Obesity as a driver of international differences in COVID-19 death rates

AIMS: There is considerable variation in death rates from coronavirus disease 2019 (COVID-19) between countries, and these variations are not fully understood. The aim was to determine what proportion of the variation in death rates between countries can be explained in terms of obesity rates and other known risk factors for COVID-19. MATERIALS AND METHODS: COVID-19 death rates from 30 industrialized countries were analyzed using linear regression models. Covariates modelled population density, the age structure of the population, obesity, population health, per capita GDP, ethnic diversity, national temperature and government delay in imposing virus control measures. RESULTS: The multivariable regression model explained 63% of the inter-country variation in COVID-19 death rates. The initial model was optimized using stepwise selection. In descending order of absolute size of model coefficient, the covariates in the optimized model were: obesity rate, hypertension rate, population density, life expectancy, percentage of population over 65, percentage of population under 15, diabetes rate, the delay in imposing national COVID-19 control measures, per capita GDP and mean temperature (a negative coefficient indicating an association between higher national temperatures and lower death rates). CONCLUSIONS: A large proportion of the variation in COVID-19 death rates between countries can be explained by differences in obesity rates, population health, population density, age demographics, the delay in imposing national virus control measures, per capita GDP and climate. Some of the unexplained variation is probably attributable to inter-country differences in the definition of COVID-19 deaths and in the completeness of the recording of COVID-19 deaths. This article is protected by copyright. All rights reserved

A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence

Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%–20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, ”paediatric” NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention

Hepatic fibrogenesis requires sympathetic neurotransmitters

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylase deficient (Dbh(−/−)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(−/−) mice, as evidenced by reduced hepatic accumulation of α-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor β1 (TGF-β1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-β1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis

The Prevalence of Undiagnosed HIV Infection in Those Who Decline HIV Screening in an Urban Emergency Department

Objective. To determine the prevalence of occult HIV infection in patients who decline routine HIV testing in an urban emergency department. Design, Setting, and Patients. Discarded blood samples were obtained from patients who had declined routine ED HIV testing. After insuring that the samples came from patients not known to be HIV positive, they were deidentified, and rapid HIV testing was preformed using 5 μL of whole blood. Main Outcome Measures. The prevalence of occult HIV infection in those who declined testing compared with prevalence in those who accepted testing. Results. 600 consecutive samples of patients who declined routine HIV screening were screened for HIV. Twelve (2%) were reactive. Over the same period of time, 4845 patients accepted routine HIV testing. Of these, 35 (0.7%) were reactive. The difference in the prevalence of HIV infection between those who declined and those who accepted testing was significant (P = .001). The relative risk of undetected HIV infection in the group that declined testing was 2.74 times higher (95% CI 1.44–5.18) compared with those accepted testing. Conclusion. The rate of occult HIV infection is nearly three-times higher in those who decline routine ED HIV testing compared with those who accept such testing. Interventions are urgently needed to decrease the opt-out rate in routine ED HIV testing settings

Bariatric surgery as a treatment for metabolic syndrome

Obesity is the pandemic of the 21st century. Obesity comorbidities, including hypertension, dyslipidaemia and glucose intolerance define metabolic syndrome, which increases mortality risk and decreases the quality of life. Compared with lifestyles (diet and physical activity) and pharmacological interventions, bariatric surgery is by far the most effective treatment for obesity and its comorbidities. This minimally invasive surgical treatment is based on an increase of satiety (by hormonal regulation and decreasing stomach volume) or a decrease in nutrient retention (gastric and/or intestinal resection). Bariatric surgery has widely demonstrated a beneficial effect on excess body weight loss, cardiovascular risk, dyslipidaemia, non-alcoholic fatty liver disease or glucose homeostasis, among other obesity-related metabolic diseases. This review describes current efforts for the implementation of bariatric surgery in metabolic syndrome, which are mainly focused on the formulation of key definition criteria for targeting the most suitable population for this therapeutic approach. Patients should undergo appropriate nutritional and psychological follow up in order to achieve and maintain weight loss milestones and a healthy metabolic status

Ethnic differences and heterogeneity in genetic and metabolic makeup contributing to nonalcoholic fatty liver disease

Obesity is the most prevalent noncommunicable disease in the 21st century, associated with triglyceride deposition in hepatocytes leading to nonalcoholic fatty liver disease (NAFLD). NAFLD is now present in around a third of the world's population. Epidemiological studies have concluded that ethnicity plays a role in complications and treatment response. However, definitive correlations of ethnicity with NAFLD are thoroughly under-reported. A comprehensive review was conducted on ethnic variation in NAFLD patients and its potential role as a crucial effector in complications and treatment response. The highest NAFLD prevalence is observed in Hispanic populations, exhibiting a worse disease progression. In contrast, African-Caribbeans exhibit the lowest risk, with less severe steatosis and inflammation, lower levels of triglycerides, and less metabolic derangement, but conversely higher prevalence of insulin resistance. The prevalence of NAFLD in Asian cohorts is under-reported, although reaching epidemic proportions in these populations. The most well-documented NAFLD patient population is that of Caucasian ethnicity, especially from the US. The relative paucity of available literature suggests there is a vital need for more large-scale multi-ethnic clinical cohort studies to determine the incidence of NAFLD within ethnic groups. This would improve therapy and drug development, as well as help identify candidate gene mutations which may differ within the population based on ethnic background

Acetylcholine induces fibrogenic effects via M2/M3 ACh receptors in NASH and in primary human hepatic stellate cells

BACKGROUND: The parasympathetic nervous system (PNS), via neurotransmitter Acetylcholine (ACh), modulates fibrogenesis in animal models. However, the role of ACh in human hepatic fibrogenesis is unclear. AIMS: We aimed to determine the fibrogenic responses of human hepatic stellate cells (hHSC) to ACh and the relevance of the PNS in hepatic fibrosis in patients with non-alcoholic steatohepatitis (NASH). METHODS: Primary hHSC were analysed for synthesis of endogenous ACh and acetylcholinesterase (AChE), and gene expression of choline acetyltransferase (ChAT) and muscarinic acetylcholine receptors (mAChR). Cell proliferation and fibrogenic markers were analysed in hHSC exposed to ACh, Atropine (Atrop), Mecamylamine (Mec), methoctramine and 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP). MAChR expression was analysed in human NASH scored for fibrosis. RESULTS: We observed that hHSC synthesise ACh and AChE, and express ChAT and M1-M5 mAChR. We also show that M2 was increased during NASH progression, while both M2 and M3 were found upregulated in activated hHSC. Furthermore, endogenous ACh is required for hHSC basal growth. Exogenous ACh resulted in hHSC hyperproliferation via mAChR and PI-3 K and MEK signalling pathways, as well as increased fibrogenic markers. CONCLUSION: We show that ACh regulates hHSC activation via M2 and M3 mAChR involving the PI-3 K and MEK pathways in vitro. Finally, we provide evidence that the PNS may be involved in human NASH fibrosis

Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity

We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis

GLYCAEMIC VARIATIONS AFTER ADMINISTRATION OF IRVINGIA GABONENSIS SEEDS FRACTIONS IN NORMOGLYCEMIC RATS

The action of Irvingia gabonensis seed fractions in reducing or slowing down the intestinal absorption of glucose was evaluated in normoglycaemic rats. The crude seeds (CS), the defatted seeds (DS) and the protein fraction (PF) were administered at dose of 400mg/ kg body weight to normoglycemic rats submitted to oral glucose test (OGTT) with glucose (2g/kg body weight). The results obtained show a significant reduction of the postprandial glucose level after a glucose load of (2g/kg body weight) as well as fasting blood glucose levels with the three fractions