz C Bodanese, Yorghos L Michalaros, Freddy G Eliaschewitz, Maria H Vidotti, Paulo E Leaes, Roberto V Botelho, Sergio Kaiser, Euler Roberto F Fernandes Manenti, Dalton B Precoma, Jose C Moura Jorge, Pedro Silva, Jose A Silveira, Wladmir Saporito, Jose A Marin Neto, Gilson S Feitosa, Luiz Eduardo F Ritt, Juliana A de Souza, Fernando Costa, Weimar KSB Souza, Helder JL Reis, Leandro Machado, José Carlos Aidar Ayoub, Georgi V Todorov, Fedya P Nikolov, Elena S Velcheva, Maria L Tzekova, Haralambi O Benov, Stanislav L Petranov, Haralin S Tumbev, Nina S Shehova-Yankova, Dimitar T Markov, Dimitar H Raev, Mihail N Mollov, Kostadin N Kichukov, Katya A Ilieva- Pandeva, Raya Ivanova, Maryana Gospodinov, Valentina M Mincheva, Petar V Lazov, Bojidar I Dimov, Manohara Senaratne, James Stone, Jan Kornder, Stephen Pearce, Danielle Dion, Daniel Savard, Yves Pesant, Amritanshu Pandey, Simon Robinson, Gilbert Gosselin, Saul Vizel, Gordon Hoag, Ronald Bourgeois, Anne Morisset, Eric Sabbah, Bruce Sussex, Simon Kouz, Paul MacDonald, Ariel Diaz, Nicolas Michaud, David Fell, Raymond Leung, Tycho Vuurmans, Christopher Lai, Frank Nigro, Richard Davies, Gustavo Nogareda, Ram Vijayaraghavan, John Ducas, Serge Lepage, Shamir Mehta, James Cha, Robert Dupuis, Peter Fong, Sohrab Lutchmedial, Josep Rodes-Cabau, Hussein Fadlallah, David Cleveland, Thao Huynh, Iqbal Bata, Adnan Hameed, Cristian Pincetti, Sergio Potthoff, Juan C Prieto, Monica Acevedo, Arnoldo Aguirre, Margarita Vejar, Mario Yañez, Guillermo Araneda, Mauricio Fernandez, Luis Perez, Paola Varleta, Fernando Florenzano, Laura Huidobro, Carlos A Raffo, Claudia Olivares, Leonardo Nahuelpan, Humberto Montecinos, Jiyan Chen, Yugang Dong, Weijian Huang, Jianzhong Wang, Shi’An 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Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M Gilbert, Gopal Chalavarya, Charles Eaton, John F Schmedtje, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Jean- Francois Tamby, Melanie Verrier, Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. 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McClanahan, Roe, Matthew T., Blicharski, Tomasz, Bystryk, Leszek, Szpajer, Michal, Korol, Marek, Czerski, Tomasz, Gniot, Jacek, Lubinski, Andrzej, Gorny, Jerzy, Franek, Edward, Raczak, Grzegorz, Vogel, Robert, Szwed, Hanna, Monteiro, Pedro, Mesquita Bastos, Jose, Pereira, Helder H., Morais, Joao, Seixo, Filipe, Mendonça, Carlos, Botelho, Ana, Caetano, Francisca, Minescu, Bogdan, Chaitman, Bernard, Istratoaie, Octavian, Tesloianu, Dan N., Dorobantu, Maria, Cristian, Gabriel, Dumitrescu, Silviu, Podoleanu, Cristian Gc, Constantinescu, Mircea Ca, Bengus, Cristina M., Militaru, Constantin, Rosu, Doina, Kelsey, Sheryl F., Parepa, Irinel R., Matei, Adrian V., Alexandru, Tom M., Malis, Mihaela, Coman, Ioan, Shvarts, Yury, Orlikova, Olga, Kobalava, Zhanna, Barbarash, Olga L., Markov, Valentin, Olsson, Anders G., Lyamina, Nadezhda, Gordienko, Alexander, Zrazhevsky, Konstantin, Vishnevsky, Alexander Y., Gurevich, Victor, Stryuk, Raisa, Lomakin, Nikita V., Bokarev, Igor, Khlevchuk, Tatiana, Shalaev, Sergey, Rouleau, Jean-Lucien, Khaisheva, Larisa, Chizhov, Petr, Viktorova, Inna, Osokina, Natalya, Shchekotov, Vladimir, Akatova, Evgenia, Chumakova, Galina, Libov, Igor, Voevoda, Mikhail I., Tretyakova, Tatyana V., Simoons, Maarten L., Baranov, Evgeny, Shustov, Sergey, Yakushin, Sergey, Gordeev, Ivan, Khasanov, Niiaz, Reshetko, Olga, Sotnikova, Tatiana, Molchanova, Olga, Nikolaev, Konstantin, Gapon, Liudmila, Alexander, Karen, Baranova, Elena, Kosmachova, Elena, Karpov, Yuriy, Karpov, Yuri, Povzun, Anton, Egorova, Liudmila, Tyrenko, Vadim V., Ivanov, Igor G., Ilya, Masterov, Kanorsky, Sergey, Meloni, Chiara, Simic, Dragan, Ivanovic, Nikola, Davidovic, Goran, Tasic, Nebojsa, Asanin, Milika R., Stojic, Stevo, Apostolovic, Svetlana R., Ilic, Stevan, Tosic, Biljana Putnikovic, Stankovic, Aleksandar, Rosenson, Robert, Arandjelovic, Aleksandra, Radovanovic, Slavica, Todic, Branislava, Ristic, Arsen D., Balinovac, Jovan, Dincic, Dragan V., Seferovic, Petar, Karadzic, Ana, Dodic, Slobodan, Dimkovic, Sinisa, Sijbrands, Eric J. G., Jakimov, Tamara, Poh, Kian-Keong, Yee Ong, Hean, Tang I-Shing, Justin, Micko, Karol, Nociar, Jan, Pella, Daniel, Fulop, Peter, Hranai, Marian, Palka, Juraj, Tricoci, Pierluigi, Mazur, Juraj, Majercák, Ivan, Dzupina, Andrej, Fazekas, František, Gonsorcik, Jozef, Bugan, Viliam, Murin, Jan, Selecky, Juraj, Kamensky, Gabriel, Strbova, Jaroslava, Alexander, John H., Smik, Rudolf, Dukat, Andrej, Olexa, Peter, Žuran, Ivan, Poklukar, Janez, Šuligoj, Nataša Černič, Cevc, Matija, Fras, Zlatko, Cyster, Henry P., Ranjith, Naresh, Armaganijan, Luciana, Corbett, Clive, Bayat, Junaid, Makoali Makotoko, Ellen, du Toit Theron, Hendrik, Kapp, Ilse E., de V Basson, Matthys M., Lottering, Hanlie, Van Aswegen, Dina, Van Zyl, Louis J., Sebastian, Peter J., Bagai, Akshay, Pillay, Thayabran, Saaiman, Jan A., Commerford, Patrick J., Cassimjee, Soraya, Riaz, Garda, Ebrahim, Iftikhar O., Sarvan, Mahomed, Mynhardt, Joseph H., Dalby, Anthony J., Reuter, Helmuth, Bahit, Maria Cecilia, Moodley, Rajendran, Vida, Manuel, Fillat, Angel R. 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Matthew, Worner Diz, Fernando, Garcia-Dorado, David, Iñiguez, Andres, Gonzalez-Juanatey, Jose R., Portales, Javier Fernandez, Murillo, Fernando Civeira, Pericas, Laia Matas, Zamorano, Jose Luis, De Mora Martin, Manuel, Cortada, Jordi Bruguera, Clifton, Shaun, Alonso Martin, Joaquin J., Serrano Antolin, Jose Maria, De Berrazueta Fernández, José R., Vázquez de Prada, José Antonio, Díaz Fernández, Jose Francisco, García Lledó, José Alberto, Cosín Sales, Juan, Rodriguez, Javier Botas, Tragant, Gabriel Gusi, Benedicto, Amparo, DeVore, Adam D., Gonzalez-Juanatey, Carlos, Camprubí Potau, Mercedes, Perez, Ignacio Plaza, De La Tassa, César Morís, Rincon, Pablo Loma-Osorio, Recena, Javier Balaguer, Escudier, Juan M., Payeras, Antonio Coca, Orcajo, Norberto Alonso, Constantine, Godwin, Deloatch, Shalonda, Haniffa, Ruvaiz, Tissera, Nirmali, Amarasekera, Stanley, Ponnamperuma, Chandrike, Fernando, Nimali, Fernando, Kaputella, Jayawardena, Jayanthimala, Wijeyasingam, Santharaj, Ranasinghe, Gotabhaya, Ekanayaka, Ruvan, Dickey, Sheila, Mendis, Sepalika, Senaratne, Vajira, Mayurathan, Gnanamoorthy, Rajapaksha, Ajantha, Sirisena, Thilak, Herath, Jagath I., Amarasena, Naomali, Berglund, Stefan, Rasmanis, Gundars, Hagström, Emil, Dombrowski, Keith, Vedin, Ola, Witt, Nils, Mourtzinis, Georgios, Nicol, Peter, Hansen, Ole, Romeo, Stefano, Jensen, Steen Agergaard, Torstensson, Ingemar, Ahremark, Ulf, Sundelin, Torbjörn, Ducrocq, Grégory, Moccetti, Tiziano, Müller, Christian, Mach, Francois, Binde, Ronald, Landmesser, Ulf, Gämperli, Oliver, Chiang, Chern-En, Tsai, Wei-Chuan, Ueng, Kwo-Chang, Lai, Wen-Ter, Eapen, Zubin, Liu, Ming-En, Hwang, Juey-Jen, Yin, Wei-Hsian, Hsieh, I.-Chang, Hsieh, Ming-Jer, Hsiang Lin, Wei, Kuo, Jen-Yuan, Huang, Tsuei-Yuan, Fang, Chih-Yuan, Kaewsuwanna, Pinij, Endsley, Patricia, Soonfuang, Wasant, Jintapakorn, Woravut, Sukonthasarn, Apichard, Sritara, Piyamitr, Wongpraparut, Nattawut, Sastravaha, Krisada, Sansanayudh, Nakarin, Kehasukcharoen, Wirash, 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Eduardas, Knowles, Joshua W., Braganza, Denise, Sarkar, David, Storey, Robert, Griffiths, Huw, Mcclure, Sam, Muthusamy, Rangasamy, Smith, Simon, Kurian, John, Levy, Terry, Barr, Craig, Kolls, Bradley J., Kadr, Honer, Gerber, Robert, Simaitis, Audrius, Soran, Handrean, Brodison, Adrian, Ayaz, Mohammad, Cheema, Muhammad, Oliver, Richard, Thackray, Simon, Mudawi, Telal, Kong, David F., Rahma, Gohar, Sultan, Ayyaz, Reynolds, Timothy, Sharman, David, Spriging, David, Butler, Rob, Wilkinson, Peter, Lip, Gregory Yh, Ossei-Gerning, Nicholas, Vardi, Gil, Leonardi, Sergio, Baldari, Duccio, Brabham, David, Treasure Ii, Charles, Dahl, Charles, Palmer, Bruce, Wiseman, Alan, Khan, Abul, Puri, Sanjeev, Mohart, Ann Elizabeth, Ince, Carlos, Lillis, Linda, Flores, Enrique, Wright, Scott, Cheng, Shi-Chi, Rosenberg, Michael, Rogers, William, Kosinski, Edward, Forgosh, Les, Waltman, Jonathan, Shoukfeh, Mohammad, Dagher, Georges, Lopes, Renato D., Cambier, Patrick, Lieber, Ira, Kumar, Priya, East, Cara, Krichmar, Perry, Hasan, Mian, White, Lindsey, Knickelbine, Thomas, Haldis, Thomas, Gillespie, Eve, Maron, David J., Amidon, Thomas, Suh, David, Arif, Imran, Abdallah, Mouhamad, Akhter, Faiq, Carlson, Eric, D'Urso, Michael, El-Ahdab, Fadi, Nelson, William, Moriarty, Katie, Mahaffey, Kenneth W., Harris, Barry, Cohen, Steven, Carter, Luther, Doty, Daniel, Sabatino, Kenneth, Haddad, Tariq, Rao, Sunder, Mulkay, Angel, Jovin, Ion, Klancke, Kim, Marcus, Jill, Malhotra, Vinay, Devarapalli, Sai K., Koren, Michael, Chandna, Harish, Dodds Iii, George, Goraya, Tauqir, Bengston, James, Janik, Matthew, Moran, Joseph, Sumner, Andrew, Mathews, Robin, Kobayashi, John, Davis, William, Yazdani, Shahram, Pasquini, John, Thakkar, Maitreya, Vedere, Amarnath, Leimbach, Wayne, Rider, James, Fenton, Sarah, Singh, Narendra, Mehta, Rajendra H., Shah, Anil V., Moriarty, Patrick M., Janosik, Denise, Pepine, Carl, Berman, Brett, Gelormini, Joseph, Daniels, Christopher, Richard, Kerensky, Keating, Friederike, Kondo, Nicholas I., Mentz, Robert J., Shetty, Sanjay, Levite, Howard, Waider, Winfried, Takata, Theodore, Abu-Fadel, Mazen, Shah, Vipul, Aggarwal, Rahul, Kumar, Anil, Hattler, Brack, Do, Rose, Moreira, Humberto Graner, Link, Chad, Bortnick, Anna, Kinzfogl Iii, George, Ghitis, Arnold, Larry, John, Teufel, Edward, Kuhlman, Peter, Mclaurin, Brent, Zhang, Wenwu, Thew, Stephen, Patel, Chetan B., Abbas, Jalal, White, Matthew, Islam, Othman, Subherwal, Sumeet, Ranadive, Nandkishore, Vakili, Babak, Gring, Christian, Henderson, David, Schuchard, Timothy, Farhat, Naim, Pereira, Sabrina Bernardez, Kline, Geoffrey, Mahal, Sharan, Whitaker, Jack, Speirs, Shawn, Andersen, Rolf, Daboul, Nizar, Horwitz, Phillip, Zahr, Firas, Ponce, George, Jafar, Zubair, Perkins, Lynn, Mcgarvey, Joseph, Panchal, Vipul, Voyce, Stephen, Blok, Thomas, Sheldon, William, Azizad, Masoud M., Schmalfuss, Carsten, Picone, Mark, Pederson, Robert, Herzog, William, Povsic, Thomas J., Friedman, Keith, Lindsey, Jason, Timothy, Eichenlaub, Leonard, Parilak, Lepor, Norman, El Shahawy, Mahfouz, Weintraub, Howard, Irimpen, Anand, Alonso, Alvaro, May, Wade, Puymirat, Etienne, Christopher, Daniels, Galski, Thomas, Chu, Alan, Mody, Freny, Ramin, Ebrahimi, Hodes, Zachary, Rossi, Joseph, Rose, Gregory, Fairlamb, James, Lambert, Charles, Raisinghani, Ajit, Abbate, Antonio, Vetrovec, George, King, Marilyn, Carey, Charles, Gerber, Jaime, Younis, Liwa, Park, Hyeun Tom, Vidovich, Mladen, Knutson, Thomas, Jones, William Schuyler, Friedman, Dennis, Chaleff, Fred, Loussararian, Arthur, Rozeman, Phillip, Kimmelstiel, Carey, Kuvin, Jeffrey, Silver, Kevin, Foster, Malcolm, Tonnessen, Glen, Espinoza, Andrey, Shah, Bimal R., Amlani, Mohamadali, Wali, Andreas, Malozzi, Christopher, Jong, Geert T., Massey, Clara, Wattanakit, Keattiyoat, O'Donnell, Philip J., Singal, Dinesh, Jaffrani, Naseem, Banuru, Sridhar, Sherwood, Matthew W., Fisher, Daniel, Xenakis, Mark, Perlmutter, Neal, Bhagwat, Ravi, Strader, James, Blonder, Ronald, Akyea-Djamson, Ayim, Labroo, Ajay, Lee, Kwan, Marais, H. John, Stringfellow, Kenya, Claxton, Edmund, Weiss, Robert, Kathryn, Rohr, Berk, Martin, Rossi, Peter, Joshi, Parag, Khera, Amit, Khaira, Ajit S., Kumkumian, Greg, Lupovitch, Steven, Sujjavanich, Darin, Purow, Joshua, Welka, Stephen, Hoffman, David, Fischer, Stuart, Soroka, Eugene, Eagerton, Donald, Pancholy, Samir, Ray, Michael, Erenrich, Norman, Farrar, Michael, Toma, Mustafa, Pollock, Stewart, French, William J., Diamantis, Steve, Guy, Douglas, Gimple, Lawrence, Neustel, Mark, Schwartz, Steven, Pereira, Edward, Albert, Seals, Spriggs, Douglas, Trotter, Charlene, Strain, Janet, Mittal, Suneet, Vo, Anthony, Chane, Majed, Hall, Jason, Vijay, Nampalli, Lotun, Kapildeo, Lester, F. Martin, Nahhas, Ahed, Pope, Theodore, van Diepen, Sean F. P., Nager, Paul, Vohra, Rakesh, Sharma, Mukesh, Bashir, Riyaz, Ahmed, Hinan, Berlowitz, Michael, Fishberg, Robert, Barrucco, Robert, Yang, Eric, Radin, Michael, Wilson, Matthew D., Sporn, Daniel, Stapleton, Dwight, Eisenberg, Steven, Landzberg, Joel, Mcgough, Martin, Turk, Samir, Schwartz, Michael, Sundram, P. Sandy, Jain, Diwakar, Zainea, Mark, Tze-Kay Yan, Andrew, Bayron, Carlos, Karlsberg, Ronald, Dohad, Suhail, Lui, Henry, Keen, William, Westerhausen, Donald, Khurana, Sandeep, Agarwal, Himanshu, Birchem, Jessica, Penny, William, Schiavi, Lilia B., Chang, Mark, Murphy, Sherrill, Henry, John, Schifferdecker, Branislav, Gilbert, John M., Chalavarya, Gopal, Eaton, Charles, Schmedtje, John F., Christenson, Stuart, Dotani, Imran, Garrido, Marcelo, Denham, Douglas, Macdonell, Alexander, Gibson, Paul, Rahman, Aref, Al Joundi, Tammam, Assi, Nizar, Conrad, Gary, Kotha, Purushotham, Love, Michael, Giesler, Gregory, Alvarisqueta, Andrés F., Rubenstein, Howard, Gamil, Dawood, Akright, Laura, Krawczyk, Justine, Cobler, Joanne, Wells, Terry, Welker, James, Foster, Robert, Gilmore, Richard, Anderson, Jay, Sassone, Sonia A., Jacoby, Douglas, Harris, Bill, Gardner, Geraldine, Dandillaya, Ramprasad, Vora, Kishor, Kostis, John, Hunter, John, Laxson, David, Ball, Eric, Bordonava, Anselmo P., Egydio, Flavia, Kawakami, Anelise, Oliveira, Janaina, Goodman, Shaun G., Wozniak, Julianna, Alves De Lima, Alberto E., Matthews, Alexander, Ratky, Caroline, Valiris, Janine, Berdan, Lisa, Hepditch, Anita, Quintero, Kirby, Rorick, Tyrus, Westbrook, Melissa, Danchin, Nicolas, Schmidberg, Jorge M., Bezault, Madeleine, Drouet, Elodie, Simon, Tabassome, White, Harvey D., Alsweiler, Caroline, Sinnaeve, Peter, Luyten, Anne, Aylward, Philip E., Butters, Julie, Griffith, Liddy, Duronto, Ernesto A., Shaw, Michelle, Grunberg, Lena, Szarek, Michael, Islam, Shahidul, Brégeault, Marie-France, Bougon, Nathalie, Faustino, Douglas, Fontecave, Sylvie, Murphy, Judith, Caruso, Orlando C., Tamby, Jean-Francois, Verrier, Melanie, Agnetti, Veronique, Andersen, Dorthe, Badreddine, Emmy, Bekkouche, Mhamed, Bouancheau, Cecile, Brigui, Imane, Brocklehurst, Maddy, Cianciarulo, Joseph, Novaretto, Leonardo P., Devaul, Dawn, Domokos, Szilvia, Gache, Cecile, Gobillot, Caroline, Guillou, Severine, Healy, Jan, Heath, Megan, Jaiwal, Gayatri, Javierre, Carine, Labeirie, Julien, Hominal, Miguel Angel, Monier, Myriam, Morales, Ulises, Mrabti, Asmaa, Mthombeni, Bicky, Okan, Betim, Smith, Lucile, Sheller, Jennifer, Sopena, Sebastien, Pellan, Valerie, Benbernou, Fadela, Montaña, Oscar R., Bengrait, Nafissa, Lamoureux, Maud, Kralova, Katarina, Scemama, Michel, Bejuit, Raphael, Coulange, Anthony, Berthou, Christelle, Repincay, Jérôme, Lorenzato, Christelle, Etienne, Alexis, Caccavo, Alberto, Gouet, Valerie, Lecorps, Guillaume, Loizeau, Virginie, Normand, Mickael, Ourliac, Anne, Rondel, Christelle, Adamo, Antony, Beltran, Pascale, Barraud, Pauline, Dubois-Gache, Helene, Gomez Vilamajo, Oscar A., Halle, Benjamin, Metwally, Lamia, Mourgues, Maxime, Sotty, Marc, Vincendet, Marion, Cotruta, Raluca, Chengyue, Zhu, Fournie-Lloret, Dominique, Morrello, Christine, Perthuis, Aurelie, Lorenzatti, Alberto J., Picault, Patrick, Zobouyan, Isabelle, Colhoun, Helen M., Dempsey, Michael A., McClanahan, Mark A., Cartasegna, Luis R., Paterlini, Gustavo A., Mackinnon, Ignacio J., Caime, Guillermo D., Amuchastegui, Marcos, Salomone, Oscar, Codutti, Oscar R., Jure, Horacio O., Bono, Julio Oe, Hrabar, Adrian D., Vallejos, Julio A., Ahuad Guerrero, Rodolfo A., Novoa, Federico, Patocchi, Cristian A., Zaidman, Cesar J., Giuliano, Maria E., Schwartz, Gregory G., Dran, Ricardo D., Vico, Marisa L., Carnero, Gabriela S., Guzman, Pablo N., Medrano Allende, Juan C., Garcia Brasca, Daniela F., Bustamante Labarta, Miguel H., Nani, Sebastian, Blumberg, Eduardo Ds, Colombo, Hugo R., Bhatt, Deepak L., Liberman, Alberto, Fuentealba, Victorino, Luciardi, Hector L., Waisman, Gabriel D., Berli, Mario A., Garcia Duran, Ruben O., Cestari, Horacio G., Luquez, Hugo A., Giordano, Jorge A., Saavedra, Silvia S., Bittner, Vera A., Zapata, Gerardo, Costamagna, Osvaldo, Llois, Susana, Waites, Jonathon H., Collins, Nicholas, Soward, Allan, Hii, Chris Ls, Shaw, James, Diaz, Rafael, Arstall, Margaret A., Horowitz, John, Ninio, Daniel, Rogers, James F., Colquhoun, David, Oqueli Flores, Romulo E., Roberts-Thomson, Philip, Raffel, Owen, Lehman, Sam J., Aroney, Constantine, Coverdale, Steven Gm, Garrahy, Paul J., Starmer, Gregory, Sader, Mark, Carroll, Patrick A., Dick, Ronald, Zweiker, Robert, Hoppe, Uta, Drexel, Heinz, Huber, Kurt, Harrington, Robert A., Berger, Rudolf, Delle-Karth, Georg, Frey, Bernhard, Weidinger, Franz, Faes, Dirk, Hermans, Kurt, Pirenne, Bruno, Leone, Attilio, Hoffer, Etienne, Jukema, J. 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Gavish, Dov, Ramos López, Gabriel Arturo, Vered, Zvi, Caraco, Yoseph, Elias, Mazen, Tov, Naveh, Wolfovitz, Efrat, Lishner, Michael, Elias, Nizar, Piovaccari, Giancarlo, De Pellegrin, Annamaria, Garbelotto, Raffaella, Alings, Marco, Guardigli, Gabriele, Marco, Valgimigli, Licciardello, Giovanni, Auguadro, Carla, Scalise, Filippo, Cuccia, Claudio, Salvioni, Alessandro, Musumeci, Giuseppe, Senni, Michelle, Calabrò, Paolo, Novo, Salvatore, Faggiano, Pompilio, Metra, Marco, De Cesare, Nicoletta B., Berti, Sergio, Puccioni, Enrico, Galvani, Marcello, Tespili, Maurizio, Piatti, PierMarco, Palvarini, Michela, Halvorsen, Sigrun, De Luca, Giuseppe, Violini, Roberto, De Leo, Alessandro, Olivari, Zoran, Filardi, Pasquale Perrone, Ferratini, Maurizio, Racca, Vittorio, Dai, Kazuoki, Shimatani, Yuji, Kamiya, Haruo, Correa Flores, Roger M., Ando, Kenji, Takeda, Yoshihiro, Morino, Yoshihiro, Hata, Yoshiki, Kimura, Kazuo, Kishi, Koichi, Michishita, Ichiro, Uehara, Hiroki, Higashikata, Toshinori, 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Der Wal, Ruud Ma, Zwart, Peter, Monraats, Pascalle, Van Kesteren, Henricus, Karalis, Ioannis, de Silva, H. Asita, Jukema, Johan, Verdel, Gerardus Je, Brueren, Bart Rg, Troquay, Roland P. Th, Viergever, Eric P., Al-Windy, Nadea Yy, Bartels, Gerard L., Cornel, Jan H., Hermans, Walter Rm, Herrman, Johannes Pr, Bos, Robert J., Groutars, Reginald Gej, Van Der Zwaan, Coenraad C., Kaplan, Refik, Ronner, Eelko, Groenemeijer, Bjorn E., Bronzwaer, Patrick Na, Liem, Anho Ah, Rensing, Bernard Jwm, Bokern, Marcel Jja, Nijmeijer, Remco, Hersbach, Ferry Mrj, Willems, Frank F., Gosselink, Antonius Tm, Rasoul, Saman, Elliott, John, Wilkins, Gerard, Fisher, Raewyn, Scott, Douglas, Hart, Hamish, Stewart, Ralph, Harding, Scott, Ternouth, Ian, Fisher, Nicholas, Wilson, Samuel, Aitken, Denise, Anscombe, Russell, Davidson, Laura, Tomala, Tadeusz, Nygård, Ottar, Sparby, Jon Arne, Andersen, Kjell, Gullestad, Lars, Jortveit, Jarle, Munk, Peter S., Singsaas, Erlend Gyllensten, Hurtig, Ulf, Calderon Ticona, Jorge R., Durand Velasquez, Julio R., Negron Miguel, Sandra A., Sanabria Perez, Enrique S., Carrion Chambilla, Jesus M., Chavez Ayala, Carlos A., Castillo Leon, Reynaldo P., Vargas GonzalesC, Rolando J., Hernandez Zuniga, Jose D., Camacho Cosavalente, Luis A., Bravo Mannucci, Jorge E., Landeo, Javier Heredia, Llerena Navarro, Nassip C., Roldan Concha, Yudy M., Rodriguez Chavez, Víctor E., Anchante Hernandez, Henry A., Zea Nunez, Carlos A., Ramos, Walter Mogrovejo, Ferrolino, Arthur, Sy, Rosa Allyn G., Tirador, Louie, Matiga, Generoso, Coching, Raul Martin, Bernan, Alisa, Rogelio, Gregorio, Morales, Dante D., Tan, Edgar, Sulit, Dennis Jose, Wlodarczak, Adrian, Skonieczny, Grzegorz, Ray, Kausik K., Pawlowicz, Lidia, Wojewoda, Pawel, Busz-Papiez, Benita, Bednarski, Janusz, Goch, Aleksander, Staneta, Pawel, Dulak, Elzbieta, Saminski, Krzysztof, Krasowski, Wlodzimierz, Sudnik, Wanda, Zurakowski, Aleksander, Skorski, Marcin, Lysek, Roman, Miklaszewicz, Beata, Lipko, Jan Andrzej, Kostarska-Srokosz, Edyta, Piepiorka, Marek, Drzewiecka, Anna, Stasiewski, Arkadiusz, Bhatt, Deepak L, Bittner, Vera A, Goodman, Shaun G, Harrington, Robert A, Jukema, J Wouter, White, Harvey D, Zeiher, Andreas M, Roe, Matthew T, Mahaffey, Kenneth W, Edelberg, Jay M, Sasiela, William J, Aylward, Philip E, Lopes, Renato D, Gotcheva, Nina N, Nieminen, Markku S, Laucevičius, Aleksandras, Correa Flores, Roger M, Sy, Rody G, Ristic, Arsen D, Dalby, Anthony J, de Silva, H Asita, Ray, Kausik K, Moriarty, Patrick M, Kelsey, Sheryl F, Olsson, Anders G, Simoons, Maarten L, Sijbrands, Eric J G, Alexander, John H, Brennan, J Matthew, DeVore, Adam D, Harrison, Robert W, Hlatky, Mark A, Knowles, Joshua W, Kolls, Bradley J, Kong, David F, Maron, David J, Mehta, Rajendra H, Mentz, Robert J, Patel, Chetan B, Povsic, Thomas J, Shah, Bimal R, Sherwood, Matthew W, van Diepen, Sean F P, Wilson, Matthew D, Schiavi, Lilia B, Alvarisqueta, Andrés F, Sassone, Sonia A, Bordonava, Anselmo P, Alves De Lima, Alberto E, Schmidberg, Jorge M, Duronto, Ernesto A, Caruso, Orlando C, Novaretto, Leonardo P, Montaña, Oscar R, Gomez Vilamajo, Oscar A, Lorenzatti, Alberto J, Cartasegna, Luis R, Paterlini, Gustavo A, Mackinnon, Ignacio J, Caime, Guillermo D, Codutti, Oscar R, Jure, Horacio O, Hrabar, Adrian D, Vallejos, Julio A, Ahuad Guerrero, Rodolfo A, Patocchi, Cristian A, Zaidman, Cesar J, Giuliano, Maria E, Dran, Ricardo D, Vico, Marisa L, Carnero, Gabriela S, Guzman, Pablo N, Medrano Allende, Juan C, Garcia Brasca, Daniela F, Bustamante Labarta, Miguel H, Colombo, Hugo R, Luciardi, Hector L, Waisman, Gabriel D, Berli, Mario A, Garcia Duran, Ruben O, Cestari, Horacio G, Luquez, Hugo A, Giordano, Jorge A, Saavedra, Silvia S, Waites, Jonathon H, Arstall, Margaret A, Rogers, James F, Oqueli Flores, Romulo E, Lehman, Sam J, Garrahy, Paul J, Carroll, Patrick A, Wolf, Luc De, Nicolau, Jose C, Giorgeto, Flavio E, Silva, Ricardo P, Abrantes, José Antonio M, Bodanese, Luiz C, Michalaros, Yorghos L, Eliaschewitz, Freddy G, Vidotti, Maria H, Leaes, Paulo E, Botelho, Roberto V, Manenti, Euler Roberto F Fernandes, Precoma, Dalton B, Moura Jorge, Jose C, Silveira, Jose A, Neto, Jose A Marin, Feitosa, Gilson S, Ritt, Luiz Eduardo F, de Souza, Juliana A, Todorov, Georgi V, Nikolov, Fedya P, Velcheva, Elena S, Tzekova, Maria L, Benov, Haralambi O, Petranov, Stanislav L, Tumbev, Haralin S, Shehova-Yankova, Nina S, Markov, Dimitar T, Raev, Dimitar H, Mollov, Mihail N, Kichukov, Kostadin N, Ilieva-Pandeva, Katya A, Mincheva, Valentina M, Lazov, Petar V, Dimov, Bojidar I, Prieto, Juan C, Raffo, Carlos A, Luna Botia, Diana C, De Salazar, Dora I Molina, Bonfanti, Alberto J Cadena, Barrera Silva, Sandra I, Garcia Lozada, Henry J, Coronel Arroyo, Julian A, Accini Mendoza, Jose L, Fernandez Ruiz, Ricardo L, Quintero Ossa, Alvaro M, Manzur Jatin, Fernando G, Urina Triana, Miguel A, Trujillo, Angela M Fernandez, Poulsen, Steen H, Bang, Lia E, Hove, Jens D, Kristensen, Kjeld S, Lomholdt, Jens D, Klausen, Ib C, Fausto Ovando, Sergio R, Arango Benecke, Juan L, Rodriguez De Leon, Edgar R, Premchand, Rajendra K, Abhyanakar, Atul D, Govinda, Ravishankar A, Patil, Sachin N, Joshi, Abhijeet B, Pothineni, Ramesh B, Monteiro, Minguel R, Iyengar, Shamanna S, Fulwani, Mahesh C, Chopra, Vijay K, Goyal, Naresh K, Manakshe, Gajendra V, Pellegrin, Annamaria De, De Cesare, Nicoletta B, Piatti, Piermarco, Luca, Giuseppe De, Leo, Alessandro De, Petrulionienė, Žaneta, Šakalytė, Gintarė, Šlapikas, Rimvydas, Liew, Houng B, Breedveld, Robert W, Wiersma, Jacobijne J, Troquay, Roland PTh, Viergever, Eric P, Bartels, Gerard L, Cornel, Jan H, Bos, Robert J, Van Der Zwaan, Coenraad C, Groenemeijer, Bjorn E, Willems, Frank F, Munk, Peter S, Calderon Ticona, Jorge R, Durand Velasquez, Julio R, Negron Miguel, Sandra A, Sanabria Perez, Enrique S, Carrion Chambilla, Jesus M, Chavez Ayala, Carlos A, Castillo Leon, Reynaldo P, Vargas GonzalesC, Rolando J, Hernandez Zuniga, Jose D, Camacho Cosavalente, Luis A, Bravo Mannucci, Jorge E, Llerena Navarro, Nassip C, Roldan Concha, Yudy M, Rodriguez Chavez, Víctor E, Anchante Hernandez, Henry A, Zea Nunez, Carlos A, Sy, Rosa Allyn G, Morales, Dante D, Pereira, Helder H, Tesloianu, Dan N, Bengus, Cristina M, Parepa, Irinel R, Matei, Adrian V, Alexandru, Tom M, Barbarash, Olga L, Vishnevsky, Alexander Y, Lomakin, Nikita V, Voevoda, Mikhail I, Tretyakova, Tatyana V, Tyrenko, Vadim V, Ivanov, Igor G, Asanin, Milika R, Apostolovic, Svetlana R, Dincic, Dragan V, Cyster, Henry P, Kapp, Ilse E, de V Basson, Matthys M, Aswegen, Dina Van, Van Zyl, Louis J, Sebastian, Peter J, Saaiman, Jan A, Commerford, Patrick J, Ebrahim, Iftikhar O, Mynhardt, Joseph H, Fillat, Angel R Cequier, Cruz Fernández, Jose M, Gonzalez-Juanatey, Jose R, Alonso Martin, Joaquin J, De Berrazueta Fernández, José R, Escudier, Juan M, Herath, Jagath I, Hsieh, I-Chang, Barna, Olga M, Aggarwal, Rajesh K, Wong, Yuk-Ki, Devarapalli, Sai K, Shah, Anil V, Kondo, Nicholas I, Azizad, Masoud M, Jong, Geert T, O'Donnell, Philip J, Marais, H John, Khaira, Ajit S, French, William J, Lester, F Martin, Sundram, P Sandy, Gilbert, John M, Schmedtje, John F, Colhoun, Helen M, Dempsey, Michael A, and McClanahan, Mark A
Subjects: Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Anticholesteremic Agents/adverse effects, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], prevention & control, heart disease risk factors, diagnosis [Cardiovascular Diseases], Antibodies, Monoclonal, Humanized, PCSK9 inhibitors, acute coronary syndrome, apolipoproteins B, LDL cholesterol, Antibodies, acute coronary syndrome, LDL, drug therapy [Atherosclerosis], Risk Factors, Physiology (medical), therapeutic use [Hydroxymethylglutaryl-CoA Reductase Inhibitors], Monoclonal, Humans, Cardiac and Cardiovascular Systems, Humanized, Cardiovascular Diseases/diagnosis, Apolipoproteins B, Kardiologi, diagnosis [Acute Coronary Syndrome], Anticholesteremic Agents, PCSK9 inhibitors, apolipoproteins B, cholesterol, LDL, cholesterol, Atherosclerosis/drug therapy, Cholesterol, LDL, Atherosclerosis, Acute Coronary Syndrome/diagnosis, drug therapy, Cholesterol, Treatment Outcome, Cardiovascular Diseases, Heart Disease Risk Factors, epidemiology, adverse effects [Anticholesteremic Agents], Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine
Abstract: Circulation : an official journal of the American Heart Association / ed.-in-chief Ephraim Donosco 146(9), 657-672 (2022). doi:10.1161/CIRCULATIONAHA.121.057807, Published by Ovid, [Erscheinungsort nicht ermittelbar]
Published: 2022

17. Pharmacokinetics of Para‐Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance

Author: Helmuth Reuter, Peter R. Donald, Marietjie Stander, Kim T. Adams, Andreas H. Diacon, and Ahmed A. Abulfathi
Subjects: Adult, Male, medicine.medical_specialty, Gastrointestinal Diseases, Visual analogue scale, Metabolite, Antitubercular Agents, Cmax, 030226 pharmacology & pharmacy, Gastroenterology, Drug Administration Schedule, South Africa, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Bloating, Pharmacokinetics, Internal medicine, Tuberculosis, Multidrug-Resistant, medicine, Humans, Pharmacology (medical), Pharmacology, Cross-Over Studies, business.industry, Drug Resistance, Microbial, Drug Tolerance, Metabolism, Aminosalicylic Acid, Aminosalicylic Acids, Diarrhea, Regimen, chemistry, Area Under Curve, Delayed-Action Preparations, 030220 oncology & carcinogenesis, Female, medicine.symptom, business
Abstract: Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.
Published: 2019

18. Drug concentration at the site of disease in children with pulmonary tuberculosis

Author: Elisa Lopez-Varela, Ahmed A. Abulfathi, Natasha Strydom, Pierre Goussard, Abraham C. van Wyk, Anne Marie Demers, Anneen Van Deventer, Anthony J. Garcia-Prats, Johannes van der Merwe, Matthew Zimmerman, Claire L. Carter, Jacques Janson, Julie Morrison, Helmuth Reuter, Eric H. Decloedt, James A. Seddon, Elin M. Svensson, Rob Warren, Radojka M. Savic, Véronique Dartois, and Anneke C. Hesseling
Subjects: Microbiology (medical), Adult, Antitubercular Agents, Pharmacology and Toxicology, Microbiology, Pharmaceutical Sciences, South Africa, Rare Diseases, 1108 Medical Microbiology, Clinical Research, Isoniazid, Tuberculosis, Humans, Pharmacology (medical), Pharmacology & Pharmacy, Child, Lung, Tuberculosis, Pulmonary, Pharmacology, RIFAMPIN, Pediatric, Science & Technology, Evaluation of treatments and therapeutic interventions, Infant, MIC DISTRIBUTIONS, Pulmonary, Pharmacology and Pharmaceutical Sciences, POPULATION PHARMACOKINETICS, Farmaceutiska vetenskaper, Farmakologi och toxikologi, Pyrazinamide, VARIABILITY, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Orphan Drug, Infectious Diseases, Medical Microbiology, 6.1 Pharmaceuticals, HIV/AIDS, MYCOBACTERIUM-TUBERCULOSIS, Patient Safety, 1115 Pharmacology and Pharmaceutical Sciences, Infection, Life Sciences & Biomedicine, Ethambutol, 0605 Microbiology
Abstract: Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.
Published: 2021

19. Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Author: Gregory G. Schwartz, Michael Szarek, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, J. Wouter Jukema, Ulf Landmesser, Patricio López-Jaramillo, Garen Manvelian, Robert Pordy, Michel Scemama, Peter R. Sinnaeve, Harvey D. White, Ph Gabriel Steg, P.h. Gabriel Steg, Deepak L. Bhatt, Robert A. Harrington, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Steen Hvitfeldt Poulsen, Margus Viigimaa, Markku S. Nieminen, Nicolas Danchin, Vakhtang Chumburidze, Nikolaus Marx, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Rody G. Sy, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J. Dalby, José Tuñón, H. Asita de Silva, Emil Hagström, Christian Müller, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean F.P. van Diepen, Matthew D. Wilson, Andrew Tze-Kay Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. Cartasegna, Gustavo A. Paterlini, Ignacio J. Mackinnon, Guillermo D. Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R. Codutti, Horacio O. Jure, Julio O.E. Bono, Adrian D. Hrabar, Julio A. Vallejos, Rodolfo A. Ahuad Guerrero, Federico Novoa, Cristian A. Patocchi, Cesar J. Zaidman, Maria E. Giuliano, Ricardo D. Dran, Marisa L. Vico, Gabriela S. Carnero, Pablo N. Guzman, Juan C. Medrano Allende, Daniela F. Garcia Brasca, Miguel H. Bustamante Labarta, Sebastian Nani, Eduardo D.S. Blumberg, Hugo R. Colombo, Alberto Liberman, Victorino Fuentealba, Hector L. Luciardi, Gabriel D. Waisman, Mario A. Berli, Ruben O. Garcia Duran, Horacio G. Cestari, Hugo A. Luquez, Jorge A. Giordano, Silvia S. Saavedra, Gerardo Zapata, Osvaldo Costamagna, Susana Llois, Jonathon H. Waites, Nicholas Collins, Allan Soward, Chris L.S. Hii, James Shaw, Margaret A. Arstall, John Horowitz, Daniel Ninio, James F. Rogers, David Colquhoun, Romulo E. Oqueli Flores, Philip Roberts-Thomson, Owen Raffel, Sam J. Lehman, Constantine Aroney, Steven G.M. Coverdale, Paul J. Garrahy, Gregory Starmer, Mark Sader, Patrick A. Carroll, Ronald Dick, Robert Zweiker, Uta Hoppe, Kurt Huber, Rudolf Berger, Georg Delle-Karth, Bernhard Frey, Dirk Faes, Kurt Hermans, Bruno Pirenne, Attilio Leone, Etienne Hoffer, Mathias C.M. Vrolix, Luc De Wolf, Bart Wollaert, Marc Castadot, Karl Dujardin, Christophe Beauloye, Geert Vervoort, Harry Striekwold, Carl Convens, John Roosen, Emanuele Barbato, Marc Claeys, Frank Cools, Ibrahim Terzic, Fahir Barakovic, Zlatko Midzic, Belma Pojskic, Emir Fazlibegovic, Azra Durak-Nalbantic, Mehmed Kulić, Dusko Vulic, Adis Muslibegovic, Boris Goronja, Gilmar Reis, Luciano Sousa, Jose C. Nicolau, Flavio E. Giorgeto, Ricardo P. Silva, Lilia Nigro Maia, Rafael Rech, Paulo R.F. Rossi, Maria José A.G. Cerqueira, Norberto Duda, Renato Kalil, Adrian Kormann, José Antonio M. Abrantes, Pedro Pimentel Filho, Ana Priscila Soggia, Mayler O.N. de Santos, Fernando Neuenschwander, Luiz C. Bodanese, Yorghos L. Michalaros, Freddy G. Eliaschewitz, Maria H. Vidotti, Paulo E. Leaes, Roberto V. Botelho, Sergio Kaiser, Euler Roberto F. Fernandes Manenti, Dalton B. Precoma, Jose C. Moura Jorge, Pedro Silva, Jose A. Silveira, Wladmir Saporito, Jose A. Marin Neto, Gilson S. Feitosa, Luiz Eduardo F. Ritt, Juliana A. de Souza, Fernando Costa, Weimar K.S.B. Souza, Helder J.L. Reis, Leandro Machado, José Carlos Aidar Ayoub, Georgi V. Todorov, Fedya P. Nikolov, Elena S. Velcheva, Maria L. Tzekova, Haralambi O. Benov, Stanislav L. Petranov, Haralin S. Tumbev, Nina S. Shehova-Yankova, Dimitar T. Markov, Dimitar H. Raev, Mihail N. Mollov, Kostadin N. Kichukov, Katya A. Ilieva-Pandeva, Raya Ivanova, Maryana Gospodinov, Valentina M. Mincheva, Petar V. Lazov, Bojidar I. Dimov, Manohara Senaratne, James Stone, Jan Kornder, Stephen Pearce, Danielle Dion, Daniel Savard, Yves Pesant, Amritanshu Pandey, Simon Robinson, Gilbert Gosselin, Saul Vizel, Gordon Hoag, Ronald Bourgeois, Anne Morisset, Eric Sabbah, Bruce Sussex, Simon Kouz, Paul MacDonald, Ariel Diaz, Nicolas Michaud, David Fell, Raymond Leung, Tycho Vuurmans, Christopher Lai, Frank Nigro, Richard Davies, Gustavo Nogareda, Ram Vijayaraghavan, John Ducas, Serge Lepage, Shamir Mehta, James Cha, Robert Dupuis, Peter Fong, Sohrab Lutchmedial, Josep Rodes-Cabau, Hussein Fadlallah, David Cleveland, Thao Huynh, Iqbal Bata, Adnan Hameed, Cristian Pincetti, Sergio Potthoff, Juan C. Prieto, Monica Acevedo, Arnoldo Aguirre, Margarita Vejar, Mario Yañez, Guillermo Araneda, Mauricio Fernandez, Luis Perez, Paola Varleta, Fernando Florenzano, Laura Huidobro, Carlos A. Raffo, Claudia Olivares, Leonardo Nahuelpan, Humberto Montecinos, Jiyan Chen, Yugang Dong, Weijian Huang, Jianzhong Wang, Shi'An Huang, Zhuhua Yao, Xiang Li, Lan Cui, Wenhua Lin, Yuemin Sun, Jingfeng Wang, Jianping Li, Xuelian Zhang, Hong Zhu, Dandan Chen, Lan Huang, Shaohong Dong, Guohai Su, Biao Xu, Xi Su, Xiaoshu Cheng, Jinxiu Lin, Wenxia Zong, Huanming Li, Yi Feng, Dingli Xu, Xinchun Yang, Yuannan Ke, Xuefeng Lin, Zheng Zhang, Zeqi Zheng, Zhurong Luo, Yundai Chen, Chunhua Ding, Yi Zhong, Yang Zheng, Xiaodong Li, Daoquan Peng, Shuiping Zhao, Ying Li, Xuebo Liu, Meng Wei, Shaowen Liu, Yihua Yu, Baiming Qu, Weihong Jiang, Yujie Zhou, Xingsheng Zhao, Zuyi Yuan, Ying Guo, Xiping Xu, Xubo Shi, Junbo Ge, Guosheng Fu, Feng Bai, Weiyi Fang, Xiling Shou, Xiangjun Yang, Jian'An Wang, Meixiang Xiang, Yingxian Sun, Qinghua Lu, Ruiyan Zhang, Jianhua Zhu, Yizhou Xu, Zhongcai Fan, Tianchang Li, Chun Wu, Nicolas Jaramillo, Gregorio Sanchez Vallejo, Diana C. Luna Botia, Rodrigo Botero Lopez, Dora I. Molina De Salazar, Alberto J. Cadena Bonfanti, Carlos Cotes Aroca, Juan Diego Higuera, Marco Blanquicett, Sandra I. Barrera Silva, Henry J. Garcia Lozada, Julian A. Coronel Arroyo, Jose L. Accini Mendoza, Ricardo L. Fernandez Ruiz, Alvaro M. Quintero Ossa, Fernando G. Manzur Jatin, Aristides Sotomayor Herazo, Jeffrey Castellanos Parada, Rafael Suarez Arambula, Miguel A. Urina Triana, Angela M. Fernandez Trujillo, Maja Strozzi, Siniša Car, Melita Jerić, Davor Miličić, Martina Lovrić Benčić, Hrvoje Pintarić, Đeiti Prvulović, Jozica Šikić, Viktor Peršić, Dean Mileta, Kresimir Štambuk, Zdravko Babić, Vjekoslav Tomulic, Josip Lukenda, Stanka Mejic-Krstulovic, Boris Starcevic, Jindrich Spinar, David Horak, Zdenek Velicka, Josef Stasek, David Alan, Vilma Machova, Ales Linhart, Vojtech Novotny, Vladimir Kaucak, Richard Rokyta, Robert Naplava, Zdenek Coufal, Vera Adamkova, Ivo Podpera, Jiri Zizka, Zuzana Motovska, Ivana Marusincova, Premysl Svab, Petr Heinc, Jiri Kuchar, Petr Povolny, Jiri Matuska, Steen H. Poulsen, Bent Raungaard, Peter Clemmensen, Lia E. Bang, Ole May, Morten Bøttcher, Jens D. Hove, Lars Frost, Gunnar Gislason, John Larsen, Peter Betton Johansen, Flemming Hald, Peter Johansen, Jørgen Jeppesen, Tonny Nielsen, Kjeld S. Kristensen, Piotr Maria Walichiewicz, Jens D. Lomholdt, Ib C. Klausen, Peter Kaiser Nielsen, Flemming Davidsen, Lars Videbaek, Mai Soots, Veiko Vahula, Anu Hedman, Üllar Soopõld, Kaja Märtsin, Tiina Jurgenson, Arved Kristjan, Heikki Huikuri, Juhani Airaksinen Pierre Coste, Emile Ferrari, Olivier Morel, Gilles Montalescot, Jacques Machecourt, Gilles Barone-Rochette, Jacques Mansourati, Yves Cottin, Florence Leclercq, Abdelkader Belhassane, Nicolas Delarche, Franck Boccara, Franck Paganelli, Jérôme Clerc, Francois Schiele, Victor Aboyans, Vincent Probst, Jacques Berland, Thierry Lefèvre, Bernard Citron, Irakli Khintibidze, Tamaz Shaburishvili, Zurab Pagava, Ramaz Ghlonti, Zaza Lominadze, George Khabeishvili, Rayyan Hemetsberger, Kemala Edward, Ursula Rauch-Kröhnert, Matthias Stratmann, Karl-Friedrich Appel, Ekkehard Schmidt, Heyder Omran, Christoph Stellbrink, Thomas Dorsel, Emmanouil Lianopoulos, Hans Friedrich Vöhringer, Roger Marx, Andreas Zirlik, Detlev Schellenberg, Thomas Heitzer, Ulrich Laufs, Christian Werner, Stephan Gielen, Sebastian Nuding, Bernhard Winkelmann, Steffen Behrens, Karsten Sydow, Mahir Karakas, Gregor Simonis, Thomas Muenzel, Nikos Werner, Stefan Leggewie, Dirk Böcker, Rüdiger Braun-Dullaeus, Nicole Toursarkissian, Michael Jeserich, Matthias Weißbrodt, Tim Schaeufele, Joachim Weil, Heinz Völler, Johannes Waltenberger, Mohammed Natour, Susanne Schmitt, Dirk Müller-Wieland, Stephan Steiner, Lothar Heidenreich, Elmar Offers, Uwe Gremmler, Holger Killat, Werner Rieker, Sotiris Patsilinakos, Athanasios Kartalis, Athanassios Manolis, Dimitrios Sionis, Geargios Chachalis, Ioannis Skoumas, Vasilios Athyros, Panagiotis Vardas, Frangkiskos Parthenakis, John Lekakis, Apostolos Hatzitolios, Sergio R. Fausto Ovando, Juan L. Arango Benecke, Edgar R. Rodriguez De Leon, Bryan P.Y. Yan, David C.W. Siu, Tibor Turi, Bela Merkely, Imre Ungi, Geza Lupkovics, Lajos Nagy, András Katona, István Édes, Gábor Müller, Iván Horvath, Tibor Kapin, Zsolt Szigeti, József Faluközy, Mukund Kumbla, Manjinder Sandhu, Sharath Annam, Naveen Reddy Proddutur, Reddy Regella, Rajendra K. Premchand, Ajaykumar Mahajan, Sudhir Pawar, Atul D. Abhyanakar, Prafulla Kerkar, Ravishankar A. Govinda, Abraham Oomman, Dhurjati Sinha, Sachin N. Patil, Dhiman Kahali, Jitendra Sawhney, Abhijeet B. Joshi, Sanjeev Chaudhary, Pankaj Harkut, Santanu Guha, Sanjay Porwal, Srimannarayana Jujjuru, Ramesh B. Pothineni, Minguel R. Monteiro, Aziz Khan, Shamanna S. Iyengar, Jasprakash Singh Grewal, Manoj Chopda, Mahesh C. Fulwani, Aparna Patange, Patil Sachin, Vijay K. Chopra, Naresh K. Goyal, Rituparna Shinde, Gajendra V. Manakshe, Nitin Patki, Sumeet Sethi, Vengatesh Munusamy, Sunil Karnaand Sunil Thanvi, Srilakshmi Adhyapak, Chandrakant Patil, Ulhas Pandurangi, Rishabh Mathur, Jugal Gupta, Suhas Kalashetti, Ajit Bhagwat, Bagirath Raghuraman, Shiv Kumar Yerra, Prasant Bhansali, Rohidas Borse, Patil Rahul, Srihari Das, Vinay Kumar, Jabir Abdullakutty, Shireesh Saathe, Priya Palimkar, Jabir Abdullkutty, Shireesh Sathe, Shaul Atar, Michael Shechter, Morris Mosseri, Yaron Arbel, Chorin Ehud, Havakuk Ofer, Chaim Lotan, Uri Rosenschein, Amos Katz, Yaakov Henkin, Adi Francis, Marc Klutstein, Eugenia Nikolsky, Robert Zukermann, Yoav Turgeman, Majdi Halabi, Alon Marmor, Ran Kornowski, Michael Jonas, Offer Amir, Yonathan Hasin, Yoseph Rozenman, Shmuel Fuchs, Vered Zvi, Osamah Hussein, Dov Gavish, Zvi Vered, Yoseph Caraco, Mazen Elias, Naveh Tov, Efrat Wolfovitz, Michael Lishner, Nizar Elias, Giancarlo Piovaccari, Annamaria De Pellegrin, Raffaella Garbelotto, Gabriele Guardigli, Valgimigli Marco, Giovanni Licciardello, Carla Auguadro, Filippo Scalise, Claudio Cuccia, Alessandro Salvioni, Giuseppe Musumeci, Michelle Senni, Paolo Calabrò, Salvatore Novo, Pompilio Faggiano, Marco Metra, Nicoletta B. De Cesare, Sergio Berti, Claudio Cavallini, Enrico Puccioni, Marcello Galvani, Maurizio Tespili, Piermarco Piatti, Michela Palvarini, Giuseppe De Luca, Roberto Violini, Alessandro De Leo, Zoran Olivari, Pasquale Perrone Filardi, Maurizio Ferratini, Vittorio Racca, Kazuoki Dai, Yuji Shimatani, Haruo Kamiya, Kenji Ando, Yoshihiro Takeda, Yoshihiro Morino, Yoshiki Hata, Kazuo Kimura, Koichi Kishi, Ichiro Michishita, Hiroki Uehara, Toshinori Higashikata, Atsushi Hirayama, Keiji Hirooka, Yasuji Doi, Satoru Sakagami, Shuichi Taguchi, Akihiro Koike, Hiroyuki Fujinaga, Shinji Koba, Ken Kozuma, Tomohiro Kawasaki, Yujiro Ono, Masatoshi Shimizu, Yousuke Katsuda, Atsuyuki Wada, Toshiro Shinke, Junya Ako, Kenshi Fujii, Toshiyuki Takahashi, Tomohiro Sakamoto, Koichi Nakao, Yutaka Furukawa, Hiroshi Sugino, Ritsu Tamura, Toshiaki Mano, Masaaki Uematsu, Noriaki Utsu, Kashima Ito, Takuya Haraguchi, Katsuhiko Sato, Yasunori Ueda, Akira Nishibe, Kazuteru Fujimoto, Motomaru Masutani, Jung Han Yoon, Hack-Lyoung Kim, Hun Sik Park, In-Ho Chae, Moo Hyun Kim, Myung Ho Jeong, Seungwoon Rha, Chongjin Kim, Hae Young Kim, Taekjong Hong, Seung-Jea Tahk, Youngkwon Kim, Arija Busmane, Natalija Pontaga, Aldis Strelnieks, Iveta Mintale, Iveta Sime, Zaneta Petrulioniene, Roma Kavaliauskiene, Ruta Jurgaitiene, Gintare Sakalyte, Rimvydas Slapikas, Sigute Norkiene, Nerijus Misonis, Aleksandras Kibarskis, Raimondas Kubilius, Stojko Bojovski, Nensi Lozance, Aleksandar Kjovkaroski, Snezana Doncovska, Tiong Kiam Ong, Sazzli Kasim, Oteh Maskon, Balachandran Kandasamy, Houng B. Liew, Wan Mohd Izani Wan Mohamed, Armando García Castillo, Jorge Carrillo Calvillo, Pedro Fajardo Campos, Juan Carlos Núñez Fragoso, Edmundo Alfredo Bayram Llamas, Marco Antonio Alcocer Gamba, Jaime Carranza Madrigal, Luis Gerardo González Salas, Enrique López Rosas, Belinda González Díaz, Eduardo Salcido Vázquez, Alfredo Nacoud Ackar, Guillermo Antonio Llamas Esperón, Carlos Rodolfo Martínez Sánchez, María Guerrero De Leon, Rodrigo Suarez Otero, Guillermo Fanghänel Salmón, Jesús Antonio Pérez Ríos, José Angel Garza Ruíz, Robert W. Breedveld, Margriet Feenema-Aardema, Alida Borger-Van Der Burg, Pieter A.M. Hoogslag, Harry Suryapranata, Antonius Oomen, Paulus Van Haelst, Margriet Feenema-Aradema, Jacobijne J. Wiersma, Dirk Basart, Ruud M.A. Van Der Wal, Peter Zwart, Pascalle Monraats, Henricus Van Kesteren, Ioannis Karalis, Johan Jukema, Gerardus J.E. Verdel, Bart R.G. Brueren, Roland PTh Troquay, Eric P. Viergever, Nadea Y.Y. Al-Windy, Gerard L. Bartels, Jan H. Cornel, Walter R.M. Hermans, Johannes P.R. Herrman, Robert J. Bos, Reginald G.E.J. Groutars, Coenraad C. Van Der Zwaan, Refik Kaplan, Raymond Lionarons, Eelko Ronner, Bjorn E. Groenemeijer, Patrick N.A. Bronzwaer, Anho A.H. Liem, Bernard J.W.M. Rensing, Marcel J.J.A. Bokern, Remco Nijmeijer, Ferry M.R.J. Hersbach, Frank F. Willems, Antonius T.M. Gosselink, Saman Rasoul, John Elliott, Gerard Wilkins, Raewyn Fisher, Douglas Scott, Hamish Hart, Ralph Stewart, Scott Harding, Ian Ternouth, Nicholas Fisher, Samuel Wilson, Denise Aitken, Russell Anscombe, Laura Davidson, Tadeusz Tomala, Ottar Nygård, Jon Arne Sparby, Kjell Andersen, Lars Gullestad, Jarle Jortveit, Peter S. Munk, Erlend gyllensten Singsaas, Ulf Hurtig, Jorge R. Calderon Ticona, Julio R. Durand Velasquez, Sandra A. Negron Miguel, Enrique S. Sanabria Perez, Jesus M. Carrion Chambilla, Carlos A. Chavez Ayala, Reynaldo P. Castillo Leon, Rolando J. Vargas Gonzales, Jose D. Hernandez Zuniga, Luis A. Camacho Cosavalente, Jorge E. Bravo Mannucci, Javier Heredia Landeo, Nassip C. Llerena Navarro, Yudy M. Roldan Concha, Víctor E. Rodriguez Chavez, Henry A. Anchante Hernandez, Carlos A. Zea Nunez, Walter Mogrovejo Ramos, Arthur Ferrolino, Rosa Allyn G. Sy, Louie Tirador, Generoso Matiga, Raul Martin Coching, Alisa Bernan, Gregorio Rogelio, Dante D. Morales, Edgar Tan, Dennis Jose Sulit, Adrian Wlodarczak, Krystyna Jaworska, Grzegorz Skonieczny, Lidia Pawlowicz, Pawel Wojewoda, Benita Busz-Papiez, Janusz Bednarski, Aleksander Goch, Pawel Staneta, Elzbieta Dulak, Krzysztof Saminski, Wlodzimierz Krasowski, Wanda Sudnik, Aleksander Zurakowski, Marcin Skorski, Roman Lysek, Beata Miklaszewicz, Jacek Kubica, Jan Andrzej Lipko, Edyta Kostarska-Srokosz, Marek Piepiorka, Anna Drzewiecka, Ryszard Sciborski, Arkadiusz Stasiewski, Tomasz Blicharski, Leszek Bystryk, Michal Szpajer, Marek Korol, Tomasz Czerski, Ewa Mirek-Bryniarska, Jacek Gniot, Andrzej Lubinski, Jerzy Gorny, Edward Franek, Grzegorz Raczak, Hanna Szwed, Pedro Monteiro, Jose Mesquita Bastos, Helder H. Pereira, Dinis Martins, Filipe Seixo, Carlos Mendonça, Ana Botelho, Francisca Caetano, Bogdan Minescu, Octavian Istratoaie, Dan N. Tesloianu, Gabriel Cristian, Silviu Dumitrescu, Cristian G.C. Podoleanu, Mircea C.A. Constantinescu, Cristina M. Bengus, Constantin Militaru, Doina Rosu, Irinel R. Parepa, Adrian V. Matei, Tom M. Alexandru, Mihaela Malis, Ioan Coman, Rodica Stanescu-Cioranu, Doina Dimulescu, Yury Shvarts, Olga Orlikova, Zhanna Kobalava, Olga L. Barbarash, Valentin Markov, Nadezhda Lyamina, Alexander Gordienko, Konstantin Zrazhevsky, Alexander Y. Vishnevsky, Victor Gurevich, Raisa Stryuk, Nikita V. Lomakin, Igor Bokarev, Tatiana Khlevchuk, Sergey Shalaev, Larisa Khaisheva, Petr Chizhov, Inna Viktorova, Natalya Osokina, Vladimir Shchekotov, Evgenia Akatova, Galina Chumakova, Igor Libov, Mikhail I. Voevoda, Tatyana V. Tretyakova, Evgeny Baranov, Sergey Shustov, Sergey Yakushin, Ivan Gordeev, Niiaz Khasanov, Olga Reshetko, Tatiana Sotnikova, Olga Molchanova, Konstantin Nikolaev, Liudmila Gapon, Elena Baranova, Zaur Shogenov, Elena Kosmachova, Yuriy Karpov, Anton Povzun, Liudmila Egorova, Vadim V. Tyrenko, Igor G. Ivanov, Masterov Ilya, Sergey Kanorsky, Dragan Simic, Nikola Ivanovic, Goran Davidovic, Nebojsa Tasic, Milika R. Asanin, Stevo Stojic, Svetlana R. Apostolovic, Stevan Ilic, Biljana Putnikovic Tosic, Aleksandar Stankovic, Aleksandra Arandjelovic, Slavica Radovanovic, Branislava Todic, Jovan Balinovac, Dragan V. Dincic, Petar Seferovic, Ana Karadzic, Slobodan Dodic, Sinisa Dimkovic, Tamara Jakimov, Kian-Keong Poh, Hean Yee Ong, Justin Tang I-Shing, Karol Micko, Jan Nociar, Daniel Pella, Peter Fulop, Marian Hranai, Juraj Palka, Juraj Mazur, Ivan Majercák, Andrej Dzupina, František Fazekas, Jozef Gonsorcik, Viliam Bugan, Juraj Selecky, Gabriel Kamensky, Jaroslava Strbova, Rudolf Smik, Andrej Dukat, Peter Olexa, Ivan Žuran, Janez Poklukar, Nataša Černič Šuligoj, Matija Cevc, Henry P. Cyster, Naresh Ranjith, Clive Corbett, Junaid Bayat, Ellen Makoali Makotoko, Hendrik du Toit Theron, Ilse E. Kapp, Matthys M. de V Basson, Hanlie Lottering, Dina Van Aswegen, Louis J. Van Zyl, Peter J. Sebastian, Thayabran Pillay, Jan A. Saaiman, Patrick J. Commerford, Soraya Cassimjee, Garda Riaz, Iftikhar O. Ebrahim, Mahomed Sarvan, Joseph H. Mynhardt, Helmuth Reuter, Rajendran Moodley, Manuel Vida, Angel R. Cequier Fillat, Vicente Bodí Peris, Francisco Fuentes Jimenez, Francisco Marín, Jose M. Cruz Fernández, Rafael Jesus Hidalgo Urbano, Blas Gil-Extremera, Pablo Toledo, Fernando Worner Diz, David Garcia-Dorado, Andres Iñiguez, José Tuñón Fernández, Jose R. Gonzalez-Juanatey, Javier Fernandez Portales, Fernando Civeira Murillo, Laia Matas Pericas, Jose Luis Zamorano, Manuel De Mora Martin, Jordi Bruguera Cortada, Joaquin J. Alonso Martin, Jose Maria Serrano Antolin, José R. De Berrazueta Fernández, José Antonio Vázquez de Prada, Jose Francisco Díaz Fernández, José Alberto García Lledó, Juan Cosín Sales, Javier Botas Rodriguez, Gabriel Gusi Tragant, Amparo Benedicto, Carlos Gonzalez-Juanatey, Mercedes Camprubí Potau, Ignacio Plaza Perez, César Morís De La Tassa, Pablo Loma-Osorio Rincon, Javier Balaguer Recena, Juan M. Escudier, Antonio Coca Payeras, Norberto Alonso Orcajo, Pedro Valdivielso, Godwin Constantine, Ruvaiz Haniffa, Nirmali Tissera, Stanley Amarasekera, Chandrike Ponnamperuma, Nimali Fernando, Kaputella Fernando, Jayanthimala Jayawardena, Santharaj Wijeyasingam, Gotabhaya Ranasinghe, Ruvan Ekanayaka, Sepalika Mendis, Vajira Senaratne, Gnanamoorthy Mayurathan, Ajantha Rajapaksha, Thilak Sirisena, Jagath I. Herath, Naomali Amarasena, Stefan Berglund, Gundars Rasmanis, Ola Vedin, Nils Witt, Georgios Mourtzinis, Peter Nicol, Ole Hansen, Stefano Romeo, Steen Agergaard Jensen, Ingemar Torstensson, Ulf Ahremark, Torbjörn Sundelin, Tiziano Moccetti, Francois Mach, Ronald Binde, Oliver Gämperli, Wei-Chuan Tsai, Kwo-Chang Ueng, Wen-Ter Lai, Ming-En Liu, Juey-Jen Hwang, Wei-Hsian Yin, I-Chang Hsieh, Ming-Jer Hsieh, Wei Hsiang Lin, Jen-Yuan Kuo, Tsuei-Yuan Huang, Chih-Yuan Fang, Pinij Kaewsuwanna, Wasant Soonfuang, Woravut Jintapakorn, Apichard Sukonthasarn, Nattawut Wongpraparut, Krisada Sastravaha, Nakarin Sansanayudh, Wirash Kehasukcharoen, Dilok Piyayotai, Paiboon Chotnoparatpat, Ahmet Camsari, Hakan Kultursay, Bulent Mutlu, Murat Ersanli, Mustafa Demirtas, Cevat Kirma, Ertan Ural, Lale Koldas, Oleksandr Karpenko, Alexander Prokhorov, Ihor Vakaluyk, Halyna Myshanych, Dmytro Reshotko, Valeriy Batushkin, Leonid Rudenko, Ihor Kovalskyi, Mykola Kushnir, Vira Tseluyko, Yuriy Mostovoy, Mykola Stanislavchuk, Yulian Kyiak, Yuriy Karpenko, Yaroslav Malynovsky, Andriy Klantsa, Oles Kutniy, Ekaterina Amosova, Viktor Tashchuk, Oleh Leshchuk, Mykola Rishko, Mykola Kopytsya, Andriy Yagensky, Mykola Vatutin, Andriy Bagriy, Olga M. Barna, Olexiy Ushakov, Georgiy Dzyak, Borys Goloborodko, Anatolii Rudenko, Volodymyr Zheleznyy, Jasper Trevelyan, Azfar Zaman, Kaeng Lee, Andrew Moriarty, Rajesh K. Aggarwal, Piers Clifford, Yuk-Ki Wong, Syed M.R. Iqbal, Eduardas Subkovas, Denise Braganza, David Sarkar, Robert Storey, Huw Griffiths, Sam Mcclure, Rangasamy Muthusamy, Simon Smith, John Kurian, Terry Levy, Craig Barr, Honer Kadr, Robert Gerber, Audrius Simaitis, Handrean Soran, Anthony Mathur, Adrian Brodison, Mohammad Ayaz, Muhammad Cheema, Richard Oliver, Simon Thackray, Telal Mudawi, Gohar Rahman, Ayyaz Sultan, Timothy Reynolds, David Sharman, null david Sprigings, Rob Butler, Peter Wilkinson, Gregory Y.H. Lip, Julian Halcox, Sean Gallagher, Nicholas Ossei-Gerning, Gil Vardi, Duccio Baldari, David Brabham, Charles Treasure, Charles Dahl, Bruce Palmer, Alan Wiseman, Abul Khan, Sanjeev Puri, Ann Elizabeth Mohart, Carlos Ince, Enrique Flores, Scott Wright, Shi-Chi Cheng, Michael Rosenberg, William Rogers, Edward Kosinski, Les Forgosh, Jonathan Waltman, Misal Khan, Mohammad Shoukfeh, Georges Dagher, Patrick Cambier, Ira Lieber, Priya Kumar, Cara East, Perry Krichmar, Mian Hasan, Lindsey White, Thomas Knickelbine, Thomas Haldis, Eve Gillespie, Thomas Amidon, David Suh, Imran Arif, Mouhamad Abdallah, Faiq Akhter, Eric Carlson, Michael D'Urso, Fadi El-Ahdab, William Nelson, Katie Moriarty, Barry Harris, Steven Cohen, Luther Carter, Daniel Doty, Kenneth Sabatino, Tariq Haddad, Amir Malik, Sunder Rao, Angel Mulkay, Ion Jovin, Kim Klancke, Vinay Malhotra, Sai K. Devarapalli, Michael Koren, Harish Chandna, George Dodds, Tauqir Goraya, James Bengston, Matthew Janik, Joseph Moran, Andrew Sumner, John Kobayashi, William Davis, Shahram Yazdani, John Pasquini, Maitreya Thakkar, Amarnath Vedere, Wayne Leimbach, James Rider, Sarah fenton, Narendra Singh, Anil V. Shah, Denise Janosik, Carl Pepine, Brett Berman, Joseph Gelormini, Christopher Daniels, Kerensky Richard, Friederike Keating, Nicholas I. Kondo, Sanjay Shetty, Howard Levite, Winfried Waider, Theodore Takata, Mazen Abu-Fadel, Vipul Shah, Rahul Aggarwal, Mark Izzo, Anil Kumar, Brack Hattler, Rose Do, Chad Link, Anna Bortnick, George Kinzfogl, Arnold Ghitis, John Larry, Edward Teufel, Peter Kuhlman, Brent Mclaurin, Wenwu Zhang, Stephen Thew, Jalal Abbas, Matthew White, Othman Islam, Sumeet Subherwal, Nandkishore Ranadive, Babak Vakili, Christian Gring, David Henderson, Timothy Schuchard, Naim Farhat, Geoffrey Kline, Sharan Mahal, Jack Whitaker, Shawn Speirs, Rolf Andersen, Nizar Daboul, Phillip Horwitz, Firas Zahr, George Ponce, Zubair Jafar, Joseph Mcgarvey, Vipul Panchal, Stephen Voyce, Thomas Blok, William Sheldon, Masoud M. Azizad, Carsten Schmalfuss, Mark Picone, Robert Pederson, William Herzog, Keith Friedman, Jason Lindsey, Rosemary Nowins, Eichenlaub Timothy, Parilak Leonard, Norman Lepor, Mahfouz El Shahawy, Howard Weintraub, Anand Irimpen, Alvaro Alonso, Wade May, Daniels Christopher, Thomas Galski, Alan Chu, Freny Mody, Ebrahimi Ramin, Zachary Hodes, Joseph Rossi, Gregory Rose, James Fairlamb, Charles Lambert, Ajit Raisinghani, Antonio Abbate, George Vetrovec, Marilyn King, Charles Carey, Jaime Gerber, Liwa Younis, Hyeun Park, Mladen Vidovich, Thomas Knutson, Dennis Friedman, Fred Chaleff, Arthur Loussararian, Phillip Rozeman, Carey Kimmelstiel, Jeffrey Kuvin, Kevin Silver, Malcolm Foster, Glen Tonnessen, Andrey Espinoza, Mohamadali Amlani, Andreas Wali, Christopher Malozzi, Geert T. Jong, Clara Massey, Keattiyoat Wattanakit, Philip J. O'Donnell, Dinesh Singal, Naseem Jaffrani, Sridhar Banuru, Daniel Fisher, Mark Xenakis, Neal Perlmutter, Ravi Bhagwat, James Strader, Ronald Blonder, Ayim Akyea-Djamson, Ajay Labroo, Kwan Lee, H. John Marais, Edmund Claxton, Robert Weiss, Rohr Kathryn, Martin Berk, Peter Rossi, Parag Joshi, Amit Khera, Ajit S. Khaira, Greg Kumkumian, Steven Lupovitch, Joshua Purow, Stephen Welka, David Hoffman, Stuart Fischer, Eugene Soroka, Donald Eagerton, Samir Pancholy, Michael Ray, Norman Erenrich, Michael Farrar, Stewart Pollock, William J. French, Steve Diamantis, Douglas Guy, Lawrence Gimple, Mark Neustel, Steven Schwartz, Edward Pereira, Seals Albert, Douglas Spriggs, Janet Strain, Suneet Mittal, Anthony Vo, Majed Chane, Jason Hall, Nampalli Vijay, Kapildeo Lotun, F. Martin Lester, Ahed Nahhas, Theodore Pope, Paul Nager, Rakesh Vohra, Mukesh Sharma, Riyaz Bashir, Hinan Ahmed, Michael Berlowitz, Robert Fishberg, Robert Barrucco, Eric Yang, Michael Radin, Daniel Sporn, Dwight Stapleton, Steven Eisenberg, Joel Landzberg, Martin Mcgough, Samir Turk, Michael Schwartz, P. Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M Gilbert, Gopal Chalavarya, Charles Eaton, John F. Schmedtje, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Andrea Pascual, Carla Rovito, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Melanie Verrier, null Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. Colhoun, Michael A. Dempsey, Mark A. McClanahan, Masira, and Laucevičius, Aleksandras
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, Cardiac & Cardiovascular Systems, Randomization, PCSK9 inhibitor, LOW-DENSITY-LIPOPROTEIN, Antibodies, Monoclonal, Humanized, acute coronary syndrom, Placebo, Gastroenterology, lipoprotein(a), Internal medicine, medicine, Humans, Low-density lipoprotein cholesterol, Aged, Alirocumab, RISK, low-density lipoprotein cholesterol, Science & Technology, biology, business.industry, PCSK9, PCSK9 Inhibitors, Hazard ratio, ALIROCUMAB, acute coronary syndrome, Cholesterol, LDL, Lipoprotein(a), Middle Aged, EFFICACY, medicine.disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, SAFETY, Cardiovascular System & Cardiology, biology.protein, Female, lipids (amino acids, peptides, and proteins), STATIN, low-density lipoprotein, cholesterol PCSK9 inhibitor, CORONARY, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine, Mace
Abstract: Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud
Published: 2021

