Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism

A Systematic Review of Animal Models of NAFLD Finds High‐Fat, High‐Fructose Diets Most Closely Resemble Human NAFLD

Background and Aims: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. Approach and Results: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high‐fat, high‐fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. Conclusions: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication

A Systematic Review of Animal Models of NAFLD Finds High‐Fat, High‐Fructose Diets Most Closely Resemble Human NAFLD

Background and Aims: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. Approach and Results: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high‐fat, high‐fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. Conclusions: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication

The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning.

BACKGROUND: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL). METHOD: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times. RESULTS: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content. DISCUSSION: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training

Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise.

BACKGROUND: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors. METHOD: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail. RESULTS: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs. CONCLUSIONS: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety

Association between physical activity and risk of depression

Importance Depression is the leading cause of mental health–related disease burden and may be reduced by physical activity, but the dose-response relationship between activity and depression is uncertain. Objective To systematically review and meta-analyze the dose-response association between physical activity and incident depression from published prospective studies of adults. Data Sources PubMed, SCOPUS, Web of Science, PsycINFO, and the reference lists of systematic reviews retrieved by a systematic search up to December 11, 2020, with no language limits. The date of the search was November 12, 2020. Study Selection We included prospective cohort studies reporting physical activity at 3 or more exposure levels and risk estimates for depression with 3000 or more adults and 3 years or longer of follow-up. Data Extraction and Synthesis Data extraction was completed independently by 2 extractors and cross-checked for errors. A 2-stage random-effects dose-response meta-analysis was used to synthesize data. Study-specific associations were estimated using generalized least-squares regression and the pooled association was estimated by combining the study-specific coefficients using restricted maximum likelihood. Main Outcomes and Measures The outcome of interest was depression, including (1) presence of major depressive disorder indicated by self-report of physician diagnosis, registry data, or diagnostic interviews and (2) elevated depressive symptoms established using validated cutoffs for a depressive screening instrument. Results Fifteen studies comprising 191 130 participants and 2 110 588 person-years were included. An inverse curvilinear dose-response association between physical activity and depression was observed, with steeper association gradients at lower activity volumes; heterogeneity was large and significant (I2 = 74%; P < .001). Relative to adults not reporting any activity, those accumulating half the recommended volume of physical activity (4.4 marginal metabolic equivalent task hours per week [mMET-h/wk]) had 18% (95% CI, 13%-23%) lower risk of depression. Adults accumulating the recommended volume of 8.8 mMET hours per week had 25% (95% CI, 18%-32%) lower risk with diminishing potential benefits and higher uncertainty observed beyond that exposure level. There were diminishing additional potential benefits and greater uncertainty at higher volumes of physical activity. Based on an estimate of exposure prevalences among included cohorts, if less active adults had achieved the current physical activity recommendations, 11.5% (95% CI, 7.7%-15.4%) of depression cases could have been prevented. Conclusions and Relevance This systematic review and meta-analysis of associations between physical activity and depression suggests significant mental health benefits from being physically active, even at levels below the public health recommendations. Health practitioners should therefore encourage any increase in physical activity to improve mental health. Key Points Question What is the dose-response association between physical activity and incident depression in adults? Findings This systematic review and meta-analysis of 15 prospective studies including more than 2 million person-years showed an inverse curvilinear association between physical activity and incident depression, with greater differences in risk at lower exposure levels. Adults meeting physical activity recommendations (equivalent to 2.5 h/wk of brisk walking) had lower risk of depression, compared with adults reporting no physical activity. Meaning In this study, relatively small doses of physical activity were associated with substantially lower risks of depression

rs641738C&gt;T near MBOAT7 is associated with liver fat, ALT, and fibrosis in NAFLD : a meta-analysis

Background &amp; Aims: A common genetic variant near MBOAT7 (rs641738C&gt;T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C&gt;T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C&gt;T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C&gt;T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02\u20130.05], pz = 4.8 710\u20135) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05\u20131.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03\u20131.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5 710\u20134). rs641738C&gt;T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C&gt;T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including \u2018cirrhosis\u2019). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (\u2018variant\u2019) in one gene (\u2018MBOAT7\u2019) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.JPM is supported by a Wellcome Trust Fellowship (216329/Z/19/Z