The implications of defining obesity as a disease: a report from the Association for the Study of Obesity 2021 annual conference

Unlike various countries and organisations, including the World Health Organisation and the European Parliament, the United Kingdom does not formally recognise obesity as a disease. This report presents the discussion on the potential impact of defining obesity as a disease on the patient, the healthcare system, the economy, and the wider society. A group of speakers from a wide range of disciplines came together to debate the topic bringing their knowledge and expertise from backgrounds in medicine, psychology, economics, and politics as well as the experience of people living with obesity. The aim of their debate was not to decide whether obesity should be classified as a disease but rather to explore what the implications of doing so would be, what the gaps in the available data are, as well as to provide up-to-date information on the topic from experts in the field. There were four topics where speakers presented their viewpoints, each one including a question-and-answer section for debate. The first one focused on the impact that the recognition of obesity could have on people living with obesity regarding the change in their behaviour, either positive and empowering or more stigmatising. During the second one, the impact of defining obesity as a disease on the National Health Service and the wider economy was discussed. The primary outcome was the need for more robust data as the one available does not represent the actual cost of obesity. The third topic was related to the policy implications regarding treatment provision, focusing on the public's power to influence policy. Finally, the last issue discussed, included the implications of public health actions, highlighting the importance of the government's actions and private stakeholders. The speakers agreed that no matter where they stand on this debate, the goal is common: to provide a healthcare system that supports and protects the patients, strategies that protect the economy and broader society, and policies that reduce stigma and promote health equity. Many questions are left to be answered regarding how these goals can be achieved. However, this discussion has set a good foundation providing evidence that can be used by the public, clinicians, and policymakers to make that happen

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Probing the viability of oxo-coupling pathways in iridium-catalyzed oxygen evolution

[Image: see text] A series of Cp*Ir(III) dimers have been synthesized to elucidate the mechanistic viability of radical oxo-coupling pathways in iridium-catalyzed O(2) evolution. The oxidative stability of the precursors toward nanoparticle formation and their oxygen evolution activity have been investigated and compared to suitable monomeric analogues. We found that precursors bearing monodentate NHC ligands degraded to form nanoparticles (NPs), and accordingly their O(2) evolution rates were not significantly influenced by their nuclearity or distance between the two metals in the dimeric precursors. A doubly chelating bis-pyridine–pyrazolide ligand provided an oxidation-resistant ligand framework that allowed a more meaningful comparison of catalytic performance of dimers with their corresponding monomers. With sodium periodate (NaIO(4)) as the oxidant, the dimers provided significantly lower O(2) evolution rates per [Ir] than the monomer, suggesting a negative interaction instead of cooperativity in the catalytic cycle. Electrochemical analysis of the dimers further substantiates the notion that no radical oxyl-coupling pathways are accessible. We thus conclude that the alternative path, nucleophilic attack of water on high-valent Ir-oxo species, may be the preferred mechanistic pathway of water oxidation with these catalysts, and bimolecular oxo-coupling is not a valid mechanistic alternative as in the related ruthenium chemistry, at least in the present system

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

AI in Education: learner choice and fundamental rights

This article examines benefits and risks of Artificial Intelligence (AI) in education in relation to fundamental human rights. The article is based on an EU scoping study [Berendt, B., A. Littlejohn, P. Kern, P. Mitros, X. Shacklock, and M. Blakemore. 2017. Big Data for Monitoring Educational Systems. Luxembourg: Publications Office of the European Union. https://publications.europa.eu/en/publication-detail/-/publication/94cb5fc8-473e-11e7-aea8-01aa75ed71a1/]. The study takes into account the potential for AI and ‘Big Data’ to provide more effective monitoring of the education system in real-time, but also considers the implications for fundamental human rights and freedoms of both teachers and learners. The analysis highlights a need to balance the benefits and risks as AI tools are developed, marketed and deployed. We conclude with a call to embed consideration of the benefits and risks of AI in education as technology tools into the development, marketing and deployment of these tools. There are questions around who – which body or organisation – should take responsibility for regulating AI in education, particularly since AI impacts not only data protection and privacy, but on fundamental rights in general. Given AI’s global impact, it should be regulated at a trans-national level, with a global organisation such as the UN taking on this role

Soil gas diffusivity controls N₂O and N₂ emissions and their ratio

Knowledge of soil biological and physical interactions with respect to N₂O and N₂ fluxes is essential to ensure that agricultural land management is environmentally and economically sustainable. This study determined how varying soil relative gas diffusivity (Dp/Do) affected cumulative N₂O and N₂ fluxes under simulated ruminant urinary-N deposition. Using repacked soil cores, the effects of varying soil bulk density (rb; from 1.1 to 1.5 Mg m−3) and soil matric potential (y; −10 to −0.2 kPa) on Dp/Do were examined in a Templeton silt loam soil (Udic Haplustept) following the application of simulated ruminant urine (700 kg N ha−1). Fluxes of N₂O and N₂, soil inorganic N, pH, and dissolved organic C (DOC) dynamics were monitored over 35 d. Soil Dp/Do declined as soil bulk density and soil moisture increased. Soil N₂O emissions increased exponentially as Dp/Do decreased until Dp/Do equaled 0.005, where upon N₂O fluxes decreased rapidly due to complete denitrification, such that N₂ fluxes reached a maximum of 60% of N applied at a Dp/Do of <0.005. Regression analysis showed that Dp/Do was better able to explain the variation in N₂O and N₂ fluxes than water-filled pore space (WFPS) because it accounted for the interaction of soil rb and y. This study demonstrates that soil Dp/Do can explain cumulative N₂O and N₂ emissions from agricultural soils. Under grazed pasture systems, potential exists to reduce the emissions of the greenhouse gas N₂O and significant economic losses of N as N₂ if soil management and irrigation can be maintained to maximize Dp/Do

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation

The uncertain reasoner: Bayes, logic, and rationality

Human cognition requires coping with a complex and uncertain world. This suggests that dealing with uncertainty may be the central challenge for human reasoning. In Bayesian Rationality we argue that probability theory, the calculus of uncertainty, is the right framework in which to understand everyday reasoning. We also argue that probability theory explains behavior, even on experimental tasks that have been designed to probe people's logical reasoning abilities. Most commentators agree on the centrality of uncertainty; some suggest that there is a residual role for logic in understanding reasoning; and others put forward alternative formalisms for uncertain reasoning, or raise specific technical, methodological, or empirical challenges. In responding to these points, we aim to clarify the scope and limits of probability and logic in cognitive science; explore the meaning of the “rational” explanation of cognition; and re-evaluate the empirical case for Bayesian rationality