20. An overview of analgesics: NSAIDs, paracetamol, and topical analgesics Part 1

Author: Helmuth Reuter and R Van Rensburg
Subjects: genetic structures, business.industry, 030503 health policy & services, Pain, nociception, NSAIDs, paracetamol, topical analgesia, Public Health, Environmental and Occupational Health, macromolecular substances, Bioinformatics, Topical analgesics, 03 medical and health sciences, 0302 clinical medicine, Medicine, 030212 general & internal medicine, 0305 other medical science, Family Practice, business
Abstract: Pain is a complex and unique experience. It encompasses several pathways, involving nociceptive signal generation (transduction) and propagation (transmission), as well as perception and modulation of the nociceptive stimuli. Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily exert their analgesic effects through inhibition of cyclooxygenase (COX) enzymes, thereby attenuating prostaglandin synthesis. The COX-2 selective NSAIDs (coxibs) and aspirin have also been shown to reduce colorectal cancers, presumably by prostaglandin-inhibition mechanisms. Paracetamol appears to have both peripheral and central effects. The postulated mechanism for its peripheral effects is indirect COX inhibition, while the central effects are thought to be mediated by modulation of descending pain inhibition pathways. Topical analgesics are available in various formulations. The topical NSAIDs have the same mechanism of action as the systemic formulations, but with less systemic absorption and effects. The local anaesthetics provide a dense sensory block via inhibition of nerve impulse transmission, and are available in percutaneous and transdermal preparations. Capsicum is effective for neuropathic pain, and acts by stimulating and then desensitising peripheral sensory nerves.
Published: 2019

21. The epidemiology and severity of scorpion envenoming in South Africa as managed by the Tygerberg Poisons Information Centre over a 10 year period

Author: Daniël J. van Hoving, Cherylynn A. Wium, C J Marks, Helmuth Reuter, Dmitrij Sachno, G J Müller, and Catharina E. Du Plessis
Subjects: medicine.medical_specialty, Original article, Epidemiology, Antivenom, lcsh:Medicine, Scorpion stings, complex mixtures, 03 medical and health sciences, South Africa, 0302 clinical medicine, Geochemistry and Petrology, medicine, Scorpion sting, 030212 general & internal medicine, Envenomation, lcsh:R5-920, business.industry, Scorpionism, Incidence (epidemiology), lcsh:R, 030208 emergency & critical care medicine, Odds ratio, medicine.disease, Confidence interval, Sting, Poisons centre, Emergency medicine, Emergency Medicine, lcsh:Medicine (General), business, Gerontology
Abstract: Introduction: South Africa has a wide distribution of scorpion species, yet limited data are available regarding the incidence and severity of scorpion envenomation. The aim of this study was to analyse South African epidemiological data of scorpion stings and envenomation as reported to the Tygerberg Poisons Information Centre (TPIC). Methods: A retrospective analysis was conducted of scorpion-related telephonic consultations to the TPIC over a ten year period (1 January 2005 to 31 December 2014). Data were entered onto a Microsoft Excel® spreadsheet and descriptive statistics are presented for all variables. Associations with severity of envenomation are presented as odds ratios (OR) with 95% confidence intervals (95%CI). Results: During the study period 52,163 consultations were processed by the TPIC of which 740 (1.4%) cases involved scorpion stings. Of these, 146 (19.7%) cases were deemed serious envenomations. Antivenom was recommended to be administered in 131 (90%) of these cases. Healthcare professionals made most calls (63%), but were less likely to phone for non-serious cases (OR 0.16; 95%CI 0.09 to 0.29). The Western Cape Province had the highest incidence of calls (6.9 scorpion-related calls/100 000 people). Adults (>20 years) were victims in 71.4% of cases, and were more likely to experience less serious stings (OR 0.57; 95%CI 0.37 to 0.86). The TPIC was consulted within six hours of the sting occurring in 356 (48.1%) cases with a significant association to less severity (OR 3.51; 95%CI 1.9 to 6.3). Only 2% (15) of the scorpions were available for identification. Conclusion: The incidence of severe scorpionism to the TPIC was low. Care should be taken when children are involved and when calls are received more than six hours after the sting. TPIC consultants as well as healthcare professionals working in semi-arid regions should be aware of these high risk populations. Keywords: Scorpion sting, Scorpionism, Envenomation, Epidemiology, Poisons centre, South Africa
Published: 2019

22. Outcome of clinical and subclinical myocardial injury in systemic lupus erythematosus - A prospective cohort study

Author: Riette Du Toit, Alfonso Pecoraro, Christelle Ackerman, Anton Doubell, Dirk Claassen, Helmuth Reuter, P G Herbst, and Henry P Cyster
Subjects: Adult, Male, medicine.medical_specialty, Myocarditis, Adolescent, Magnetic Resonance Imaging, Cine, Ventricular Function, Left, Tertiary Care Centers, South Africa, Young Adult, Rheumatology, Internal medicine, medicine, Humans, Lupus Erythematosus, Systemic, cardiovascular diseases, Prospective Studies, Prospective cohort study, Subclinical infection, Systemic lupus erythematosus, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Myocardium, Magnetic resonance imaging, Stroke Volume, medicine.disease, Logistic Models, Echocardiography, Multivariate Analysis, cardiovascular system, Female, business
Abstract: Objectives To determine the outcome of subclinical lupus myocarditis (LM) over twelve months with regards to: mortality; incidence of clinical LM and change in imaging parameters (echocardiography and cardiac magnetic resonance [CMR]). To evaluate the impact of immunosuppression on CMR evidence of myocardial tissue injury. Methods SLE patients with and without CMR evidence of myocardial injury (as per 2009 Lake Louise criteria [LLC]) were included. Analysis at baseline and follow-up included: clinical evaluation, laboratory and imaging analyses (echocardiography and CMR). Clinical LM was defined as clinical features of LM supported by echocardiographic and/or biochemical evidence of myocardial dysfunction. Subclinical LM was defined as CMR myocardial injury without clinical LM. Results Forty-nine SLE patients were included with follow-up analyses (after 12 months) available in 36 patients. Twenty-five patients (51%) received intensified immunosuppressive therapy during follow-up for indications related to SLE. Disease activity (SLEDAI-2K) improved (p Conclusion CMR evidence of subclinical LM persisted despite improved SLEDAI-2K, serological markers, cardiac function and CMR mass index. Subclinical LM did not progress to clinical LM and had no significant prognostic implications over 12 months. Immunosuppressive therapy did not have any significant effect on the presence of CMR evidence of myocardial tissue injury. Improvement in CMR mass index correlated with reduction in myocardial oedema and may be used to monitor SLE myocardial injury.
Published: 2021

23. Higher SARS-CoV-2 seroprevalence in workers with lower socioeconomic status in Cape Town, South Africa

Author: Vinzeigh N. Leukes, Novel N. Chegou, Nosipho Mtala, Wolfgang Preiser, Stephanus T. Malherbe, Marika Flinn, Conita Claassen, Donald Simon, Gerhard Walzl, Candice E. MacDonald, Tracy Cummins, Jane A. Shaw, Gerard Tromp, Andre G. Loxton, Kim Stanley, Andriëtte Hiemstra, Léanie Kleynhans, Helmuth Reuter, Maynard Meiring, and Nelita du Plessis
Subjects: RNA viruses, Male, Viral Diseases, Coronaviruses, Social Sciences, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, Geographical locations, South Africa, Medical Conditions, Immunodeficiency Viruses, Seroepidemiologic Studies, Cape, Pandemic, Epidemiology, Medicine and Health Sciences, Public and Occupational Health, Pathology and laboratory medicine, Virus Testing, Multidisciplinary, Geography, Medical microbiology, Socioeconomic Aspects of Health, Infectious Diseases, Viruses, Medicine, Female, SARS CoV 2, Pathogens, medicine.symptom, Research Article, Adult, medicine.medical_specialty, SARS coronavirus, Science, Research and Analysis Methods, Human Geography, Social class, Microbiology, Asymptomatic, Diagnostic Medicine, Retroviruses, medicine, Humans, Seroprevalence, Medical history, Molecular Biology Techniques, Molecular Biology, Socioeconomic status, Biology and life sciences, SARS-CoV-2, business.industry, Lentivirus, Organisms, Viral pathogens, HIV, COVID-19, Covid 19, Reverse Transcriptase-Polymerase Chain Reaction, Microbial pathogens, Health Care, Social Class, Africa, Earth Sciences, Housing, People and places, business, Demography
Abstract: Background Inequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known. Methods We tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population. Results Of the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls. Conclusions There is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.
Published: 2021

24. Myocardial injury in systemic lupus erythematosus according to cardiac magnetic resonance tissue characterization: clinical and echocardiographic features

Author: Lloyd Joubert, P G Herbst, Helmuth Reuter, Riette Du Toit, Alfonso Pecoraro, Christelle Ackerman, Rudolf Du Toit, Anton Doubell, and Karim Hassan
Subjects: Adult, Male, medicine.medical_specialty, Myocarditis, Adolescent, Magnetic Resonance Imaging, Cine, Gadolinium, 030204 cardiovascular system & hematology, Ventricular Function, Left, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, Lupus Erythematosus, Systemic, cardiovascular diseases, Lymphocyte Count, Prospective Studies, 030203 arthritis & rheumatology, medicine.diagnostic_test, business.industry, Myocardium, Magnetic resonance imaging, Stroke Volume, Tissue characterization, medicine.disease, Fibrosis, Cross-Sectional Studies, Logistic Models, Echocardiography, cardiovascular system, Cardiology, Female, business, Cardiac magnetic resonance
Abstract: Objectives To determine the prevalence of myocardial injury (MInj) in systemic lupus erythematosus (SLE) according to cardiac magnetic resonance (CMR) criteria. To compare clinical and echocardiographic features of patients with and without MInj and identify predictors of myocardial tissue characteristics according to CMR. Methods SLE inpatients underwent CMR screening for MInj based on the Lake Louise Criteria (LLC). Tissue characteristics included inflammation (increased T2-weighted signal or early gadolinium enhancement ratio (EGEr)) and necrosis or fibrosis (late gadolinium enhancement (LGE)). Echocardiographic parameters included left (left ventricular ejection fraction (LVEF)) and right ventricular function (tricuspid annular plane systolic excursion (TAPSE)), global longitudinal strain (GLS), wall motion score (WMSi) and left ventricular internal diameter index (LVIDi). Variables were compared with regards to the presence/absence of CMR criteria. Logistic regression identified variables predictive of CMR tissue characteristics. Results A hundred and six SLE patients were screened of whom 49 patients were included. Fifty-seven patients were excluded due to intolerance of or contraindication to CMR (27/57 due to renal impairment). Twenty-three patients had CMR evidence of MInj, of which 60.9% was subclinical. Inflammation occurred in 16/23 and necrosis/fibrosis in 12/23 patients. Patients with any evidence of MInj were more frequently anti-dsDNA positive ( p = 0.026) and patients fulfilling LLC for myocarditis had higher SLE disease activity ( p = 0.022). The LVIDi ( p = 0.005), LVEF ( p = 0.005) and TAPSE ( p = 0.011) were more abnormal in patients with an increased EGEr, whereas WMSi ( p = 0.002) and GLS (0.020) were more impaired in patients with LGE. On multivariable logistic regression analyses, TAPSE predicted inflammation (OR: 0.045, p = 0.006, CI: 0.005–0.415) and GLS predicted necrosis/fibrosis (OR: 1.329, p = 0.031, CI: 1.026–1.722). A model including lymphocyte count, TAPSE and LVIDi predicted an increased EGEr on CMR (receiver operating characteristic-curve analyses: area under the curve: 0.901, p Conclusions CMR evidence of MInj frequently occurs in SLE and is often subclinical. The utility of CMR in SLE is limited by a high exclusion rate, mainly due to renal involvement. Models including echocardiographic parameters (TAPSE, LVIDi and GLS) are predictive of CMR myocardial injury. Echocardiography can be used as a cost-effective screening tool with a high negative predictive value, in particular when CMR is contraindicated or unavailable.
Published: 2020

25. Serum cytokine levels associated with myocardial injury in systemic lupus erythematosus

Author: P G Herbst, Novel N. Chegou, Riette Du Toit, Anton Doubell, Candice I. Snyders, Gerhard Walzl, and Helmuth Reuter
Subjects: Adult, Male, medicine.medical_specialty, Myocarditis, medicine.medical_treatment, Vascular Cell Adhesion Molecule-1, 030204 cardiovascular system & hematology, Gastroenterology, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Fibrosis, Internal medicine, medicine, Humans, Lupus Erythematosus, Systemic, Pharmacology (medical), Prospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, Tumor Necrosis Factor-alpha, Interleukins, Myocardium, Heart, Odds ratio, medicine.disease, Interleukin-1 Receptor-Like 1 Protein, Magnetic Resonance Imaging, Cytokine, Cross-Sectional Studies, Interleukin 18, Female, Interleukin 17, business
Abstract: Objectives To identify cytokines, markers of endothelial activation [soluble vascular cell adhesion molecule-1 (sVCAM-1)] and myocyte strain [soluble ST2 (sST2)] associated with myocardial injury (MInj) in SLE, classified by cardiac magnetic resonance (CMR) criteria. Methods CMR was performed on patients with SLE, identifying stages of MInj (inflammation and necrosis or fibrosis). Data captured included: clinical assessment, laboratory and serological analyses, cytokine (IL-1β, IL-1Ra, IL-2, IL-6, IL-10, IL-17, IL-18, TNF-alpha), sVCAM-1 and sST2 levels. Cytokines were compared with regard to SLE features and evidence of CMR MInj. Predictors of CMR MInj were determined through regression analyses. Results Forty-one patients with high disease activity (SLEDAI-2K: 13; IQR: 3–17) were included. SLE features included: LN (n = 12), neurolupus (n = 6) and clinical lupus myocarditis (LM) (n = 6). Nineteen patients had CMR evidence of MInj. Patients with a SLEDAI-2K ≥ 12 had higher sVCAM-1 (P = 0.010) and sST2 (P = 0.032) levels. Neurolupus was associated with higher IL-1Ra (P = 0.038) and LN with lower IL-1Ra (P = 0.025) and sVCAM-1 (P = 0.036) levels. Higher IL-1Ra (P = 0.012), IL-17 (P = 0.045), IL-18 (P = 0.003), and sVCAM-1 (P = 0.062) levels were observed in patients with CMR MInj compared with those without. On multivariable logistic regression, IL-1Ra predicted CMR inflammation and fibrosis/necrosis (P < 0.005) while anti-Ro/SSA [odds ratio (OR): 1.197; P = 0.035] and the SLE damage index (OR: 4.064; P = 0.011) predicted fibrosis/necrosis. Conclusion This is a novel description of associations between cytokines and SLE MInj. IL-18 and IL-1Ra were significantly higher in patients with MInj. IL-1Ra independently predicted different stages of CMR MInj. Exploration of the role of these cytokines in the pathogenesis of SLE MInj may promote targeted therapies for LM.
Published: 2020

26. The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance

Author: Helmuth Reuter, Andreas H. Diacon, Ahmed A. Abulfathi, Kim T. Adams, Elin M. Svensson, and Peter R. Donald
Subjects: Tuberculosis, Antitubercular Agents, Microbial Sensitivity Tests, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, Para-aminosalicylic acid, Minimum inhibitory concentration, 0302 clinical medicine, Pharmacokinetics, Tuberculosis, Multidrug-Resistant, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, Review Articles, Bacteriostatic agent, business.industry, Antituberculosis agent, medicine.disease, Aminosalicylic Acid, Regimen, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Delayed-Action Preparations, business, medicine.drug
Abstract: Contains fulltext : 229215.pdf (Publisher’s version ) (Closed access) Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.
Published: 2020

27. P607Myocardial injury in systemic lupus erythematosus defined by cardiac magnetic resonance imaging: clinical and echocardiographic characteristics

Author: R. Du Toit, Helmuth Reuter, P G Herbst, Christelle Ackerman, Anton Doubell, A. du Plessis, and A J K Pecoraro
Subjects: Pathology, medicine.medical_specialty, Myocarditis, biology, medicine.diagnostic_test, business.industry, Cost effectiveness, Anti-dsDNA antibodies, Cardiomyopathy, medicine.disease, Antiphospholipid syndrome, Fibrosis, Cardiac magnetic resonance imaging, medicine, biology.protein, Beta 2-Glycoprotein I, Cardiology and Cardiovascular Medicine, business
Abstract: Background Lupus myocarditis (LM) occurs in 5–10% of patients with systemic lupus erythematosus (SLE). Subclinical myocardial inflammation is detected in 37% at post mortem. Echocardiographic strain analyses (speckle tracking [STE]) supports subclinical myocardial dysfunction in SLE. Tissue characterization by cardiac magnetic resonance (CMR) identifies myocardial inflammation, necrosis/fibrosis, detecting clinical and subclinical myocardial injury (MIN). It is the non-invasive diagnostic modality of choice for myocarditis (all types) based on the Lake Louise criteria (LLC). The utility of CMR is limited by cost (in resource limited settings) as well as intolerance of / contra-indications to CMR. Purpose Determine prevalence of MIN in SLE (as per LLC). Compare clinical and echocardiographic features of patients with and without MIN. Identify echocardiographic predictors of MIN. Methods A prospective crossectional study was done at Tygerberg Hospital, Western Cape, South Africa. Adult inpatients, fulfilling the 2012 classification criteria for SLE were screened for inclusion. Echocardiography (echo) included strain analyses (segmental and global [GLS]) through STE and regional function assessment (wall motion score (WMS)). Patients were grouped according to CMR evidence of MIN (absent LLC [AC]; single criterion [SC]; fulfilling LLC). Clinical, laboratory and echo parameters were compared between groups. Logistic regression and ROC were used to determine predictors of MIN. Results 49/106 SLE patients screened were included (Figure 1). The median age was 27 years (IQR: 22–35) and 88% were female. 46.9% of patients had MIN (≥1 criterion): 12.2% fulfilled LLC and 34.7% had a SC. Demographic features, cardiac risk factors (including antiphospholipid syndrome) and renal disease were similar among groups. Compared to the AC group, SLE disease activity was higher in patients fulfilling LLC (p=0.022), but not in the SC group (p=0.813). A clinical and echo diagnosis of LM was made in all patients fulfilling LLC (p Figure 1 Conclusion CMR is limited by a high exclusion rate in SLE, mainly due to renal disease. CMR evidence of MIN is common in SLE, even in the absence of clinical myocardial dysfunction or high lupus activity. Impaired echo regional and global function occurs more frequently in patients with MIN. STE combined with LVID predicts the presence of MIN detected by CMR and has potential as a cost effective screening tool.
Published: 2019

28. Critical evaluation of causality assessment of herb-drug interactions in patients

Author: Memela Makiwane, Christo J. F. Muller, Helmuth Reuter, Bernd Rosenkranz, Charles Awortwe, and Johan Louw
Subjects: Pharmacology, medicine.medical_specialty, business.industry, Warfarin, MEDLINE, Drug interaction, Cochrane Library, 030226 pharmacology & pharmacy, Causality, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Severity of illness, Medicine, Pharmacology (medical), Observational study, In patient, business, medicine.drug
Abstract: The aim of this review was to assess the severity of adverse drug reactions (ADRs) due to herb-drug interactions (HDI) in patients taking herbs and prescribed medications based on published evidence. Electronic databases of PubMed, the Cochrane Library, Medline and Scopus were searched for randomized or nonrandomized clinical studies, case-control and case reports of HDI. The data were extracted and the causal relationship of ADRs as consequences of HDI assessed using Horn's drug interaction probability scale or Roussel Uclaf Causality Assessment Method scoring systems. The mechanism of interaction was ascertained using Stockley's herbal medicine interaction companion. Forty-nine case reports and two observational studies with 15 cases of ADRs were recorded. The majority of the patients were diagnosed with cardiovascular diseases (30.60%), cancer (22.45%) and renal transplants (16.32%) receiving mostly warfarin, alkylating agents and cyclosporine, respectively. HDI occurred in patients resulting in clinical ADRs with different severity. Patients may poorly respond to therapeutic agents or develop toxicity due to severe HDI, which in either scenario may increase the cost of treatment and/or lead to or prolong patient hospitalization. It is warranted to increase patient awareness of the potential interaction between herbs and prescribed medicines and their consequences to curb HDI as a potential health problem.
Published: 2018

29. Teaching Medicines Development in Africa

Author: Helmuth Reuter and Lejandra Hanekom
Subjects: Economic growth, Applied Mathematics, General Mathematics, Political science
Published: 2018

30. Speckle tracking echocardiography in acute lupus myocarditis: comparison to conventional echocardiography

Author: P G Herbst, Annari van Rensburg, Anton Doubell, H W Snyman, Riette Du Toit, and Helmuth Reuter
Subjects: 030203 arthritis & rheumatology, Advanced and Specialized Nursing, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Myocarditis, Systemic lupus erythematosus, Radiological and Ultrasound Technology, business.industry, Research, Speckle tracking echocardiography, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, systemic lupus erythematosus, lcsh:RC666-701, Internal medicine, medicine, Cardiology, Radiology, Nuclear Medicine and imaging, myocarditis, business, skin and connective tissue diseases, speckle tracking echocardiography
Abstract: Aims Lupus myocarditis occurs in 5–10% of patients with systemic lupus erythematosus (SLE). No single feature is diagnostic of lupus myocarditis. Speckle tracking echocardiography (STE) can detect subclinical left ventricular dysfunction in SLE patients, with limited research on its utility in clinical lupus myocarditis. We report on STE in comparison to conventional echocardiography in patients with clinical lupus myocarditis. Methods and results A retrospective study was done at a tertiary referral hospital in South Africa. SLE patients with lupus myocarditis were included and compared to healthy controls. Echocardiographic images were reanalyzed, including global longitudinal strain through STE. A poor echocardiographic outcome was defined as final left ventricular ejection fraction (LVEF) r = −0.808; P = 0.001) and regional (wall motion score: r = 0.715; P P = 0.023), wall motion score (P = 0.005) and diastolic function (P = 0.004) were significantly impaired vs controls. Following treatment, LVEF (35–47% (P = 0.023)) and wall motion score (1.88–1.5 (P = 0.017)) improved but not global longitudinal strain. Initial LVEF (34%; P = 0.046) and global longitudinal strain (−9.5%; P = 0.095) were lower in patients with a final LVEF Conclusions This is the first known report on STE in a series of patients with clinical lupus myocarditis. Global longitudinal strain correlated with regional and global left ventricular function. Global longitudinal strain, wall motion score and diastolic parameters may be more sensitive markers of lupus myocarditis in patients presenting with a preserved LVEF ≥50%. A poor initial LVEF and global longitudinal strain were associated with a persistent LVEF
Published: 2017

31. FRI0230 CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF MYOCARDIAL INJURY IN SYSTEMIC LUPUS ERYTHEMATOSUS, CLASSIFIED ACCORDING TO CARDIAC MAGNETIC RESONANCECRITERIA

Author: Anne-Marie du Plessis, Helmuth Reuter, P G Herbst, Riette Du Toit, Alfonso Pecoraro, Christelle Ackerman, and Anton Doubell
Subjects: medicine.medical_specialty, Myocarditis, Systemic lupus erythematosus, medicine.diagnostic_test, business.industry, Autopsy, Magnetic resonance imaging, Gold standard (test), medicine.disease, Basal (phylogenetics), Internal medicine, medicine, Cardiology, In patient, business, Subclinical infection
Abstract: Background: Lupus myocarditis (LM) occurs in 5-10% of patients with systemic lupus erythematosus (SLE). Subclinical myocardial inflammation occurs in 37% at post mortem.1 Echocardiographic strain (STE) supports subclinical myocardial dysfunction in SLE.2 Tissue characterisation by cardiac magnetic resonance (CMR) identifies myocardial inflammation, necrosis and/or fibrosis, detecting clinical and subclinical myocardial injury (MIN) in SLE. It‘s the non-invasive gold standard for diagnosing myocarditis (all types) based on the Lake Louise criteria (LLC).3 Objectives: Determine prevalence of MIN in SLE (LLC). Compare clinical and echocardiographic (echo) features of patients with and without MIN. Identify echo predictors of MIN. Methods: A prospective crossectional study was done at Tygerberg Hospital, Western Cape, South Africa. Adult inpatients, fulfilling the 2012 SLICC criteria were screened. Echo analyses included STE and regional function (wall motion score (WMS)). Patients were grouped according to evidence of MIN (absent criteria [AC]; single criterion [SAC]; fulfilling LLC), comparing clinical, laboratory and echo data. Logistic regression and ROC were used to determine predictors of MIN. Results: 49/106 SLE patients screened were included (Figure 1). 46.9% of patients had MIN (≥1 criterion): 12.2% fulfilled LLC for LM and 34.7% had a SAC. SLE disease activity (SLEDAI) (p=0.022) was higher in patients fulfilling LLC, but not in the SAC group. A clinical and echo diagnosis of LM was made in all patients fulfilling LLC, in 17.6% of patients in the SAC group and none in the AC group (Table 1). Anti-DsDNA and anti-B2GP1 were more frequently positive in SAC vs the AC group (p=0.054 and 0.081). WMS was higher in LLC and SAC groups (p=0.006;p=0.083) with mid and basal STE more impaired in patients with MIN (p=0.047;p=0.043). LVID and mid STE score combined was the best predictor of MIN (Table 2; Figure 2). Conclusion: CMR evidence of MIN is common in SLE, even in the absence of clinical myocardial dysfunction or high lupus activity. Impaired echo regional and global function occurs more frequently in patients with MIN. STE combined with LVID predicts MIN detected by CMR and has potential as a cost effective screening tool. CMR is limited by a high exclusion rate in SLE, mainly due to renal impairment. References: [1] Panchal L, et al. Cardiovascular involvement in systemic lupus erythematosus: an autopsy study of 27 patients in India. J Postgrad Med. 2006;52:5-10. [2] Gusetu G, et al. Subclinical myocardial impairment in SLE: insights from novel ultrasound techniques and clinical determinants. Med Ultrason. 2016;18:47-56. [3] Friedrich M, et al. Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper. J Am Coll Cardiol. 2009;53:1475–87. Disclosure of Interests: Riette du Toit Grant/research support from: I received a sponsorship to attend EULAR 2018 from Pfizer. I have received a donation form ROCHE in 2018 for upgrading of our outpatient clinical area in Tygerberg Hospital., Phillip Herbst: None declared, Alfonso JK Pecoraro: None declared, Christelle Ackerman: None declared, Anne-Marie du Plessis: None declared, Helmuth Reuter Speakers bureau: Received Honorarium as speaker at regional meetings, South Africa, Anton F Doubell: None declared
Published: 2019

32. Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis

Author: Eric H Decloedt, Helmuth Reuter, Ahmed A. Abulfathi, Elin M. Svensson, Andreas H. Diacon, and Peter R. Donald
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Tuberculosis, Drug-Related Side Effects and Adverse Reactions, medicine.drug_class, 030106 microbiology, Antibiotics, Cmax, Drug Resistance, Administration, Oral, Comorbidity, Microbial Sensitivity Tests, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Mortality, Antibiotics, Antitubercular, Pharmacology, medicine.diagnostic_test, business.industry, Pyrazinamide, Middle Aged, medicine.disease, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Biological Variation, Population, Therapeutic drug monitoring, Pharmacogenetics, Pharmacodynamics, Drug Therapy, Combination, Female, Drug Monitoring, Rifampin, business, Rifampicin, medicine.drug
Abstract: Item does not contain fulltext The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >/= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 mug/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >/= 8 microg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax >/= 22 mug/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) >/= 70 mug.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.
Published: 2019

33. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Author: Kausik K Ray, Helen M Colhoun, Michael Szarek, Marie Baccara-Dinet, Deepak L Bhatt, Vera A Bittner, Andrzej J Budaj, Rafael Diaz, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, J Wouter Jukema, Virginie Loizeau, Renato D Lopes, Angèle Moryusef, Jan Murin, Robert Pordy, Arsen D Ristic, Matthew T Roe, José Tuñón, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, Philippe Gabriel Steg, Gregory G. Schwartz, Ph. Gabriel Steg, Deepak L. Bhatt, Vera A. Bittner, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Harvey D. White, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Guillaume Lecorps, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Patricio López-Jaramillo, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Margus Viigimaa, Markku S. Nieminen, Vakhtang Chumburidze, Nikolaus Marx, Nicolas Danchin, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Zlatko Fras, Anthony J. Dalby, H. Asita de Silva, Emil Hagström, Ulf Landmesser, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez-Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean Van Diepen, Matthew D. Wilson, Andrew T. Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. Cartasegna, Gustavo A. Paterlini, Ignacio J. Mackinnon, Guillermo D. Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R. Codutti, Horacio O. Jure, Julio OE Bono, Adrian D. Hrabar, Julio A. Vallejos, Rodolfo A. Ahuad Guerrero, Federico Novoa, Cristian A. Patocchi, Cesar J. Zaidman, Maria E. Giuliano, Ricardo D. Dran, Marisa L. Vico, Gabriela S. Carnero, Pablo N. Guzman, Juan C. Medrano Allende, Daniela F. 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Negron Miguel, S, Sanabria Perez, E, Carrion Chambilla, J, Chavez Ayala, C, Castillo Leon, R, Vargas Gonzales, R, Hernandez Zuniga, J, Camacho Cosavalente, L, Bravo Mannucci, J, Heredia Landeo, J, Llerena Navarro, N, Roldan Concha, Y, Rodriguez Chavez, V, Anchante Hernandez, H, Zea Nunez, C, Mogrovejo Ramos, W, Ferrolino, A, Sy, R, Tirador, L, Matiga, G, Coching, R, Bernan, A, Rogelio, G, Morales, D, Tan, E, Sulit, D, Wlodarczak, A, Jaworska, K, Skonieczny, G, Pawlowicz, L, Wojewoda, P, Busz-Papiez, B, Bednarski, J, Goch, A, Staneta, P, Dulak, E, Saminski, K, Krasowski, W, Sudnik, W, Zurakowski, A, Skorski, M, Miklaszewicz, B, Kubica, J, Andrzej Lipko, J, Kostarska-Srokosz, E, Piepiorka, M, Drzewiecka, A, Stasiewski, A, Blicharski, T, Bystryk, L, Szpajer, M, Korol, M, Czerski, T, Mirek-Bryniarska, E, Gniot, J, Lubinski, A, Gorny, J, Franek, E, Raczak, G, Szwed, H, Monteiro, P, Mesquita Bastos, J, Pereira, H, Martins, D, Seixo, F, Mendonca, C, Botelho, A, Caetano, F, Minescu, B, Istratoaie, O, Tesloianu, D, Cristian, G, Dumitrescu, S, Podoleanu, C, Constantinescu, M, Bengus, C, Militaru, C, Rosu, D, Parepa, I, Matei, A, Alexandru, T, Malis, M, Coman, I, Stanescu-Cioranu, R, Dimulescu, D, Shvarts, Y, Orlikova, O, Kobalava, Z, Barbarash, O, Markov, V, Lyamina, N, Gordienko, A, Zrazhevsky, K, Vishnevsky, A, Gurevich, V, Stryuk, R, Lomakin, N, Bokarev, I, Khlevchuk, T, Shalaev, S, Khaisheva, L, Chizhov, P, Viktorova, I, Osokina, N, Shchekotov, V, Akatova, E, Chumakova, G, Libov, I, Voevoda, M, Tretyakova, T, Baranov, E, Shustov, S, Yakushin, S, Gordeev, I, Khasanov, N, Reshetko, O, Sotnikova, T, Molchanova, O, Nikolaev, K, Gapon, L, Baranova, E, Shogenov, Z, Kosmachova, E, Povzun, A, Egorova, L, Tyrenko, V, Ivanov, I, Ilya, M, Kanorsky, S, Simic, D, Ivanovic, N, Davidovic, G, Tasic, N, Asanin, M, Stojic, S, Apostolovic, S, Ilic, S, Putnikovic Tosic, B, Stankovic, A, Arandjelovic, A, Radovanovic, S, Todic, B, Balinovac, J, Dincic, D, Seferovic, P, Karadzic, A, Dodic, S, Dimkovic, S, Jakimov, T, Poh, K, Ong, H, Tang I-Shing, J, Micko, K, Nociar, J, Pella, D, Fulop, P, Hranai, M, Palka, J, Mazur, J, Majercak, I, Dzupina, A, Fazekas, F, Gonsorcik, J, Bugan, V, Selecky, J, Kamensky, G, Strbova, J, Smik, R, Dukat, A, Zuran, I, Poklukar, J, Cernic Suligoj, N, Cevc, M, Cyster, H, Ranjith, N, Corbett, C, Bayat, J, Makotoko, E, du Toit Theron, H, Kapp, I, de V Basson, M, Lottering, H, Van Aswegen, D, Van Zyl, L, Sebastian, P, Pillay, T, Saaiman, J, Commerford, P, Cassimjee, S, Riaz, G, Ebrahim, I, Sarvan, M, Mynhardt, J, Reuter, H, Moodley, R, Vida, M, Cequier Fillat, A, Bodi Peris, V, Fuentes Jimenez, F, Marin, F, Cruz Fernandez, J, Hidalgo Urbano, R, Gil-Extremera, B, Toledo, P, Worner Diz, F, Garcia-Dorado, D, Iniguez, A, Gonzalez-Juanatey, J, Fernandez Portales, J, Civeira Murillo, F, Matas Pericas, L, Zamorano, J, De Mora Martin, M, Bruguera Cortada, J, Alonso Martin, J, Serrano Antolin, J, De Berrazueta Fernandez, J, Vazquez de Prada, J, Diaz Fernandez, J, Garcia Lledo, J, Cosin Sales, J, Botas Rodriguez, J, Gusi Tragant, G, Benedicto, A, Gonzalez-Juanatey, C, Camprubi Potau, M, Plaza Perez, I, De La Tassa, C, Loma-Osorio Rincon, P, Balaguer Recena, J, Escudier, J, Payeras, A, Alonso Orcajo, N, Valdivielso, P, Constantine, G, Haniffa, R, Tissera, N, Amarasekera, S, Ponnamperuma, C, Fernando, N, Fernando, K, Jayawardena, J, Wijeyasingam, S, Ranasinghe, G, Ekanayaka, R, Mendis, S, Senaratne, V, Mayurathan, G, Sirisena, T, Rajapaksha, A, Herath, J, Amarasena, N, Berglund, S, Rasmanis, G, Vedin, O, Witt, N, Mourtzinis, G, Nicol, P, Hansen, O, Romeo, S, Agergaard Jensen, S, Torstensson, I, Ahremark, U, Sundelin, T, Moccetti, T, Muller, C, Mach, F, Binde, R, Tsai, W, Ueng, K, Lai, W, Liu, M, Hwang, J, Yin, W, Hsieh, I, Hsieh, M, Kuo, J, Huang, T, Fang, C, Kaewsuwanna, P, Soonfuang, W, Jintapakorn, W, Sukonthasarn, A, Wongpraparut, N, Sastravaha, K, Sansanayudh, N, Kehasukcharoen, W, Piyayotai, D, Chotnoparatpat, P, Camsari, A, Kultursay, H, Mutlu, B, Ersanli, M, Demirtas, M, Kirma, C, Ural, E, Koldas, L, Karpenko, O, Prokhorov, A, Vakaluyk, I, Myshanych, H, Reshotko, D, Batushkin, V, Rudenko, L, Kovalskyi, I, Kushnir, M, Tseluyko, V, Mostovoy, Y, Stanislavchuk, M, Kyiak, Y, Karpenko, Y, Malynovsky, Y, Klantsa, A, Kutniy, O, Amosova, E, Tashchuk, V, Leshchuk, O, Rishko, M, Kopytsya, M, Yagensky, A, Vatutin, M, Bagriy, A, Barna, O, Ushakov, O, Dzyak, G, Goloborodko, B, Rudenko, A, Zheleznyy, V, Trevelyan, J, Zaman, A, Lee, K, Moriarty, A, Aggarwal, R, Clifford, P, Wong, Y, Iqbal, S, Subkovas, E, Braganza, D, Sarkar, D, Storey, R, Griffiths, H, Mcclure, S, Muthusamy, R, Smith, S, Kurian, J, Levy, T, Barr, C, Kadr, H, Gerber, R, Simaitis, A, Soran, H, Mathur, A, Brodison, A, Ayaz, M, Cheema, M, Oliver, R, Thackray, S, Mudawi, T, Rahman, G, Sultan, A, Sharman, D, Sprigings, D, Butler, R, Wilkinson, P, Lip, G, Halcox, J, Gallagher, S, Ossei-Gerning, N, Vardi, G, Baldari, D, Brabham, D, Treasure II, C, Dahl, C, Palmer, B, Wiseman, A, Puri, S, Mohart, A, Ince, C, Flores, E, Wright, S, Cheng, S, Rosenberg, M, Rogers, W, Kosinski, E, Forgosh, L, Waltman, J, Khan, M, Shoukfeh, M, Dagher, G, Cambier, P, Lieber, I, Kumar, P, East, C, Krichmar, P, Hasan, M, White, L, Knickelbine, T, Haldis, T, Gillespie, E, Amidon, T, Suh, D, Arif, I, Abdallah, M, Akhter, F, Carlson, E, D'Urso, M, El-Ahdab, F, Nelson, W, Moriarty, K, Harris, B, Cohen, S, Carter, L, Doty, D, Sabatino, K, Haddad, T, Malik, A, Rao, S, Mulkay, A, Jovin, I, Klancke, K, Malhotra, V, Devarapalli, S, Koren, M, Chandna, H, Dodds III, G, Goraya, T, Bengston, J, Janik, M, Moran, J, Sumner, A, Kobayashi, J, Davis, W, Yazdani, S, Pasquini, J, Thakkar, M, Vedere, A, Leimbach, W, Rider, J, Fenton, S, Singh, N, Shah, A, Janosik, D, Pepine, C, Berman, B, Gelormini, J, Daniels, C, Richard, K, Keating, F, Kondo, N, Shetty, S, Levite, H, Waider, W, Takata, T, Abu-Fadel, M, Shah, V, Izzo, M, Kumar, A, Hattler, B, Do, R, Link, C, Bortnick, A, Kinzfogl III, G, Ghitis, A, Larry, J, Teufel, E, Kuhlman, P, Mclaurin, B, Zhang, W, Thew, S, Abbas, J, White, M, Islam, O, Subherwal, S, Ranadive, N, Vakili, B, Gring, C, Henderson, D, Schuchard, T, Farhat, N, Kline, G, Mahal, S, Whitaker, J, Speirs, S, Andersen, R, Daboul, N, Horwitz, P, Zahr, F, Ponce, G, Jafar, Z, Mcgarvey, J, Panchal, V, Voyce, S, Blok, T, Sheldon, W, Azizad, M, Schmalfuss, C, Picone, M, Pederson, R, Herzog, W, Friedman, K, Lindsey, J, Nowins, R, Timothy, E, Leonard, P, Lepor, N, El Shahawy, M, Weintraub, H, Irimpen, A, Alonso, A, May, W, Christopher, D, Galski, T, Chu, A, Mody, F, Ramin, E, Hodes, Z, Rossi, J, Rose, G, Fairlamb, J, Lambert, C, Raisinghani, A, Abbate, A, Vetrovec, G, King, M, Carey, C, Gerber, J, Younis, L, Vidovich, M, Knutson, T, Friedman, D, Chaleff, F, Loussararian, A, Rozeman, P, Kimmelstiel, C, Kuvin, J, Silver, K, Foster, M, Tonnessen, G, Espinoza, A, Amlani, M, Wali, A, Malozzi, C, Jong, G, Massey, C, Wattanakit, K, O'Donnell, P, Singal, D, Jaffrani, N, Banuru, S, Fisher, D, Xenakis, M, Perlmutter, N, Bhagwat, R, Strader, J, Blonder, R, Akyea-Djamson, A, Labroo, A, Marais, H, Claxton, E, Weiss, R, Kathryn, R, Berk, M, Joshi, P, Khera, A, Khaira, A, Kumkumian, G, Lupovitch, S, Purow, J, Welka, S, Hoffman, D, Fischer, S, Soroka, E, Eagerton, D, Pancholy, S, Ray, M, Erenrich, N, Farrar, M, Pollock, S, French, W, Diamantis, S, Guy, D, Gimple, L, Neustel, M, Schwartz, S, Pereira, E, Albert, S, Spriggs, D, Strain, J, Mittal, S, Vo, A, Chane, M, Hall, J, Vijay, N, Lotun, K, Lester, F, Nahhas, A, Pope, T, Nager, P, Vohra, R, Sharma, M, Bashir, R, Ahmed, H, Berlowitz, M, Fishberg, R, Barrucco, R, Yang, E, Radin, M, Sporn, D, Stapleton, D, Eisenberg, S, Landzberg, J, Mcgough, M, Turk, S, Schwartz, M, Sundram, P, Jain, D, Zainea, M, Bayron, C, Karlsberg, R, Dohad, S, Lui, H, Keen, W, Westerhausen, D, Khurana, S, Agarwal, H, Birchem, J, Penny, W, Chang, M, Murphy, S, Henry, J, Schifferdecker, B, Gilbert, J, Chalavarya, G, Eaton, C, Schmedtje, J, Christenson, S, Dotani, I, Denham, D, Macdonell, A, Gibson, P, Rahman, A, Al Joundi, T, Assi, N, Conrad, G, Kotha, P, Love, M, Giesler, G, Rubenstein, H, Gamil, D, Akright, L, Krawczyk, J, Cobler, J, Wells, T, Welker, J, Foster, R, Gilmore, R, Anderson, J, Jacoby, D, Gardner, G, Dandillaya, R, Vora, K, Kostis, J, Hunter, J, Laxson, D, Ball, E, Egydio, F, Kawakami, A, Oliveira, J, Wozniak, J, Matthews, A, Ratky, C, Valiris, J, Berdan, L, Hepditch, A, Quintero, K, Rorick, T, Westbrook, M, Pascual, A, Rovito, C, Bezault, M, Drouet, E, Simon, T, Alsweiler, C, Luyten, A, Butters, J, Griffith, L, Shaw, M, Grunberg, L, Islam, S, Bregeault, M, Bougon, N, Faustino, D, Fontecave, S, Murphy, J, Verrier, M, Agnetti, V, Andersen, D, Badreddine, E, Bekkouche, M, Bouancheau, C, Brigui, I, Brocklehurst, M, Cianciarulo, J, Devaul, D, Domokos, S, Gache, C, Gobillot, C, Guillou, S, Healy, J, Heath, M, Jaiwal, G, Javierre, C, Labeirie, J, Monier, M, Morales, U, Mrabti, A, Mthombeni, B, Okan, B, Smith, L, Sheller, J, Sopena, S, Pellan, V, Benbernou, F, Bengrait, N, Lamoureux, M, Kralova, K, Scemama, M, Bejuit, R, Coulange, A, Berthou, C, Repincay, J, Lorenzato, C, Etienne, A, Gouet, V, Normand, M, Ourliac, A, Rondel, C, Adamo, A, Beltran, P, Barraud, P, Dubois-Gache, H, Halle, B, Metwally, L, Mourgues, M, Sotty, M, Vincendet, M, Cotruta, R, Chengyue, Z, Fournie-Lloret, D, Morrello, C, Perthuis, A, Picault, P, Zobouyan, I, Dempsey, M, Mcclanahan, M, ODYSSEY OUTCOMES Comm Investigato, and Ege Üniversitesi
Subjects: Male, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, STATIN THERAPY, blood-glucose, Endocrinology, Diabetes and Metabolism, GUIDELINES, PCSK9, 0302 clinical medicine, Endocrinology, GENETIC-VARIANTS, Cardiovascular Disease, Diabetes Complication, Aged Antibodies, Monoclonal, Humanized / therapeutic use* Cardiovascular Diseases / blood Cardiovascular Diseases / prevention & control* Diabetes Complications / blood Diabetes Complications / prevention & control* Female Humans Male Middle Aged Substances, Clinical endpoint, Medicine, guidelines, 030212 general & internal medicine, Prediabetes, Myocardial infarction, myocardial-infarction, genetic-variants, statin therapy, risk, pcsk9, association, liraglutide, evolocumab, RISK, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, BLOOD-GLUCOSE, ASSOCIATION, Middle Aged, Cardiovascular Diseases, Female, Life Sciences & Biomedicine, Human, medicine.medical_specialty, Acute coronary syndrome, PCSK9 inhibitor, acute coronary syndrome, lipoprotein(a), low-density lipoprotein cholesterol, 030209 endocrinology & metabolism, Antibodies, Monoclonal, Humanized, Diabetes Complications, Endocrinology & Metabolism, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, Humans, Aged, Alirocumab, diabetes, PCSK9, hyperlipidemia, Science & Technology, ODYSSEY OUTCOMES Committees and Investigators, business.industry, Unstable angina, EVOLOCUMAB, medicine.disease, MYOCARDIAL-INFARCTION, LIRAGLUTIDE, Human medicine, business
Abstract: Doi, Yasuji/0000-0002-8368-0827; galvani, marcello/0000-0001-5897-667X; Gislason, Gunnar H/0000-0002-0548-402X; Taskinen, Marja-Riitta/0000-0002-6229-3588; Sherwood, Matthew/0000-0002-4305-5883; Malynovsky, Yaroslav V/0000-0002-9118-1104; Viktorova, vic-inna@mail.ru I.A./0000-0001-8728-2722; bastos, jose/0000-0002-9526-3123; Yang, Eric H/0000-0003-4889-7454; Rudenko, Anatoliy Viktorovich/0000-0003-1099-1613; Novotny, Vojtech/0000-0003-3521-9945; Nikolaev, Konstantin/0000-0003-4601-6203; Reshetko, Olga/0000-0003-3107-7636; Leonardi, Sergio/0000-0002-4800-6132; Muenzel, Thomas/0000-0001-5503-4150; Ushakov, Alexei V/0000-0002-7020-4442; Tse, Hung Fat/0000-0002-9578-7808; Podoleanu, Cristian/0000-0001-9987-2519; Raffel, Owen C/0000-0001-5470-7050; Khasanov, Niiaz/0000-0002-7760-0763; Chumakova, Galina A/0000-0002-2810-6531; Ersanli, Murat/0000-0003-1847-3087; cornel, jan hein/0000-0002-1006-2112; Abbate, Antonio/0000-0002-1930-785X; Racca, Vittorio/0000-0002-4465-3789; Urina-Triana, Miguel A/0000-0001-6003-4622; Rasputina, Lesia/0000-0003-1230-4039; Racca, Vittorio/0000-0002-4465-3789; Reis, Gilmar/0000-0002-4847-1034; Sandhu, Manjinder/0000-0003-2538-2079; Keskin, Kudret/0000-0002-9049-1530; PAREPA, IRINEL/0000-0002-7571-9015; Manakshe, Gajendra/0000-0002-4983-4271; Nicolau, Jose C/0000-0002-9680-3689; Strelnieks, Aldis/0000-0003-3493-2562; Budaj, Andrzej/0000-0002-6395-2098; Marin, Francisco/0000-0001-7246-7708; Wongpraparut, Nattawut/0000-0002-1541-3313; Yuan, Zuyi/0000-0002-4141-0298; Jeong, Myung Ho/0000-0003-2424-810X; Mostovoy, Yuriy/0000-0002-7041-1230; Pepine, Carl/0000-0002-6011-681X; Lopez-Jaramillo, Patricio/0000-0002-9122-8742; Garcia-Lledo, Alberto/0000-0002-8986-2584; Tesloianu, Nicolae-Dan/0000-0002-1007-3022; Kosmacheva, Elena/0000-0001-8600-0199; Kunz Sebba Barroso Souza, Weimar/0000-0002-1265-1930; Katz, Amos/0000-0003-0422-934X; Tunon, Jose/0000-0002-1373-0999; Acevedo, Monica/0000-0002-7989-6633; Hove, Jens/0000-0002-5600-5623; Yakushin, Sergey/0000-0001-7202-742X; Gonzalez Juanatey, Jose Ramon/0000-0001-9681-3388; Lyamina, Nadezhda/0000-0001-6939-3234; Aylward, Philip/0000-0002-5358-8552; Apostolovic, Svetlana/0000-0001-9015-297X; Airaksinen, Juhani/0000-0002-0193-568X; Nahhas, Prof. Dr. Ahmed/0000-0002-2887-8187; Barbarash, Olga/0000-0002-4642-3610, WOS: 000475553300016, PubMed: 31272931, Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1: 1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0.65-1.30 mmol/L. in this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA(1c) or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. the primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials. gov, number NCT01663402. Findings At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2.20-2.28 mmol/L), after 4 months' treatment with alirocumab (0.80 mmol/L), or after 4 months' treatment with placebo (2.25-2.28 mmol/L). in the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78-2.46, p, Sanofi; Regeneron Pharmaceuticals, Sanofi and Regeneron Pharmaceuticals.
Published: 2019

