Willingness to participate in South African HIV vaccine trials - concerns of medical professionals in the Western Cape

Objectives. To evaluate the willingness of medical doctors working at a tertiary hospital to participate in HIV vaccine trials, their perceptions ofpatients' willingness to participate, and the major reasons underlying these views.Design. A self-administered, anonymous postal survey conducted in two rounds between May and July 2001.Setting. A tertiary care hospital in the Western Cape. Subjects. All medical doctors listed on the hospital's staff directory.Outcome measures. Willingness to participate in, and to recruit patients into, HIV vaccine trials, and the reasons for this.Results and conclusions. Of the 289 individuals surveyed, 80% stated either that they would not be willing to participate in HIV vaccine trials or that they were unsure about their participation. Meanwhile, 37% stated that they would be willing to recruit patients into vaccine trials. The most common concerns with trial participation were the possibility of vaccine-induced infection and the possibility of testing positive for antibodies to HIV. The surprisingly low level of willingness to participate in trials in this sample of medical professionals highlights the importance of preparatory work to overcome substantial barriers to HIV vaccine trial participation

Methadone use for acute opioid withdrawal in Tshwane shelters during the COVID-19 lockdown

Background: Temporary shelters were established for street-based people during the national level 5 coronavirus disease 2019 (COVID-19) lockdown. However, street-based substance users’ need to access substances was not addressed, resulting in large numbers of people experiencing withdrawal. The Community Oriented Substance Use Programme (COSUP) in Tshwane provided methadone to manage opioid withdrawal. Methods: A cross-sectional, descriptive study was conducted using the daily methadone dosing records from shelters in Tshwane between March 2020 and September 2020. Results: The final analysis included 495 participants, of which 64 (12.9%) were initiated on 20 mg – 30 mg of methadone, 397 (80.2%) on 40 mg – 50 mg, and 34 (6.9%) on 60 mg – 70 mg. A total of 194 (39.2%) participants continued their initiation dose for 1–2 months, after which 126 (64.9%) had their doses increased, and 68 (35.1%) had their doses decreased. Approximately 12 (2.4%) participants were weaned off methadone after 1–3 months and 46 (9.3%) after 4–6 months. In all, 100 (20.2%) participants left the shelter prematurely and did not continue with methadone. A total of 126 (25.5%) participants continued to stay in the shelters and received methadone for 6 months, with 125 (25.3%) participants leaving the shelter with continued follow-up at a COSUP site. Conclusion: This study demonstrates variability in methadone dosing regimens among shelter residents. As the lockdown measures eased, many chose to leave the shelters, while others remained to receive methadone and other services. The COSUP appears to be effective during periods of increased vulnerability, since a large number of participants were successfully followed up. Contribution: Opioid dependence is a persistent, lifelong disease. It is multifaceted with complex environmental and individual determinants. This study highlighted the use of opioid substitution therapy during a period of increased vulnerability

Antibiotic resistance profiles and relatedness of enteric bacterial pathogens isolated from HIV/AIDS patients with and without diarrhoea and their household drinking water in rural communities in Limpopo Province South Africa

