Background Atrial fibrillation (AF) is the most common arrhythmia. Although it was recently identified as a risk factor for coronary heart disease (CHD), the underlying pathophysiology is not well understood. Biomarkers could provide insights on underlying mechanisms and identify potential predictors of CHD among people with AF. Methods The REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study enrolled 30 239 White and Black adults aged 45 and older in 2003 to 2007. Among those with baseline AF and no history of stroke or CHD, 13 cardiovascular risk biomarkers were measured at baseline. We calculated hazard ratios (HR) for incident CHD by biomarkers using Cox proportional hazards model adjusting for risk factors and use of statins, aspirin, and anticoagulants. Results Among 1818 participants with prevalent AF mean age was 69 years (SD 10 years). There were 201 (11%) cases of incident CHD over 9 years. Several biomarkers were associated with incident CHD: NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), C‐reactive protein, interleukin‐6, D‐dimer, cholesterol, lipoprotein(a), triglycerides, low‐density lipoprotein, and gamma‐glutamyl transferase, with HRs 1.17 to 1.69 per SD increment. There were no associations for Factor VIII, galectin 3, and high‐density lipoprotein. The largest associations were for NT‐proBNP and GDF‐15 with respective HRs per SD 1.69 (95% CI, 1.42–2.01) and 1.45 (95% CI, 1.21–1.74). Comparing the top versus bottom tertile, the largest associations were NT‐proBNP (HR 3.14 [95% CI 2.03–4.84]), interleukin‐6 (HR, 2.69 [95% CI, 1.78–4.06]), and GDF‐15 (HR, 2.20 [95% CI, 1.38–3.51]). Conclusions Multiple biomarkers were associated with incident CHD in AF with the largest associations being myocardial strain and inflammation.

Introduction: Atrial fibrillation (AF) is highly prevalent, and its health effects outside of stroke are under intense study. AF increases dementia risk, but underlying mechanisms are unknown. Stroke or cerebrovascular pathophysiology, possibly attenuated with anticoagulation, may be contributory. Hypotheses: We assessed two hypotheses: (1) that higher levels of 9 circulating biomarkers (see Figure) would be associated with greater risk of incident cognitive impairment (ICI) in REGARDS participants with AF, and (2) that associations would be attenuated after adjusting for oral anticoagulant use. Methods: REGARDS enrolled 30,239 persons > 45 years old in 2003-07. AF was defined by self-report or ECG. ICI was defined during follow-up by robust cognitive norms based on the Montreal Cognitive Assessment and Six-Item Screener. Biomarkers were measured at baseline in participants with AF and no prior stroke. HRs of time to ICI by biomarkers were calculated by Cox proportional hazards models, with covariates shown in the Figure. Interaction testing by baseline oral anticoagulant use was also performed. Results: Among 2,261 participants with baseline AF, mean follow-up was 10.6 years (mean age 66.5 years, 51% women, 28.7% Black), and there were 149 ICI cases (7%). Higher NT-proBNP, FVIII, and GDF15 were each associated with ICI (Figure), with the largest association for FVIII (HR adj 2.41 per SD higher FVIII). Added adjustment for anticoagulant use did not attenuate associations, but the association of GDF15 was lower among those on anticoagulation (HR 1.0, 95% CI 0.4-2.6 compared to HR 1.8, 95% CI 1.1-3.0 without anticoagulation; p interaction 0.07). Conclusion: Higher NT-proBNP, FVIII, and GDF15 were associated with ICI in this biracial cohort with AF. Risk associated with GDF15, an inflammation marker, might be reduced with anticoagulation, but further study is needed.

Introduction: Atrial fibrillation (AF) is the most common arrhythmia worldwide. Although it was recently identified as a risk factor for coronary heart disease (CHD), the underlying pathophysiology is not well understood. Initial studies suggested an embolic mechanism when compared to those without AF. We studied several biomarkers to understand possible mechanisms and identify potential predictors of CHD in this population. Methods: The REGARDS cohort study enrolled 30,239 White and Black adults aged 45 and older in 2003-7. We included those with baseline AF and no history of stroke, myocardial infarction (MI), or coronary revascularization. We calculated hazard ratios (HR) for incident CHD, defined as definite or probable MI, per 1 SD increment of each biomarker using Cox models adjusted for CHD risk factors and medications. Results: The 1,807 participants had mean age 66 years; 33% were Black, 57% female, 76% had hypertension, and 21% diabetes. Incident CHD was seen in 201 participants (39.8% fatal) over a mean follow-up of 9 years. Among the 14 biomarkers (figure), significant associations were seen with cholesterol (HR 2.9; 1.4-6.2), cystatin C (HR 2.6; 1.6-4.2), GDF15 (HR 2.0; 1.5-2.9), serum creatinine (HR 1.8; 1.1-2.9) NTproBNP (HR 1.4; 1.3-1.6), D-dimer (HR 1.4; 1.2-1.7), IL6 (HR 1.3; 1.2-1.5), CRP (HR 1.3; 1.1-1.5), GGT (HR 1.25; 1.02-1.54), and LP(a) (HR 1.22; 1.05-1.41). Conclusions: Total cholesterol, LP(a), D-dimer, GGT, and biomarkers of kidney function (cystatin C, creatinine), myocardial strain (NTproBNP), and inflammation (IL6, CRP, GDF15) were associated with incident CHD in AF. These findings lay the groundwork for further research to determine potential therapeutic targets to prevent CHD in people with AF.

