Why is there a paucity of clinical trials in Africa?

Disproportionately few clinical trials are undertaken on the African continent, in part due to lingering neocolonial attitudes in the Global North which keep research activity primarily in developing countries, while being skeptical of the abilities of those in the Global South to undertake organized clinical studies. In the era of the COVID-19 pandemic, applicable research and clinical trials should be undertaken in relevant populations in order to extrapolate to a population level. This is all the more important in Africa, which has a rich genetic diversity. We suggest that a lack of organized research ethics committees across the continent and a deficiency of appropriate training are responsible in part for the reluctance of clinical trial organizers in the developed countries of the Global North to engage with medical leadership in Africa. We consider ways of alleviating this problem, including suggesting a pan-continental surveillance of ethics committee agendas and of training, either through the auspices of the African Union or the World Health Organization. In addition, medical leadership in African nations must be encouraged to take ownership of their medical ethics agendas to facilitate decent international clinical trial participation for the good of the continent as a whole.

Personal perspectives: having a series of cardiac events.

It has never been clear to me whether being a medically qualified patient has positive or negative associations. In 2019, after a prostatectomy, where I had extended bleeding per urethra, I suffered two myocardial infarctions, underwent three coronary angiograms and eventually coronary stenting. Junior doctors never examined me at any point, while senior ones worried over the risk of stent placement in an actively bleeding patient. I report my views on how this seemed as a largely passive, but still actively thinking patient.

The COVID-19 era: the view from Nigeria.

If we were told that one day the entire world would take its guidance for managing a health crisis from empirical thought, nobody would have believed it. However, with the December 2019 arrival of COVID-19 in China, the world subsequently went into a frenzied state that resulted in the widespread adoption of untested strategies or potential cures; circumstantial evidence provided without randomized control trials (RCTs) was published rapidly and widely considered the gold standard in medical research and therapeutics. Nigeria and much of the rest of the world blindly adopted treatments like chloroquine or hydroxychloroquine and various prevention strategies, often without monitoring the efficacy of these treatment and social control strategies. COVID-19 provided Nigeria a critical opportunity to create or strengthen its national laboratory system by building up its Level 3 laboratories in all parts of the country with the capability to perform PCR tests and viral isolation. There was also an opportunity to establish hospitals in every region of a sufficient standard to reduce the numbers of Nigerians travelling abroad to seek medical treatment; to invest in building capacity to develop antiviral medications and vaccines in Nigeria, and to ensure better international health policies. Rather, Nigerian leaders, government and health managers decided (like most other nations of the world) to shut down the society using isolationist policies that were not necessarily tailored to local needs. Despite adopting these methods, COVID-19 cases continued to skyrocket in Nigeria. In the future, before adopting such broad sweeping policies, there should be local tailoring to assess their effectiveness in different communities. Given that the country has much experience in controlling Lassa and Marburg Fever outbreaks, Nigeria should lead by developing new strategies, new protocols and new local guidelines, based on validated and reproducible studies to ensure that the public health authorities are not caught unaware by any new outbreaks of emerging or remerging diseases.

Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging.

BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.

Hepatitis E virus infection and acute-on-chronic liver failure in West Africa: a case-control study from The Gambia.

BACKGROUND: In sub-Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute-on-chronic liver failure (ACLF). AIMS: To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. METHODS: We first conducted an HEV sero-survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti-HEV IgG as a marker of exposure to HEV, and anti-HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. RESULTS: In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6-19.2) were positive for anti-HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti-HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), ≥70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28-day mortality. CONCLUSIONS: Hepatitis E virus infection is endemic in The Gambia, where both faecal-oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute-on-chronic liver failure in The Gambia.

Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients.

Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.

Research collaborations in Tajikistan: lessons to be learnt.

We have been working on an association of physicians 'links with developing countries' scheme in Tajikistan, which is a nation of 7.5 million people, 93% of which is mountainous, of a similar size to England and Wales, landlocked, resource-poor and richly licked by the brush of history. Understanding the challenges faced by academics working with Tajikistan today requires a cursory understanding of Tajikistan's genesis. Through this lens, present-day technical, organizational and socio-political challenges can be appropriately considered, with a view to improving academic collaboration in the future.

Depressive symptoms in chronic hepatitis C are associated with plasma apolipoprotein E deficiency.

Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.

Whole body fat: content and distribution.

Obesity and its co-morbidities, including type II diabetes, insulin resistance and cardiovascular diseases, have become one of the biggest health issues of present times. The impact of obesity goes well beyond the individual and is so far-reaching that, if it continues unabated, it will cause havoc with the economies of most countries. In order to be able to fully understand the relationship between increased adiposity (obesity) and its co-morbidity, it has been necessary to develop proper methodology to accurately and reproducibly determine both body fat content and distribution, including ectopic fat depots. Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) have recently emerged as the gold-standard for accomplishing this task. Here, we will review the use of different MRI techniques currently being used to determine body fat content and distribution. We also discuss the pros and cons of MRS to determine ectopic fat depots in liver, muscle, pancreas and heart and compare these to emerging MRI techniques currently being put forward to create ectopic fat maps. Finally, we will discuss how MRI/MRS techniques are helping in changing the perception of what is healthy and what is normal and desirable body-fat content and distribution.

A history of previous gestational diabetes mellitus is associated with adverse changes in insulin secretion and VLDL metabolism independently of increased intrahepatocellular lipid.

AIMS/HYPOTHESIS: We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM. METHODS: We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (n = 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B [apoB] kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM. RESULTS: pGDM was associated with increased IHCL (p = 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (p = 0.02) and acute insulin response to glucose (pGDM+/NAFLD-, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM, p = 0.03), increased VLDL apoB pool size (pGDM+/NAFLD-, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM, p = 0.02) and, at borderline significance (p = 0.05), increased rate of VLDL apoB synthesis. CONCLUSIONS/INTERPRETATION: pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.