Antibiotic resistance profiles and the correlation of enteric bacterial pathogens from HIV positive individuals with and without diarrhoea and their household drinking water were determined using the KirbyBauer disk diffusion and polymerase chain reaction methods respectively. The sef gene of Salmonella enteritidis was amplified with the primer pair sefA-1 and sefA-2. The fliC gene of Salmonella typhimurium was amplified with the primer pair flicA-1 and flicA-2. Heat-labile toxin (LT) primers (Lta and LTb) were used to amplify Escherichia coli isolates and VirA1 and VirA2 for the Vir A gene of Shigella dysenteriae. Results of antibiotic resistance profiles of enteric bacterial pathogens isolated from stool samples of HIV positive and negative individuals with and without diarrhea and their household drinking water showed very similar drug resistance patterns. Over 90% of all the organisms isolated from the various study cohorts showed resistance to penicillin, cloxacillin and amoxicillin. Conversely, almost all the organisms were sensitive to ciprofloxacin, gentamycin, meropenem and imipenem. About 50% of E. coli isolated from the various study cohorts showed multiple antibiotic resistance to penicillin, amoxicillin, ampicillin, erythromycin, tetracycline, doxycycline and cotri-moxazole ( PR, AR, APR, ER, TR, DXTR, and TSR ) whereas less than 10% resistance was consistently reported for ofloxacin, gentamycin, meropenem cefotaxime, cefuroxime and imipenem ( OFXS, GMS, MEMS, CTXS, CXMS and IMIS ). The majority of Salmonella and Shigella isolates from all the groups were sensitive to ciprofloxacin, gentamicin, amikacin, meropenem, imipenem, nalidixic acid, kanamycin, piperacillin-tazo bactam, cefuroxime, doxycyclin, cefepime and ceftazidime (CIPS, GMS, AKS, MEMS, IMIS, NAS, KNS, DXTS, CXMS, CPMS, CAZS and PTZS). For Campylobacter, over 30% of the isolates were resistant to erythromycin, ampicillin, tetracycline,cotrimoxazole and ceftazidime (ER, APR TSR and CAZR) whereas over 85% were susceptible to ciprofloxacin, ofloxacin, gentamycin, amikacin, mero-penem, and nalidixic acid (CIPS, OFXS, GMS, AKS,MEMS and NAS). In addition to penicillin, amoxicillin, ampicillin and erythromycin, Aeromonas and Plesiomonas spp were more resistant to chloramphenicol, but were susceptible to ciprofloxacin, gentamycin, amikacin, meropenem, imipenem and nalidixic acid (CIPS, GMS, AKS, MEMS, IMIS and NAS). Polymerase Chain Reaction (PCR) experiments using targeted species genes of S. enteritidis, S. typhimurium, E. coli, Sh. dysenteriae showed that isolates from stool samples of HIV positive and HIV negative individuals with and without diarrhoea were also present in the household drinking water of the same study cohorts, suggesting that drinking water may have been the sources of the organisms in stool sample. Furthermore, by showing that the primers were able to amplify the genes in both clinical and environmental isolates, the link between the virulence of the pathogens was established

South African Institute of Drug-Free Sport Position Statement on CBD (Cannabidiol) and THC (Tetrahydrocannabinol)

Cannabidiol (CBD) and Tetrahydrocannabinol (THC) have become easily available to athletes over the years. Using these substances may inadvertently expose an athlete to the possibility of an adverse analytical finding (a ”positive” test) and a sanction. Athletes need to understand the risk of an antidoping rule violation or adverse analytical finding should these products be used, especially if no therapeutic use exemption exists. This position statement attempts to clarify the use of CBD and THC and their associated risks with Anti-Doping Rule Violations (ADRV) in the athletic population. The South African Sports Medicine Association supports this position statement

The characteristics of juvenile myasthenia gravis among South Africans

Objectives. To report the characteristics of juvenile-onset

South African Institute of Drug-Free Sport position statement on CBD (Cannabidiol) and THC (Tetrahydrocannabinol)

Cannabidiol (CBD) and Tetrahydrocannabinol (THC) have become easily available to athletes over the years. Using these substances may inadvertently expose an athlete to the possibility of an adverse analytical finding (a ”positive” test) and a sanction. Athletes need to understand the risk of an antidoping rule violation or adverse analytical finding should these products be used, especially if no therapeutic use exemption exists. This position statement attempts to clarify the use of CBD and THC and their associated risks with Anti-Doping Rule Violations (ADRV) in the athletic population. The South African Sports Medicine Association supports this position statement.https://journals.assaf.org.za/index.php/sajsm/indexhj2023Sports Medicin

Numerical study of linear and circular model DNA chains confined in a slit: metric and topological properties

Advanced Monte Carlo simulations are used to study the effect of nano-slit confinement on metric and topological properties of model DNA chains. We consider both linear and circularised chains with contour lengths in the 1.2--4.8 $\mu$m range and slits widths spanning continuously the 50--1250nm range. The metric scaling predicted by de Gennes' blob model is shown to hold for both linear and circularised DNA up to the strongest levels of confinement. More notably, the topological properties of the circularised DNA molecules have two major differences compared to three-dimensional confinement. First, the overall knotting probability is non-monotonic for increasing confinement and can be largely enhanced or suppressed compared to the bulk case by simply varying the slit width. Secondly, the knot population consists of knots that are far simpler than for three-dimensional confinement. The results suggest that nano-slits could be used in nano-fluidic setups to produce DNA rings having simple topologies (including the unknot) or to separate heterogeneous ensembles of DNA rings by knot type.Comment: 12 pages, 10 figure

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors