FDA abandons the Declaration of Helsinki: The effect on the ethics of clinical trial conduct in South Africa and other developing countries

Four years ago, the US Food and Drug Administration (FDA) ceased compliance with the Declaration of Helsinki (DoH) (2000 revision andall subsequent revisions) for conduct of clinical trials outside its borders. It instead ruled that compliance with the Good Clinical Practices (GCP) of the International Conference of Harmonization (ICH) is sufficient. However, the ICH-GCP guidelines do not address certain ethical requirements stipulated in the DoH, such as the use of placebos v. standard therapy, post-trial access to treatment and other benefits for participants; public disclosure of trial design; publication of trial results; and disclosure of conflicts of interest. The FDA’s adoption of less morally stringent guidelines could encourage pharmaceutical companies to take ethical short cuts. It could also have practical consequences for trial ethics in developing countries, especially where research ethics committees may not be promotinghigh standards of protection for participants in clinical trials, due to lack of financial and human resources. Pharmaceutical companies may also pressurise research ethics committees to relax guidelines and legislation, in order to facilitate future clinical trials in developing and emerging countries that lack the resources to conduct their own clinical research on epidemics such as HIV/AIDS, which have devastating effects on their populations

The South African clinical trial industry: Implications of problems with the issuing of human tissue export permits

The National Health Act requires a valid permit before human biological tissue samples are exported from South Africa. However, delays in issuing export permits make it difficult for many researchers and pharmaceutical companies to comply. There are misconceptions about who is responsible for obtaining such a permit. Delays have caused many new trials to start without a permit, and biological samples from ongoing trials have been exported using expired permits. This could have detrimental consequences for the South African trial industry, especially with the country’s history of vulnerable populations in developing areas. Medicine Control Council inspections have listed findings related to export permits for several trial sites. Researchers must be aware that it remains their responsibility to apply for such a permit. The most important steps to ensure a smoother approval process are for applicants to (i) familiarise themselves with the permit issue process and (ii) recognise the importance of correctly completing and signing application forms

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

BACKGROUND: Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding. OBJECTIVE: This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank. METHODS: We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated. RESULTS: We included 377 294 participants (median bilirubin 8.1 μmol/L (IQR 6.4–10.4)) and 2002 lung cancer events in the MR analysis. Each 5 μmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 μmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function. CONCLUSION: Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers

Potential for medical error: Incorrectly completed request forms for thyroid function tests limit pathologists’ advice to clinicians

Background. Various publications have highlighted the significance of laboratory errors in the pre- and post-analytical phases and their impact on results. Thyroid-stimulating hormone (TSH) is a first-line thyroid function test and, if abnormal, reflex thyroxine (T4) or tri-iodothyronine (T3) testing is requested, depending on clinical and medication data provided. Interpretative comments are added to all TFTresults.Objectives. In view of the paucity of articles describing such errors, we audited laboratory request forms requesting thyroid function tests (TFT), received from primary care clinics and regional hospitals at our laboratory.Design. We assessed 482 laboratory request forms for TFT from primary health care clinics for specific parameters. Results. A total of 482 forms were analysed. Medication/s used by the patient (74.5%) and doctor’s contact number (65.1%) were the most commonly incomplete parameters. Of the 123 patients with medication details, 62 (50.4%) were on thyroxine.Conclusions. There are few studies examining the frequencyand impact of incomplete laboratory forms on laboratory errors, and even fewer studies examining interpretative comments accompanying clinical biochemistry results. We studied how pre-analytical errors in completing request forms may lead to incorrect interpretative comments and inappropriate reflex testing, and so influence the quality of the post-analytical phase

Cortical lens opacities in the young patient- an indication for a lipogram?

Aim. To determine the characteristics and prevalence of lenticular opacification in patients with underlying dyslipidaemia.Methods. Eighty patients of both genders and all ages (18- 90 years) were enrolled in the trial if they met the inclusion criteria for dyslipidaernia: Patients were included if their fasting serum cholesterol and triglyceride concentrations were > 5.2 mmol/l and > 2.3 mmol/l, respectively, when measured on three separate occasions over a 1-month period. Patients were excluded if they suffered from any condition known to cause or predispose them to elevated lipid levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil and other physical signs were documented subsequent to thorough physical evaluation.Results. In addition to the classic clinic signs of dyslipidaemia, 31% of patients had cortical lens opacities. Cortical opacities were twice as prevalent as Achilles tendon thickening (16.3%) in our study, the second most prevalent sign of elevated lipid levels. In the subgroup of patients aged under 50 years, 55% had lenticular opacities, predominantly cortical (80%).Conclusions. Cortical lens opacification was the most prevalent sign of dyslipidaemia and it occurred at a relatively young age in our trial population in those patients who were affected. Cortical lenticular opacification should be regarded as an indication for blood lipid profile evaluation

The singlet scalar as FIMP dark matter

The singlet scalar model is a minimal extension of the Standard Model that can explain the dark matter. We point out that in this model the dark matter constraint can be satisfied not only in the already considered WIMP regime but also, for much smaller couplings, in the Feebly Interacting Massive Particle (FIMP) regime. In it, dark matter particles are slowly produced in the early Universe but are never abundant enough to reach thermal equilibrium or annihilate among themselves. This alternative framework is as simple and predictive as the WIMP scenario but it gives rise to a completely different dark matter phenomenology. After reviewing the calculation of the dark matter relic density in the FIMP regime, we study in detail the evolution of the dark matter abundance in the early Universe and the predicted relic density as a function of the parameters of the model. A new dark matter compatible region of the singlet model is identified, featuring couplings of order 10^-11 to 10^-12 for singlet masses in the GeV to TeV range. As a consequence, no signals at direct or indirect detection experiments are expected. The relevance of this new viable region for the correct interpretation of recent experimental bounds is emphasized.Comment: 12 pages, 6 figure

Extended spectrum β-lactamase-and AmpC β-lactamase-producing Enterobacterales associated with urinary tract infections in the New Zealand community: A case-control study.

(c) The Author/sOBJECTIVES: To assess whether having a pet in the home is a risk factor for community-acquired urinary tract infections associated with extended spectrum β-lactamase (ESBL)- or AmpC β-lactamase (ACBL)- producing Enterobacterales. METHODS: An unmatched case-control study was conducted between August 2015 and September 2017. Cases (n=141) were people with community-acquired urinary tract infection (UTI) caused by ESBL- or ACBL- producing Enterobacterales. Controls (n=525) were recruited from the community. A telephone questionnaire on pet ownership, and other factors was administered, and associations were assessed using logistic regression. RESULTS: Pet ownership was not associated with ESBL- or ACBL-producing Enterobacterales related human UTIs. A positive association was observed for recent antimicrobial treatment, travel to Asia in the previous year, and a doctor's visit in the previous six months. Among isolates with an ESBL-/ACBL-producing phenotype 126/134 (94%) were Escherichia coli, with sequence type (ST) 131 being the most common (47/126). CONCLUSIONS: Companion animals in the home were not found to be associated with ESBL- or ACBL-producing Enterobacterales related community-acquired UTI in New Zealand. Risk factors included overseas travel, recent antibiotic use, and doctor visits.Published onlin

Flavor Phenomenology in General 5D Warped Spaces

We have considered a general 5D warped model with SM fields propagating in the bulk and computed explicit expressions for oblique and non-oblique electroweak observables as well as for flavor and CP violating effective four-fermion operators. We have compared the resulting lower bounds on the Kaluza-Klein (KK) scale in the RS model and a recently proposed model with a metric modified towards the IR brane, which is consistent with oblique parameters without the need for a custodial symmetry. We have randomly generated 40,000 sets of O(1) 5D Yukawa couplings and made a fit of the quark masses and CKM matrix elements in both models. This method allows to identify the percentage of points consistent with a given KK mass, which in turn provides us with a measure for the required fine-tuning. Comparison with current experimental data on Rb, FCNC and CP violating operators exhibits an improved behavior of our model with respect to the RS model. In particular, allowing 10% fine-tuning the combined results point towards upper bounds on the KK gauge boson masses around 3.3 TeV in our model as compared with 13 TeV in the RS model. One reason for this improvement is that fermions in our model are shifted, with respect to fermions in the RS model, towards the UV brane thus decreasing the strength of the modifications of electroweak observables.Comment: 28 pages, 7 figures, 4 table

A latent class analysis of young women’s co-occurring health risks in urban informal settlements in Durban, South Africa

This is the final version. Available on open access from Elsevier via the DOI in this recordAvailability of data and material (data transparency): Data are available in a public, open access repository. De-identified data sets for the project are available from http://medat.samrc.ac.za/index.php/catalog/WW managed by the South African Medical Research Council.In South Africa, substance use, violence, and HIV risk disproportionately affect young poor Black women. Few studies have explicitly measured the co-occurrence of these health risks or the impact on mental health and wellbeing for this population. To this aim, we use a person-centred approach to explore the clustering of health risks among young Black women from urban informal settlements in Durban, South Africa, enrolled in an intervention trial. Latent class analysis identified three health risk subgroups with increasing levels of health risk co-occurrence: while all three subgroups had high rates of emotional/economic intimate partner violence, they differed in their levels of the other health risks, with one (“lower-risk”) subgroup defined by experiencing violence against women (VAW), another by the co-occurrence of VAW with problematic alcohol use (i.e. “mid-risk”), and the last (“high-risk”) subgroup by the co-occurrence of VAW, problematic alcohol use and sexual risk behaviour. Descriptive analyses showed that lower education and food insecurity were associated with greater health risk co-occurrence and that this in turn was associated with increased chances of depression and suicidal ideation. Between subgroup differences persisted over time - after two years, the chances of experiencing violence, problematic alcohol use, transactional sex and depression remained elevated for the women who initially experienced more health risks. Persistent yet differing levels of risk suggest the need for urgent structural interventions that address these health risks synergistically while taking account of individual differing primary and secondary prevention needs. Our analyses highlight that social epidemics such as poverty, racism and gender inequality play into the production of poor health outcomes, including poor mental health. These are the underlying structural issues that need to be addressed in order to protect women’s health and reduce harm.UKR