Introduction: Hypertension, a risk factor for cardiovascular disease and chronic kidney disease, poses a significant burden in the U.S, especially among Black U.S. adults. Higher pro-enkephalin A (PENK-A), a byproduct of endogenous opioid peptide processing and a novel marker for estimation of glomerular filtration rate, is associated with antihypertensive use and greater risk of stroke, heart failure, and renal dysfunction. Whether low PENK-A is a risk factor for incident hypertension is unknown. Hypotheses: We hypothesized that lower PENK-A will be associated with greater risk of incident hypertension. Methods: REGARDS cohort study enrolled 30,239 Black and White U.S adults aged ≥45 years, with an initial visit between 2003-2007 and a follow-up visit in 2013-2016. A race-sex stratified sample of 4,400 participants were randomly selected. Hypertension was defined with a blood pressure (BP) threshold of 140/90 mm Hg or use of antihypertensive medications. We excluded those with prevalent hypertension, missing model covariates, or missing PENK-A, resulting in an analytical population of 1,859 participants. Proportion of incident hypertension events were calculated by tertile of PENK-A. Modified Poisson regression estimated unadjusted and adjusted risk ratios (RR) of incident hypertension per 1-SD higher of log-transformed PENK-A. Results: Among 1,859 participants (mean [SD] age 62 [8] years, 51% female, and 36% Black race), median (IQR) follow up was 9.5 (8.7 to 10.0) years. Median (IQR) PENK-A was 59.7 (49.6-72.4) pmol/L. Hypertension developed in 35.4% of participants overall, (37.7% of tertile 1, 34.9% of tertile 2, and 33.7% of tertile 3 of PENK-A). However, there was no difference in RR of incident hypertension per 1-SD higher of log PENK-A in unadjusted (RR 0.96; 95% CI 0.90-1.02) or fully-adjusted models (RR 1.01; 95% CI 0.94-1.08). Restricted cubic splines depict no difference in RR of incident hypertension across the means of PENK-A levels relative to the median value ( Figure ). Conclusions: PENK-A was not associated with greater risk of incident hypertension in a contemporary cohort study. PENK-A does not appear to influence risk for stroke and heart failure through hypertension, but whether PENK-A modifies cardiovascular disease risk among persons with hypertension is unclear given its bidirectional role in the cardiorenal pathway.

Acute kidney injury (AKI) is a frequent complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but few studies have focused on AKI treated with kidney replacement therapy (AKI-KRT), particularly among critically ill patients. We investigated the incidence, risk factors, and 90-day mortality associated with AKI-KRT in 529 critically ill adult allo-HSCT recipients admitted to the ICU within 1-year post-transplant at two academic medical centers between 2011 and 2021. AKI-KRT occurred in 111 of the 529 patients (21.0%). Lower baseline eGFR, veno-occlusive disease, thrombotic microangiopathy, admission to an ICU within 90 days post-transplant, and receipt of invasive mechanical ventilation (IMV), total bilirubin ≥5.0 mg/dl, and arterial pH <7.40 on ICU admission were each associated with a higher risk of AKI-KRT. Of the 111 patients with AKI-KRT, 97 (87.4%) died within 90 days. Ninety-day mortality was 100% in each of the following subgroups: serum albumin ≤2.0 g/dl, total bilirubin ≥7.0 mg/dl, arterial pH ≤7.20, IMV with moderate-to-severe hypoxemia, and ≥3 vasopressors/inotropes at KRT initiation. AKI-KRT was associated with a 6.59-fold higher adjusted 90-day mortality in critically ill allo-HSCT vs. non-transplanted patients. Short-term mortality remains exceptionally high among critically ill allo-HSCT patients with AKI-KRT, highlighting the importance of multidisciplinary discussions prior to KRT initiation.