34. Severe disease presentation and poor outcomes among pediatric systemic lupus erythematosus patients in South Africa

Author: Priya Ambaram, Priya Gajjar, Laura B Lewandowski, Ikechi G. Okpechi, Helmuth Reuter, Peter Nourse, Asgar Ali Kalla, Graeme Spittal, Christiaan Scott, Gail Faller, A. Phuti, Laura E. Schanberg, and Nathan M. Thielman
Subjects: Male, Nephrology, medicine.medical_specialty, Time Factors, Adolescent, Cyclophosphamide, Health Status, Population, Lupus nephritis, Azathioprine, Severity of Illness Index, Article, South Africa, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Risk Factors, Internal medicine, medicine, Humans, Lupus Erythematosus, Systemic, Registries, 030212 general & internal medicine, Age of Onset, Child, education, Retrospective Studies, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Prognosis, medicine.disease, Lupus Nephritis, United States, Cross-Sectional Studies, Phenotype, Renal pathology, Cohort, Physical therapy, Female, business, Biomarkers, Immunosuppressive Agents, medicine.drug
Abstract: Background Systemic lupus erythematosus (SLE) is a life-threatening multisystem autoimmune disease that is more severe in patients of African ancestry and children, yet pediatric SLE on the African continent has been understudied. This study describes a cohort of pediatric SLE (PULSE) patients in South Africa. Methods Patients with a diagnosis of SLE (1997 American College of Rheumatology criteria) diagnosed prior to age 19 years in Cape Town, South Africa, were enrolled in this cross-sectional study from September 2013 to December 2014. Information on clinical and serological characteristics was extracted from medical records. Results were compared to a well-described North American pediatric SLE cohort. Results Seventy-two South African patients were enrolled in the study; mean age 11.5 years; 82% were girls. The racial distribution was 68% Coloured, 24% Black, 5% White and 3% Asian/Indian. Most patients presented with severe lupus nephritis documented by renal biopsy (61%). Of patients with lupus nephritis, 63% presented with International Society of Nephrology/Renal Pathology Society class III or IV. Patients in the PULSE cohort were more likely to be treated with cyclophosphamide, methotrexate and azathioprine. The PULSE cohort had high disease activity at diagnosis (mean Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) 20.6). The SLEDAI-2K at enrolment in the PULSE cohort (5.0) did not differ from the North American pediatric SLE cohort (4.8). Sixty-three per cent of the PULSE cohort had end organ damage with Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI) score >0 (mean SLICC-DI 1.9), compared to 23% in a previously reported US cohort. Within the PULSE cohort, nine (13%) developed end-stage renal disease with six (8%) requiring transplant, strikingly higher than North American peers (transplant rate Conclusions The PULSE cohort had highly active multiorgan disease at diagnosis and significant disease damage at enrolment in the South African registry. South African patients have severe lupus nephritis and poor renal outcomes compared to North American peers. Our study revealed a severe disease phenotype in the PULSE cohort resulting in poor outcomes in this high-risk population.
Published: 2016

35. Clinical features and outcome of lupus myocarditis in the Western Cape, South Africa

Author: R. Du Toit, L du Plessis, P G Herbst, Anton Doubell, Helmuth Reuter, and A. van Rensburg
Subjects: Adult, Male, Time Factors, Myocarditis, Adolescent, Population, Lupus nephritis, Ethnic group, 030204 cardiovascular system & hematology, Ventricular Function, Left, South Africa, Ventricular Dysfunction, Left, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Lymphopenia, Prevalence, medicine, Humans, Lupus Erythematosus, Systemic, education, Retrospective Studies, 030203 arthritis & rheumatology, education.field_of_study, Systemic lupus erythematosus, business.industry, Racial Groups, Prognosis, medicine.disease, Acute Disease, Immunology, Western cape, Female, business, Demography, American Ethnicity
Abstract: Background African American ethnicity is independently associated with lupus myocarditis compared with other ethnic groups. In the mixed racial population of the Western Cape, South Africa, no data exists on the clinical features/outcome of lupus myocarditis. Objectives The objective of this study was to give a comprehensive description of the clinical features and outcome of acute lupus myocarditis in a mixed racial population. Methods Clinical records (between 2008 and 2014) of adult systemic lupus erythematosus (SLE) patients at a tertiary referral centre were retrospectively screened for a clinical and echocardiographic diagnosis of lupus myocarditis. Clinical features, laboratory results, management and outcome were described. Echocardiographic images stored in a digital archive were reanalysed including global and regional left ventricular function. A poor outcome was defined as lupus myocarditis related mortality or final left ventricular ejection fraction (LVEF) Results Twenty-eight of 457 lupus patients (6.1%) met inclusion criteria: 92.9% were female and 89.3% were of mixed racial origin. Fifty-three per cent of patients presented within three months after being diagnosed with SLE. Seventy-five per cent had severely active disease (SLE disease activity index ≥ 12) and 67.9% of patients had concomitant lupus nephritis. Laboratory results included: lymphopenia (69%) and an increased aRNP (61.5%). Treatment included corticosteroids (96%) and cyclophosphamide (75%); 14% of patients required additional immunosuppression including rituximab. Diastolic dysfunction and regional wall motion abnormalities occurred in > 90% of patients. LVEF improved from 35% to 47% ( p = 0.023) and wall motion score from 1.88 to 1.5 ( p = 0.017) following treatment. Overall mortality was high (12/28): five patients (17.9%) died due to lupus myocarditis (bimodal pattern). Patients who died of lupus myocarditis had a longer duration of SLE ( p = 0.045) and a lower absolute lymphocyte count ( p = 0.041) at diagnosis. LVEF at diagnosis was lower in patients who died of lupus myocarditis ( p = 0.099) and in those with a persistent LVEF Conclusions This is the largest reported series on lupus myocarditis. The mixed racial population had a similar prevalence, but higher mortality compared with other ethnic groups (internationally published literature). Patients typically presented with high SLE disease activity and the majority had concomitant lupus nephritis. Lymphopenia and low LVEF at presentation were of prognostic significance, associated with lupus myocarditis related mortality or a persistent LVEF
Published: 2016

36. Benefit v. risk when using chloroquine in patients with severe COVID-19 disease

Author: Arifa Parker, Eric H Decloedt, Helmuth Reuter, Brian W. Allwood, Coenraad F.N. Koegelenberg, Marc Blockman, and Jantjie J Taljaard
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Hydroxychloroquine, General Medicine, Disease, Azithromycin, medicine.disease, Pneumonia, Chloroquine, Internal medicine, medicine, In patient, Medical journal, business, medicine.drug
Abstract: CITATION: Decloedt, E. H. et al. 2020. Benefit v. risk when using chloroquine in patients with severe COVID-19 disease. South African Medical Journal, doi.org/10.7196/SAMJ.2020.v110i5.14761.
Published: 2020

37. South African Marine Envenomations and Poisonings as Managed Telephonically by the Tygerberg Poisons Information Centre: A 20-Year Retrospective Review

Author: Cherylynn Angela Wium, Helmuth Reuter, Carine Marks, Daniël J. van Hoving, Dmitrij Sachno, Catharina E. Du Plessis, and G.J. Muller
Subjects: Male, medicine.medical_specialty, Poison Control Centers, Poison control, Suicide prevention, Occupational safety and health, 03 medical and health sciences, South Africa, 0302 clinical medicine, Environmental health, Injury prevention, Epidemiology, medicine, Animals, Humans, Bites and Stings, Envenomation, Retrospective Studies, business.industry, Public health, Public Health, Environmental and Occupational Health, 030208 emergency & critical care medicine, 030229 sport sciences, Odds ratio, Seafood, Emergency Medicine, Female, Marine Toxins, business
Abstract: Introduction South Africa has an abundance of marine life, and the potential for hazardous exposure to marine life is high. To our knowledge, this is the first epidemiological review regarding marine toxicity that has ever been conducted in sub-Saharan Africa. The aim of this review was to investigate marine toxicology data as managed telephonically by the Tygerberg Poisons Information Centre. Methods Marine toxicology cases were retrospectively analyzed for a 20-y period (January 1, 1995 to December 31, 2014). Data were extracted from archived consultation forms. Descriptive statistics are presented, and post hoc analyses compared age, sex, province, and caller's background with severity and type of toxicology. Results A total of 311 calls involved 392 cases. Most calls involved adults (n=317, 81%) and males (n=214, 55%) and presented with no or minor symptoms (n=242, 62%). Poisoning from ingestion (n=239; 61%) was more commonly encountered than was marine envenomation (n=153; 39%), with paralytic shellfish poisoning (n=118; 30%), scombroid poisoning (n=93; 24%), and envenomation from stingrays (n=36; 9%) and bluebottles (n=33; 8%) occurring often. Healthcare professionals were more likely to consult for severe cases (odds ratio 3.3; 95% CI 1.9–5.9) and poisoning-related cases (odds ratio 1.8; 95% CI 1.1–2.9). Conclusion The proportion of marine-related toxicology cases was low. Telephonic consultations by healthcare professionals relating to poisoning were generally of a serious nature. The data can be used to drive public health awareness campaigns.
Published: 2018

38. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial

Author: Roy Fleischmann, Eduardo Mysler, Stephen Hall, Alan J Kivitz, Robert J Moots, Zhen Luo, Ryan DeMasi, Koshika Soma, Richard Zhang, Liza Takiya, Svitlana Tatulych, Christopher Mojcik, Sriram Krishnaswami, Sujatha Menon, Josef S Smolen, Luthando Adams, Mahmood M Ally, Maria C du Plooy, Ingrid C Louw, Savithree Nayiager, Christoffel B Nel, Debra Nel, Helmuth Reuter, Ahmed S Soloman, Catherine E Spargo, Maureen Rischmueller, Shunil D Sharma, Robert K Will, Peter P Youssef, Caroline Arroyo, Rosario P Baes, Roger B Dulos, Llewellyn T Hao, Allan E Lanzon, Juan Javier T Lichauco, Jill H Mangubat, Edgar B Ramiterre, Bernadette Heizel M Reyes, Perry P Tan, Jung-Yoon Choe, Young Mo Kang, Seong Ryul Kwon, Sang-Heon Lee, Shin-Seok Lee, Dae-Hyun Yoo, Hsiao-Yi Lin, Shue-Fen Luo, Shih-Tzu Tsai, Wen-Chan Tsai, Jui-Cheng Tseng, Cheng-Chung C Wei, Paijit Asavatanabodee, Kanokrat Nantiruj, Surasak Nilganuwong, Parichat Uea-Areewongsa, Ljubinka Bozic Majstorovic, Suada Mulic Bacic, Anastas Z Batalov, Gabriela Georgieva-Slavcheva, Mariyana Mihailova, Nikolay G Nikolov, Dimitar P Penev, Yuliy A Spasov, Krasimira Stanimirova, Stoyan Todorov, Antoaneta R Toncheva, Nadezhda Yordanova, Zdenka Mosterova, Libor Novosad, Leona Prochazkova, Helena Stehlikova, Zuzana Stejfova, Natalia Kiseleva, Lea Pank, Triin Savi, Balbir-Gurman Alexandra, Howard Amital, Dror Mevorach, Itzhak A Rosner, Anna Mihailova, Evija Stumbra-Stumberga, Vida Basijokiene, Virginija Lietuvininkiene, Dalia Unikiene, Jan Brzezicki, Anna M Dudek, Maria B Glowacka-Kulesz, Barbara Grabowicz-Wasko, Sabina Hajduk-Kubacka, Joanna Hilt, Pawel Hrycaj, Slawomir Jeka, Renata Kolasa, Marek Krogulec, Hanna Mastalerz, Anna Olak-Popko, Elzbieta Owczarek, Zofia Ruzga, Alina Walczak, Codrina I Ancuta, Ioan Ancuta, Andra R Balanescu, Florian Berghea, Silvia Bojin, Mihaela A Ianuli Arvunescu, Ruxandra M Ionescu, Eugenia Mociran, Mariana Pavel, Simona Rednic, Adriana Voie, Carmen M Zainea, Olga V Bugrova, Alexander Demin, Olga B Ershova, Inna A Gavrisheva, Diana G Krechikova, Gennady V Kuropatkin, Irina M Marusenko, Irina V Menshikova, Sergey M Noskov, Andrey P Rebrov, Svetlana A Smakotina, Sergey S Yakushin, Evgeny Zhilyaev, Juan Jose Amarelo Ramos, Francisco Javier Blanco Garcia, Antonio Fernandez Nebro, Silvia Perez Esteban, Juan Miguel Sanchez Burson, Raimon Sanmarti Sala, Sebnem Ataman, Sami Hizmetli, Omer Kuru, Karen M Douglas, Paul Emery, Voon H Ong, Thomas P Sheeran, Rafat Y Faraawi, Clode Lessard, Carlos Abud Mendoza, Hilario Ernesto Avila-Armengol, Francisco I Avila Zapata, Fedra Consuelo Irazoque-Palazuelos, Marco Antonio Maradiaga Cecena, Cesar F Pacheco-Tena, Juan C Rizo-Rodriguez, Isaura M Rodriguez-Torres, Jacob A Aelion, Barbara A Caciolo, James M Calmes, Prem Chatpar, Nimesh Dayal, Alex De Jesus, Ara H Dikranian, Erdal Diri, Michael J Fairfax, Ira F Fenton, Roy M Fleischmann, Norman B Gaylis, Ronald L George, Dale G Halter, Paul Hernandez, Susan A Hole, Antony C Hou, John P Huff, Suzanne Kafaja, Alastair C Kennedy, Howard Kenney, Steven C Kimmel, Brian S Kirby, Clarence W Legerton, Stephen M Lindsey, Jyothi R Mallepalli, Steven D Mathews, Samy K Metyas, Wesley T Mizutani, Sabeen Najam, Joao M Nascimento, Shirley W Pang, Rakesh C Patel, Jeffrey E Poiley, Carlos E Ramirez, Riteesha Reddy, Qaiser Rehman, William M Schnitz, Craig D Scoville, William J Shergy, Joel C Silverfield, Atul K Singhal, Yvonne R Smallwood-Sherrer, Suthin N Songcharoen, Michael T Stack, William Stohl, Tien-I K Su, James Udell, Saleem Waraich, Charles E Weidmann, Nathan Wei, Craig W Wiesenhutter, Anne E Winkler, Karen E Zagar, Alberto Berman, Eduardo F Mysler, Rodolfo A Pardo Hidalgo, Horacio O Venarotti, Irmgadt Annelise Goecke Sariego, Renato E Jimenez Calabresse, Juan Ignacio Vargas Ruiz-Tagle, Luis Fernando M Bellatin Vargas, Alfredo E Berrocal, Manuel Gustavo Leon Portocarrero, Felix Jesus, and Romero Pena
Subjects: 0301 basic medicine, musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Filgotinib, Arthritis, Administration, Oral, Pharmacology, Severity of Illness Index, Drug Administration Schedule, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Piperidines, Internal medicine, medicine, Adalimumab, Humans, Pyrroles, skin and connective tissue diseases, Janus kinase inhibitor, 030203 arthritis & rheumatology, Tofacitinib, business.industry, General Medicine, Middle Aged, medicine.disease, Rheumatology, stomatognathic diseases, 030104 developmental biology, Methotrexate, Pyrimidines, Treatment Outcome, Rheumatoid arthritis, Antirheumatic Agents, Drug Therapy, Combination, Female, business, medicine.drug
Abstract: Summary Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.
Published: 2017

39. Diagnosing tuberculous pericarditis

Author: Doubell Af, Helmuth Reuter, W. van Vuuren, and Lesley J. Burgess
Subjects: Male, medicine.medical_specialty, Pathology, Pericardial effusion, Gastroenterology, Sputum culture, South Africa, Pericarditis, Internal medicine, medicine, Humans, Prospective Studies, medicine.diagnostic_test, business.industry, Tuberculous pericarditis, Pericardial fluid, Mycobacterium tuberculosis, Pericarditis, Tuberculous, General Medicine, medicine.disease, Blood chemistry, Absolute neutrophil count, Sputum, Female, medicine.symptom, business
Abstract: Definitive diagnosis of tuberculous pericarditis requires isolation of the tubercle bacillus from pericardial fluid, but isolating the organism is often difficult.To improve diagnostic efficiency for tuberculous pericarditis, using available tests.Prospective observational study.Consecutive patients (n = 233) presenting with pericardial effusions underwent a predetermined diagnostic work-up. This included (i) clinical examination; (ii) pericardial fluid tests: biochemistry, microbiology, cytology, differential white blood cell (WBC) count, gamma interferon (IFN-gamma), adenosine deaminase (ADA) levels, polymerase chain reaction testing for Mycobacterium tuberculosis; (iii) HIV; (iv) sputum smear and culture; (v) blood biochemistry; and (vi) differential WBC count. A model was developed using 'classification and regression tree' analysis. The cut-off for the total diagnostic index (DI) was optimized using receiver operating characteristic (ROC) curves.Fever, night sweats, weight loss, serum globulin (40 g/l) and peripheral blood leukocyte count (10 x 10(9)/l) were independently predictive. The derived prediction model had 86% sensitivity and 84% specificity when applied to the study population. Pericardial fluid IFN-gammaor=50 pg/ml, concentration had 92% sensitivity, 100% specificity and a positive predictive value (PPV) of 100% for the diagnosis of tuberculous pericarditis; pericardial fluid ADAor=40 U/l had 87% sensitivity and 89% specificity. A diagnostic model including pericardial ADA, lymphocyte/neutrophil ratio, peripheral leukocyte count and HIV status had 96% sensitivity and 97% specificity; substituting pericardial IFN-gamma for ADA yielded 98% sensitivity and 100% specificity.Basic clinical and laboratory features can aid the diagnosis of tuberculous pericarditis. If available, pericardial IFN-gamma is the most useful diagnostic test. Otherwise we propose a prediction model that incorporates pericardial ADA and differential WBC counts.
Published: 2006

40. Beijing and Haarlem Genotypes Are Overrepresented among Children with Drug-Resistant Tuberculosis in the Western Cape Province of South Africa

Author: H. Simon Schaaf, Nulda Beyers, Helmuth Reuter, Ben J. Marais, Madeleine Barnard, Anneke C. Hesseling, Wendy Brittle, Tommie C. Victor, Jordaan Am, Rob Warren, and Paul D. van Helden
Subjects: Male, Microbiology (medical), medicine.medical_specialty, Pediatrics, Tuberculosis, Genotype, Population, Antitubercular Agents, Drug resistance, Gene mutation, Mycobacterium tuberculosis, South Africa, Antibiotic resistance, Drug Resistance, Multiple, Bacterial, Internal medicine, Humans, Medicine, Child, education, education.field_of_study, biology, business.industry, Infant, Newborn, Infant, Mycobacteriology and Aerobic Actinomycetes, biology.organism_classification, medicine.disease, Child, Preschool, Female, business, Rifampicin, medicine.drug
Abstract: Drug resistance among children with culture-confirmed tuberculosis (TB) provides an accurate measure of transmitted drug resistance within the community. We describe the genotype diversity in children with culture-confirmed TB and investigate the relationship between genotype and drug resistance. A prospective study was conducted from March 2003 through August 2005 at Tygerberg Children's Hospital, in the Western Cape Province of South Africa. All children (
Published: 2006

41. updAIDS in SA Family Practice

Author: Helmuth Reuter, Helena Rabie, Ben J Marais, Mark F Cotton, and Walter Kloeck
Subjects: Court case, Battle, business.industry, media_common.quotation_subject, Law, Public Health, Environmental and Occupational Health, Medicine, Family Practice, business, Column (database), media_common, Front (military)
Abstract: At the time of writing this column the most talked about issue was the court case between Matthias Rath and the treatment action campaign (TAC). The TAC and Rath were involved in a legal battle over the controversial dissident's widely publicized claims that the TAC is a front for the pharmaceutical industry.
Published: 2006

42. Characterization of the immunological features of tuberculous pericardial effusions in HIV positive and HIV negative patients in contrast with non-tuberculous effusions

Author: Machteld E. Carstens, Anton Doubell, Helmuth Reuter, and Lesley J. Burgess
Subjects: CD4-Positive T-Lymphocytes, Microbiology (medical), Tuberculosis, Lymphocyte, medicine.medical_treatment, Immunology, HIV Infections, CD8-Positive T-Lymphocytes, Microbiology, Pericardial Effusion, Interferon-gamma, Leukocyte Count, Necrosis, Immune system, medicine, Humans, Prospective Studies, AIDS-Related Opportunistic Infections, business.industry, Monocyte, Pericarditis, Tuberculous, Th1 Cells, Flow Cytometry, medicine.disease, CD4 Lymphocyte Count, Interleukin-10, Infectious Diseases, medicine.anatomical_structure, Cytokine, Pericardiocentesis, Cytokines, Differential Leukocyte Count, business, Pericardium, CD8
Abstract: Summary Objective To investigate the immunopathogenesis of pericardial tuberculosis (TB) and the influence of human immunodeficiency virus (HIV) on the anti-tuberculous immune response. Design Consecutive patients presenting with large pericardial effusions were subjected to a full clinical examination and pericardiocentesis. Aspirated fluid was sent for biochemistry, differential leukocyte count, flow cytometric analysis and determination of cytokine levels. Pericardial tissue was sent for TB culture and histopathological evaluation. Diagnoses were made according to pre-determined criteria. Results Fifty-six patients were included and divided into HIV positive TB ( n = 2 2 ), HIV negative TB ( n = 2 1 ) and non-tuberculous effusions ( n = 1 3 ). Peripheral blood neutrophil, lymphocyte and monocyte counts were significantly lower in HIV positive TB patients. Lymphocytes were the dominant cell type in tuberculous pericardial effusions. CD4+ cells dominated in HIV negative tuberculous effusions, whereas CD8+ cells dominated in HIV positive TB. The difference in the concentration of IFN- γ levels in the tuberculous and non-tuberculous pericardial effusions was statistically significant. Despite significant differences in pericardial CD4+ cell counts, IFN- γ levels were similarly elevated in HIV negative and HIV positive tuberculous effusions. Highest levels of pericardial IL-10 were observed in samples associated with least tissue necrosis, suggesting the possibility of a tissue protective immunoregulatory role for IL-10. Conclusions Tuberculous pericardial effusions result from a T helper1 (Th1)-dominant immune response. IFN- γ producing CD4+ lymphocytes dominate in HIV negative patients, whereas CD8+ seem to play a more important role in HIV positive patients. Infection with HIV leads to the depletion of immunocompetent cells such as monocytes, NK cells and neutrophils.
Published: 2006

43. Non-allopathic adjuvant management of osteoarthritis by alkalinisation of the diet

Author: F. Otto Müller, Martin Kidd, David P van Velden, and Helmuth Reuter
Subjects: Male, medicine.medical_specialty, Pathology, medicine.drug_class, Population, lcsh:Medicine, Osteoarthritis, Placebo, South Africa, Internal medicine, medicine, Antiemetic, Humans, education, Adverse effect, Adjuvants, Pharmaceutic, Aged, Original Research, Alkaline diet, Aged, 80 and over, education.field_of_study, Cross-Over Studies, business.industry, lcsh:Public aspects of medicine, lcsh:R, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, General Medicine, Middle Aged, medicine.disease, Crossover study, Regimen, Dietary Supplements, Female, Antacids, Family Practice, business
Abstract: Background: Osteoarthritis (OA) is a chronic condition. Nonsteroidal anti-inflammatory drugs recommended for treatment have serious adverse effects. A compelling body of anecdotal evidence alerted the authors to the therapeutic potential of dietary supplementation with Multiforce® (MF) Alkaline Powder for relief of OA symptoms. Aim: The aim of the study was to test the hypothesis that dietary supplementation with MF relieves clinical signs and symptoms of OA of the hands. Setting: The study was done at the MEDSAC hospital in Somerset West, Western Cape, South Africa. Methods: The research was conducted in two stages. An open interventional study (n = 40) confirmed the notion that MF 7.5 g twice daily is likely to be an effective alternative or adjunct for relief of symptoms of OA of the hands. The main study was conducted with 100 eligible, consenting volunteers (aged 47–89 years) according to a randomised, placebo-controlled, crossover design. Study duration was 56 days, 28 days per regimen; crossover to alternate regimens took place on day 28. Results: Compared to placebo, MF intake over 28 days was associated with significant reductions ( p < 0.005) in pain, tenderness and stiffness of interphalangeal and metacarpophalangeal joints of the hand. Confirmation of systemic alkalinisation by MF, which is rich in organic anions in the form of citrate salts, was reflected by a significant and sustained increase in urine pH. Conclusion: A dietary supplement, Multiforce® Alkaline Powder, containing citrate salts which are converted into bicarbonate in vivo, was efficacious and safe as sole therapeutic intervention, significantly attenuating OA-associated signs and symptoms of the hands.
Published: 2014

44. Determinants of unprotected sex among HIV-positive patients in South Africa

Author: Helmuth Reuter, B. O. Olley, Faniswa Gxamza, Soraya Seedat, and Dan J. Stein
Subjects: Adult, Male, Coping (psychology), medicine.medical_specialty, Health (social science), Social Psychology, Population, HIV Infections, Logistic regression, law.invention, Condoms, South Africa, Condom, Unsafe Sex, Acquired immunodeficiency syndrome (AIDS), Risk Factors, law, Surveys and Questionnaires, Humans, Medicine, Psychiatry, education, education.field_of_study, business.industry, Public Health, Environmental and Occupational Health, medicine.disease, Substance abuse, Sexual intercourse, Logistic Models, Female, business, Demography
Abstract: This study examined the prevalence of unprotected sex, other sexual risk behaviours, and factors associated with unprotected sex among men and women recently diagnosed with HIV in South Africa. One hundred and forty-nine outpatients (44 males and 105 females) were assessed, of whom 101 were sexually active at least 6 months prior to study entry. Subjects were asked about sexual risk behaviours with reference to their most recent sexual encounter. Logistic regression analysis was employed to determine the predictors of condom use, with independent variables selected from five general categories: (1) sociodemographic characteristics; (2) situational characteristics regarding sexual intercourse (i.e. alcohol or drugs used before intercourse); (3) clinical diagnoses; (4) negative life events; and (5) coping styles. Fifty-five patients (19 males and 36 females), representing 54.4% of those sexually active in the 6 months preceding the study, had not used a condom during the most recent intercourse. Compared with those who used condoms, participants who did not significantly reported shorter duration of HIV infection (t = -2.7, p0.001), have a current partner (chi2 = 3.98, p = 0.005), and lack knowledge of their partner's HIV status (chi2 = 4.78, p = 0.004). Also they were significantly more likely to engage in denial (t = 3.2, p0.002) and to use substances (t = 1.98, p0.05) as a means of coping. Logistic regression showed that shorter duration of illness (odds ratio (OR) = 1.2, 95% confidence interval (CI) = 1.01-1.41) and coping styles characterized by denial (OR = 0.6, 95% CI = 0.45-0.96) were significantly associated with unprotected sex. These data suggest the need for interventions to further reduce sexual risk behaviours in HIV-positive patients in South Africa.
Published: 2005

45. Infective endocarditis in the Western Cape Province of South Africa: a three-year prospective study

Author: Coenraad F.N. Koegelenberg, Helmuth Reuter, H. Orth, and Anton Doubell
Subjects: Adult, Male, medicine.medical_specialty, Heart disease, South Africa, Risk Factors, Internal medicine, Epidemiology, medicine, Humans, Mitral valve prolapse, Endocarditis, Prospective Studies, Risk factor, business.industry, Mortality rate, Rheumatic Heart Disease, Endocarditis, Bacterial, General Medicine, Middle Aged, medicine.disease, Surgery, Infective endocarditis, Rheumatic fever, Female, business
Abstract: Background: The last 50 years have seen major changes in the epidemiology of infective endocarditis (IE). Aim: To evaluate local patient characteristics, risk factors, clinical sequelae, microbiology, morbidity and mortality in patients with definite IE. Design: Prospective observational study. Methods: Over a three‐year period, patients referred with probable IE were prospectively enrolled. All received a standardized diagnostic evaluation. Epidemiological data were documented; underlying risk factors for IE were sought. Initial evaluation and follow‐up (to 6 months) included the documentation of vascular or immunological phenomena, morbidity and mortality. Results: Of 92 patients referred with probable IE, 47 had definite IE. These patients had a mean age of 37.7 years with a male predominance (1.6:1). Rheumatic heart disease was present in 36 (76.6%). Eight had prosthetic valves. Three had congenital heart disease, mitral valve prolapse or multiple central intravascular catheters, respectively. All denied the use of intravenous recreational drugs and only one tested seropositive for HIV. Renal involvement (59.6%) and clubbing (29.8%) were commonly observed. The 6‐month mortality rate was 35.6%, while 44.7% needed valvular replacement. An aetiological diagnosis was made in 21, with viridans streptococci the most common isolate. Discussion: Infective endocarditis in the Western Cape of South Africa is a disease of younger adults, with a male predominance. Rheumatic heart disease is the major predisposing factor. Degenerative heart disease and intravenous drug abuse are not important risk factors. Our data do not support the notion that HIV infection is an independent risk factor for IE. Local mortality rates are much higher than recent international figures, as is the proportion of ‘culture‐negative’ IE.
Published: 2003

46. The Use of Adenosine Deaminase and Interferon-γ as Diagnostic Tools for Tuberculous Pericarditis

Author: Lesley J. Burgess, Machteld E. Carstens, J.J. Frans Taljaard, Helmuth Reuter, and Doubell Af
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, Adenosine Deaminase, Critical Care and Intensive Care Medicine, Gastroenterology, Pericardial effusion, Pericardial Effusion, Diagnosis, Differential, Interferon-gamma, South Africa, Pericarditis, Adenosine deaminase, Predictive Value of Tests, Internal medicine, medicine, Humans, Prospective Studies, Aged, biology, business.industry, Tuberculous pericarditis, Pericardial fluid, Pericarditis, Tuberculous, Middle Aged, medicine.disease, Surgery, Predictive value of tests, biology.protein, Female, Differential diagnosis, Cardiology and Cardiovascular Medicine, business
Abstract: Traditional diagnostic tests for pericardial tuberculosis (TB) are insensitive and often require long culture periods, and this has led to more emphasis being placed on biochemical tests such as the pericardial adenosine deaminase (ADA) test. However, controversy exists as to its diagnostic utility. In addition, the use of interferon (IFN)-gamma, which is a reliable indicator of pleural and peritoneal TB, has not been explored in pericardial effusions. We investigated ADA and IFN-gamma levels in pericardial effusions of different etiologies.A prospective study was carried out from February 1995 to February 1998 at Tygerberg Hospital (South Africa), with pericardial taps being performed under echocardiographic guidance. During this period, 110 consecutive patients presenting with large pericardial effusions were included in the study. Diagnoses were made according to predetermined criteria, and they included TB (n = 64), malignancy (n = 12), nontuberculous infections (n = 5), other effusions (n = 19), and effusions of uncertain origin (n = 10). The median ADA level in the tuberculous group was 71.7 U/L (range, 10.3 to 303.6 U/L), which was significantly higher than that in any other group (p0.05). With a cutoff level for ADA activity of 30 U/L, sensitivity was 94%, specificity was 68%, and positive predictive value was 80%. IFN-gamma levels were determined in 30 subjects. The median IFN-gamma concentration in the tuberculous group was1,000 pg/L, which was significantly higher than in any other diagnostic group (p0.0005). A cutoff value of 200 pg/L for IFN-gamma resulted in a sensitivity and specificity of 100% for the diagnosis of pericardial TB.Pericardial fluid levels of ADA and IFN-gamma are useful in the diagnosis of tuberculous pericarditis.
Published: 2002

47. Role of Biochemical Tests in the Diagnosis of Large Pericardial Effusions

Author: Doubell Af, Helmuth Reuter, Lesley J. Burgess, and J.J. Frans Taljaard
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, L-Lactate Dehydrogenase, Heart disease, business.industry, Pericardial fluid, Bilirubin, Critical Care and Intensive Care Medicine, medicine.disease, Pericardial effusion, Pericardial Effusion, Surgery, Pericarditis, Cholesterol, Effusion, Aortic valve replacement, medicine, Etiology, Humans, Prospective Studies, Cardiology and Cardiovascular Medicine, business, Prospective cohort study
Abstract: Study objectives: To determine the biochemical characteristics of large pericardial effusions in various disease states, and to assess their utility as diagnostic tools. Setting: An academic university hospital in the Western Cape, South Africa. Design: Consecutive, prospective case series. Patients: One hundred ten hospital patients > 12 years old, who presented to the echocardiography department with large pericardial effusions, and 12 control subjects who underwent open-heart surgery (coronary artery bypass graft or aortic valve replacement). Measurements: Fluid was sent for examination of biochemistry, adenosine deaminase, microbiology, hematology, and cytology. The etiology of each pericardial fluid sample was established using predetermined criteria. Results: The biochemistry of pericardial exudates differed significantly from pericardial transudates. Light’s criteria (whereby an exudate is defined as having one or more of the following: pleural fluid/serum protein ratio > 0.5; pleural fluid/serum lactate dehydrogenase [LDH] ratio > 0.6; and/or pleural fluid LDH level > 200 U/L) were applied to pericardial fluids and demonstrated to be the most reliable diagnostic tool for identifying pericardial exudates. The corresponding sensitivity was 98%. Conclusion: Although laboratory tests are a useful guideline when assessing the etiology and pathophysiology of pericardial effusions, the majority of large, clinically significant pericardial effusions result from exudative causes. (CHEST 2002; 121:495– 499)
Published: 2002

48. Interventions for increasing the proportion of health professionals practising in rural and other underserved areas

Author: Liesl Grobler, Ben J Marais, SA Mabunda, PN Marindi, Helmuth Reuter, and Jimmy Volmink
Subjects: Medicine General & Introductory Medical Sciences, National Health Programs, business.industry, Rural health, Psychological intervention, Taiwan, Medically Underserved Area, Interrupted Time Series Analysis, CINAHL, Rural Health, Cochrane Library, Nursing, Health care, Global health, Medicine, Humans, Pharmacology (medical), Health education, Observational study, Health Workforce, business
Abstract: Background The inequitable distribution of health professionals, within countries, poses an important obstacle to the optimal functioning of health services. Objectives To assess the effectiveness of interventions aimed at increasing the proportion of health professionals working in rural and other underserved areas. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, including specialised register of the Cochrane Effective Practice and Organisation of Care Group; March 2014), MEDLINE (1966 to March 2014), EMBASE (1988 to March 2014), CINAHL (1982 to March 2014), LILACS (February 2014), Science Citation Index and Social Sciences Citation Index (up to April 2014), Global Health (March 2014) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (June 2013). We also searched reference lists of all papers and relevant reviews identified, and contacted authors of relevant papers regarding any further published or unpublished work. Selection criteria Randomised trials, non-randomised trials, controlled before-and-after studies and interrupted time series studies evaluating the effects of various interventions (e.g. educational, financial, regulatory or support strategies) on the recruitment or retention, or both, of health professionals in underserved areas. Data collection and analysis Two review authors independently screened titles and abstracts and assessed full texts of potentially relevant studies for eligibility. Two review authors independently extracted data from eligible studies. Main results For this first update of the original review, we screened 8945 records for eligibility. We retrieved and assessed the full text of 125 studies. Only one study met the inclusion criteria of the review. This interrupted time series study, conducted in Taiwan, found that the implementation of a National Health Insurance scheme in 1995 was associated with improved equity in the geographic distribution of physicians and dentists. We judged the certainty of the evidence provided by this one study very low. Authors' conclusions There is currently limited reliable evidence regarding the effects of interventions aimed at addressing the inequitable distribution of health professionals. Well-designed studies are needed to confirm or refute findings of observational studies of educational, financial, regulatory and supportive interventions that might influence healthcare professionals' decisions to practice in underserved areas. Governments and medical schools should ensure that when interventions are implemented, their impacts are evaluated using scientifically rigorous methods to establish the true effects of these measures on healthcare professional recruitment and retention in rural and other underserved settings.
Published: 2009

49. Pulmonary manifestations of tuberculosis in adults

Author: Elvis Irusen and Helmuth Reuter
Subjects: Pediatrics, medicine.medical_specialty, Tuberculosis, business.industry, medicine, medicine.disease, business
Published: 2009

50. Tuberculosis of lymph nodes and the reticuloendothelial system in adults

Author: Helmuth Reuter and Robin Wood
Subjects: Pathology, medicine.medical_specialty, Tuberculosis, business.industry, medicine, Mononuclear phagocyte system, Anatomy, Lymph, medicine.disease, business
Published: 2009

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