Prevalence and Impact of Chronic Edema in Bariatric Patients: A LIMPRINT Study

Background: Chronic edema (CO) is a complex condition, arising from different factors, including immobility and obesity. Edema and obesity can have a significant impact on quality of life of patients and their families. Understanding how to manage edema in obese patients is an increasing challenge for both patients and clinicians. As effective treatment options are limited for this population, it is more cost-effective for patients to lose weight before starting treatment. When patients cannot maintain weight loss, one option is to have bariatric surgery.This study was part of LIMPRINT: Lymphedema IMpact and PRevalence INTernational, a study with the aim of identifying the prevalence and impact of CO in different countries and health care settings.Study Purpose: To evaluate the prevalence and impact of CO among patients in a United Kingdom bariatric surgical service.Methods and Results: The gold standard pitting test assessed the presence of edema. General (EuroQOL-5 Dimensions [EQ-5D], RAND 36-Item Short Form Health Survey, Version 1.0 [SF-36], Generalized Anxiety Disorder 7-Item Scale [GAD-7] and Patient Health Questionnaire–9 [PHQ-9]), and edema-specific (Lymphedema Quality of Life [LYMQOL]) quality-of-life questionnaires were used to evaluate impact of edema.The prevalence of edema was 52.1% (25 of 48 participants had edema), potentially linked to obesity, immobility, and medications. Most participants had International Society of Lymphology (ISL) Stage I edema. There were no statistically significant differences between the quality of life of participants with and without edema. However, comparing SF-36 results and normative population data indicated that quality of life was much lower than those in the normative population.Conclusions: This study highlights the high prevalence of edema and low quality of life of this bariatric population. ClinicalTrials.gov ID: NCT03154593

Lorcaserin improves glycemic control via a melanocortin neurocircuit.

OBJECTIVE: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. METHODS: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. RESULTS: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. CONCLUSIONS: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.

OBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. METHODS: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. RESULTS: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. CONCLUSIONS: Our data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.Yousef Jameel Fund Sir Jukes Thorn Trust Elmore Fund Chang Gung University College of Medicin

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

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

Le drôle de choc

[eng] At the end of July, most industrialised countries were already on the path of a downturn. Japan and Germany were exceptions in that respect : a slowdown was only anticipated at the beginning of 1991, when the exceptional stimulus to their internal demands would have faded. In many european countries, with different magnitudes, the rate of growth of Gnp was slowing down while that of prices was accelerating. The United Kingdom and the United States had reached the end of the cycle. The former was on the verge of an inflationist recession, the latter were heading towards a soft-landing. Imbalances between the current accounts of three great economies were slowly shrinking. The situation was worse among non OECD countries. Only a handful of far-eastern countries had good prospects for growth. In eastern european economies, the implementation of reforms and the global disorganisation were leading to depressions. So far, the Gulf crisis only means a small oil shock. The present analysis assumes that by mid-1991 diplomacy backed by the embargo would enable oil usually exported by Kuwait and Irak to find its way back on world markets. Therefore, the price of oil would fluctuate around 35 dollars/bl during the last quarter of 1990 and the first quarter of 1991, and then decline to less than 20 dollars at the end of 1991. In OECD countries, consumer prices would immediately be increased by 0,5 to 1,0%, whereas economic growth would be diminished in 1991 by the same amount. Gnp would grow by an average 2 % in Europe, half way between Japan and the United States. American production would only decline during the first semester, the year 1991 as a whole showing a small increase. For other countries, except those which are net oil exporters (among which the USSR), consequences would be far more dramatic. L.D.Cs and eastern european countries, already plagued by balance of payments difficulties, would have to cut down their imports of all products. In France, the abrupt slowdown of the first half of 1990 and the Gulf crisis will lower next year's growth by 0.5 %. Gnp will only increase by 2 % in 1991 after 3 % in 1990. Business investment wil be hampered by the worsening conditions in sales, the financial situation and the general economic climate. Households income will decelerate owing to wage moderation in the private sector and the stagnation of employment. But the savings rate will decline, enabling private consumption decelerate at a more moderate pace. Inflation will slow as soon as the oil price gees down again in 1991. Despite the widening of the trade deficit, the current account deficit will remain below 1 % of the Gnp. Economic policy will remain moderately restrictive, and will therefore not emphasize the slowdown of activity. [fre] A la fin du mois de juillet les économies industrialisées étaient, dans leur ensemble, déjà en voie de ralentissement. Au Japon et en RFA, celui-ci n'était cependant attendu que pour le début de 1991 lorsque se seraient estompés les stimulants exceptionnels de demande intérieure. Dans la plupart des pays européens, à des degrés divers, le rythme de l'activité s'infléchissait déjà tandis que celui de la hausse des prix s'accélérait. Le Royaume-Uni et les Etats-Unis étaient en fin de cycle ; le premier était au bord d'une récession inflationniste, les seconds d'un « soft-landing ». Le déséquilibre entre les balances courantes des trois grandes puissances mondiales continuait à s'atténuer. La situation des pays non OCDE était plus sombre. Parmi les PVD, seuls quelques pays d'Extrême-Orient avaient de bonnes perspectives de croissance. Dans les pays d'Europe de l'Est, la mise en place des réformes et la désorganisation générale occasionnaient de véritables dépressions. La crise du Golfe n'équivaut encore qu'à un petit choc pétrolier. L'analyse développée ici suppose que vers le milieu de l'année 1991 la diplomatie, s'appuyant sur l'embargo, rendrait vraisemblable dans un avenir proche l'évacuation du Koweït par l'Irak et le retour sur le marché mondial du pétrole habituellement exporté par ces deux pays. En conséquence, après avoir oscillé au voisinage de 35 dollars/baril au dernier trimestre 1990 et au premier trimestre 1991, le prix du pétrole retomberait jusqu'à moins de 20 dollars fin 1991. Pour les pays de l'OCDE, les prix à la consommation en seraient dès à présent accrus de + 0,5 à + 1 %, la croissance de 1991 se trouvant amputée d'un montant équivalent. Les PNB européens s'élèveraient alors en moyenne de 2 % en 1991, à mi-chemin entre le Japon et les Etats-Unis. Ce dernier pays verrait son activité diminuer au seul premier semestre, l'ensemble de l'année dégageant une variation légèrement positive. Pour les autres pays, à l'exception des exportateurs nets de pétrole (dont l'URSS), les conséquences seraient plus graves : PVD et Europe de l'Est, déjà soumis à une forte contrainte de balance des paiements, seraient contraints de réduire de manière draconienne leurs importations de tous produits. En France, un ralentissement de l'activité très marqué au premier semestre 1990 et la crise du Golfe devraient freiner la croissance d'un demi point l'an prochain. Le PIB progresserait de près de 3 % en 1990 mais de 2 % seulement en 1991. L'investissement des entreprises sera contraint par de moins bonnes perspectives d'activité, une dégradation déjà effective de la situation financière (en particulier du taux d'autofinancement) et une détérioration du climat des affaires. Le revenu des ménages se ralentira en raison d'une stagnation des effectifs et d'une modération salariale dans le secteur privé ; le freinage de la consommation sera cependant atténué par une moindre épargne. L'inflation se ralentira dès que le prix du pétrole fléchira, au début de 1991 et le déficit des paiements courants restera inférieur à 1 % du PIB malgré le creusement du solde commercial. La politique économique, peu restrictive, ne freinera pas davantage la croissance.