Background Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. Methods In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. Results At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). Conclusion While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

Introduction: Anticoagulation reduces ischemic stroke risk in atrial fibrillation (AF), but “breakthrough” stroke occurs. Blood biomarkers might help identify patients at risk for anticoagulation breakthrough stroke, but existing studies are limited by examining few biomarkers in select populations. Hypotheses: Established biomarkers of ischemic stroke risk will also be associated with ischemic stroke risk in people with AF on anticoagulation sampled from the general population. Methods: REGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 on enrollment in 2003-7 monitored for stroke. Nine established blood biomarkers of ischemic stroke risk were measured at baseline in participants with AF and with no prior stroke who were taking oral anticoagulation at baseline. Hazard ratios of ischemic stroke were estimated by Cox models adjusted for demographics and stroke risk factors. Results: Among 713 participants with AF on anticoagulation (median age 76, 36% female, 17% Black, all taking vitamin K antagonists), 67 (9%) developed a first-time ischemic stroke over 12 years. In models adjusted for demographics, there were positive associations of all biomarkers with stroke risk except for galectin-3, lipoprotein(a), and cystatin C which had inverse or null associations (Figure). Adjustment for risk factors minimally impacted interpretation of results. The greatest associations were with higher N-terminal pro-B type natriuretic peptide, factor VIII, D-dimer, and growth differentiation factor 15; associations for D-dimer and growth differentiation factor 15 were not statistically significant. Hazards for galectin-3, gamma glutamyl transferase, interleukin 6, and lipoprotein (a) were modest and not statistically significant. Conclusion: Biomarkers of cardiac strain (specifically atriopathy), coagulation, and inflammation were associated with higher ischemic stroke risk in people with AF on anticoagulation at baseline. Findings highlight new avenues for reducing stroke risk in AF.

Introduction: Chronic kidney disease (CKD) is only partly caused by traditional risk factors. Endothelial dysfunction is common in CKD and may contribute to CKD incidence. We studied the association of circulating biomarkers reflecting endothelial dysfunction with incident CKD. Methods: The Reasons for Geographical and Racial Differences in Stroke (REGARDS) study is a prospective cohort of 30,239 Black or White adults aged >= 45 years. Baseline levels of intercellular cellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), factor VIII (FVIII), and E-selectin were measured in 3300 participants without baseline CKD or albuminuria who attended a second visit 9.4 years later. Kidney outcomes were incident CKD (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m(2) and >= 40% decline or onset of new end-stage kidney disease), incident >= 30% eGFR decline, and incident albuminuria (albumin-to-creatinine ratio [ACR] >= 30 mg/g). Sequentially adjusted logistic regression models assessed the association of biomarkers with kidney outcomes. Results: Median age of participants was 62 years, 49% were women, and 46% identified as Black. Of the participants, 228 (6.9%) developed CKD, 613 (18.9%) experienced >= 30% decline in eGFR, and 356 (11.4%) developed albuminuria. The adjusted odds ratios (ORs) for incident CKD per 1 SD increment biomarker was 1.12 for ICAM-1 (95% confidence interval [CI]: 1.02-1.22), 1.10 for VCAM-1 (95% CI: 1.01-1.20), 1.15 for FVIII (95% CI: 1.06-1.24), and 1.10 for E-selectin (95% CI: 1.01-1.20). Results were similar for incident >= 30% eGFR decline but not albuminuria, where only higher FVIII was positively associated. Conclusion: Higher concentration of ICAM-1, VCAM-1, FVIII, and E-selectin were associated with incident CKD and >= 30% eGFR decline in a large cohort study. Higher FVIII was also associated with incident albuminuria.

Key Points Patients testing positive for platelet factor 4 antibodies have a >50% higher odds of developing severe AKI compared with those who test negative. The relationship between platelet factor 4 antibodies and severe AKI was independent of demographics, comorbidities, laboratory values, and severity-of-illness characteristics. Background Heparin-induced thrombocytopenia, which results from production of antibodies that bind to heparin-platelet factor 4 (PF4) complexes, is a hypercoagulable state associated with considerable morbidity and mortality due to thrombotic complications. We investigated whether PF4 antibodies are associated with an increased risk of AKI. Methods We conducted a cohort study of hospitalized adults who underwent testing for PF4 antibodies at two large medical centers in Boston between 2015 and 2021. The primary exposure was PF4 test positivity. The primary outcome was severe AKI, defined by Kidney Disease: Improving Global Outcomes stage 3 as a ≥3-fold increase in serum creatinine or receipt of KRT within 7 days after the PF4 test. We used multivariable logistic regression to adjust for potential confounders. Results A total of 4224 patients were included in our analysis, 469 (11.1%) of whom had a positive PF4 test. Severe AKI occurred in 50 of 469 patients (10.7%) with a positive PF4 test and in 235 of 3755 patients (6.3%) with a negative test (unadjusted odds ratio, 1.79 [95% confidence interval, 1.30 to 2.47]). In multivariable analyses adjusted for demographics, comorbidities, laboratory values, and severity-of-illness characteristics, PF4 test positivity remained associated with a higher risk of severe AKI (adjusted odds ratio, 1.56 [95% confidence interval, 1.10 to 2.20]). Conclusions Among hospitalized adults, the presence of PF4 antibodies is independently associated with a 56% higher odds of developing severe AKI. Additional studies are needed to investigate potential mechanisms that may underlie these findings, such as pathogenic effects of PF4 antibodies on the microvasculature of the kidneys.

Introduction: Anticoagulation reduces stroke risk in atrial fibrillation (AF) but increases bleeding. Risk calculators are used to inform decision making for anticoagulation in AF. Yet, existing tools have substantial limitations and improvement efforts failed to change practice. Hypotheses: Biomarkers of ischemic stroke risk for general populations are associated with stroke risk in AF and improve performance of a recommended risk score (CHA 2 DS 2 -VASc). Methods: REGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 monitored for stroke. Nine blood biomarkers were measured at baseline in participants with AF, no prior stroke, and not taking anticoagulation at baseline. Hazard ratios of ischemic stroke were estimated by Cox models adjusted for demographics and stroke risk factors. Models with CHA 2 DS 2 -VASc alone and with biomarkers (CHA 2 DS 2 -VASc-B) were compared using tests of fit (likelihood ratio test and Aikake information criterion [AIC]) and predictive ability (continuous net reclassification index [NRI]). Results: Among 2,411 participants with baseline AF (median age 69, 55% female, 36% Black), 163 (7%) developed stroke over 13 years. After adjustments, higher cystatin C, growth differentiation factor 15 (GDF-15), interleukin 6, lipoprotein (a), and N-terminal pro-B type natriuretic peptide (NTproBNP) were associated with higher stroke risk (Figure A). Including all biomarkers substantially improved CHA 2 DS 2 -VASc model fit (Figure B; p <0.001; ΔAIC -12.6; <-10 indicates marked improvement) and predictive ability (Figure C; 5-year NRI 0.42). Adding only GDF-15 and NTproBNP resulted in the best model fit and a similar NRI, compared to all biomarkers. Conclusions: Higher levels of five blood biomarkers were associated with ischemic stroke risk in a large general population cohort with AF. Moreover, the CHA 2 DS 2 -VASc-B model was superior to CHA 2 DS 2 -VASc. Findings suggest we can better tailor anticoagulation to reduce stroke in AF.

Health and wellbeing and susceptibility to disease are causally linked to food and nutrition intake, an observation that has informed dietary advice for centuries. However, physiological response to different food types varies greatly by individual, meaning that a “one size fits all” approach to nutritional advice may be inadequate to ensure optimum health outcomes. Personalised nutrition (PN) services, operating at the intersection between health advisory, the wellness sector, and the food system, seek to address this through individualised targeted dietary advice focused on achieving lasting dietary behaviour change that is beneficial for health. In this report we specifically analyse the evolution of personalised nutrition defined as nutritional advice based on personalised analysis of scientific data obtained from the customers’ phenotype and the scientific knowledge base underpinning such advice. We will touch on technologies that enable the personalisation of food more generally only insofar as they might impact PN in the future through wider network effects within the food system. Personalised nutrition as a clinical and academic field of study has existed for at least four decades, however recent investor interest and cheaper direct-to-consumer (D2C) testing devices have enabled a growing commercial PN sector that has evolved over the past ten years. Commercial PN services provide mostly advice, which is claimed to be based on the latest scientific evidence showing the causal connections between certain individual phenotypic traits (genes, lifestyle factors, gut microbe, blood parameters, age, sex, etc.) and the physiological response to food. In addition to advice, providers increasingly offer personalised supplements and vitamins (which are within the FSA remit) as well as personalised, tailored subscription meal plans. The sector in the UK is currently still small but represented by a number of different business models serving increasing consumer interest in health-related offerings. Moreover, there are hopes that commercial PN might, in the longer-term future, contribute to public health. In this report we have analysed the specific input trends that have enabled the emergence of the sector with the drivers and challenges that are shaping its evolution today. This analysis included a thorough assessment of the science that underpins PN services, the role of technology trends and commercial activity including an overview of the current global and UK markets, wider social trends that impact consumer uptake of PN, and the existing regulatory environment that surrounds PN, a currently unregulated commercial activity. The potential impact on public health, food safety and consumer choice as the industry develops over the coming decade were also assessed.

Background: Cardiovascular disease is a major risk for cognitive impairment. The opioid precursor peptide pro-enkephalin A (PENK-A) is a circulating hormone associated with several cardiovascular diseases and possibly vascular dementia. The objective of this study was to test the association of plasma PENK-A with incident cognitive impairment and describe potential differences by age, race, and sex. Methods: REGARDS is a prospective population-based cohort of 30,239 Black and White adults. Baseline plasma PENK-A was measured in 462 participants who developed cognitive impairment over a median 4.7 years and 556 who did not develop this. PENK-A’s association with incident cognitive impairment was assessed by logistic regression models adjusted for confounders. We tested for differences by age, sex, and race with interaction terms. Results: PENK-A concentration was comparable between cases and controls, but higher with White race, female sex, greater age, coronary artery disease, and chronic kidney disease. Categorical and linear models did not reveal an association with cognitive impairment. Spline plots showed a non-linear association with decreased odds at very high PENK-A values (adjusted OR for 95 th vs 50 th percentiles 0.66, 95% CI 0.46-0.95). This association was only apparent after final adjustment for kidney function. Interaction testing showed substantial interactions by each age and sex (all P < 0.06). In subgroup analyses, shapes of association differed but no independent trends were discernable (Figure). Conclusions: Circulating PENK-A was not particularly associated with cognitive impairment odds. High levels may be protective; this finding could be spurious. Differences by sex and age may exist, expanding upon prior findings in REGARDS of differing non-linear associations with stroke by sex and race. Further work is needed to characterize the importance of endogenous opioid pathways to cardiovascular health and differences by demographic factors.

Background: Much of chronic kidney disease (CKD) is unexplained by traditional risk factors. Endothelial dysfunction is highly prevalent in CKD and may be a potential target for reducing CKD incidence or progression. We sought to determine the association of plasma biomarkers of endothelial dysfunction with incident CKD in a large prospective cohort. Methods: REGARDS is a prospective population-based cohort of 30,239 Black and White US adults aged ≥45. Baseline biomarkers of endothelial dysfunction (plasma factor VIII, E-selectin, intercellular cellular adhesion molecule 1 (ICAM-1), and vascular cellular adhesion molecule 1 (VCAM-1)) were measured in individuals without CKD who attended a second visit a median of 9.4 years after baseline. Incident CKD was defined as eGFR <60 ml/min/1.73m 2 and a decline of 40%. We used sequential logistic regression models adjusted for confounders to assess associations and tested for interactions by each of age, sex, race, and diabetes. Results: After exclusions, we studied 3,300 participants (median age 62, 49% women, 46% Black, 50% hypertensive, 15% diabetic). 228 (6.9%) developed CKD by the second visit. Substantial interactions were observed for several markers, so stratified analyses were presented (Table). In minimally adjusted models, independent positive associations with CKD were seen with higher levels of each marker: factor VIII in White non-diabetics, E-selectin in women <65 years, ICAM-1 in all participants, and VCAM-1 in White men and women (Table). Final adjustment attenuated associations in some groups, but not all. Among the above minimally adjusted results, all associations remained independent after final adjustment except models for VCAM-1; trends for increased CKD with higher VCAM-1 were apparent in White women and Black men, but these were not statistically significant. Conclusion: Several plasma markers of endothelial dysfunction were highly relevant to CKD incidence in important subgroups, which may reveal insights into reducing the burden of CKD.

The food services sector has been evolving rapidly over the past decade, accelerated by the Covid-19 pandemic. The traditional linear model of food producers selling through wholesalers to brick and mortar retailers, restaurants and hospitality venues is increasingly being displaced by complex interactive digital ecosystems of online food services providers. Consumers are increasingly able to access food directly at various stages along the traditional value chain via interaction with digital platforms and rapid home-delivery networks, realising greater convenience, more variety in food products and services from a dynamic start-up scene, and overall enhanced value. FSA needs to stay abreast of these changes and develop regulatory responses to ensure these innovations are aligned with the public good and do not compromise food safety and public health.

OBJECTIVES: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019–associated respiratory failure. DESIGN: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of Pao 2 over the corresponding Fio 2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability–weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. SETTING: ICUs at 68 U.S. sites PATIENTS: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of Pao 2 over the corresponding Fio 2 less than or equal to 200 mm Hg. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73–0.97). CONCLUSIONS: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.

This regional profile for the Arabian Peninsula was developed in the context of the BEIS COP26 Futures We Want project. It covers the United Arab Emirates (UAE) and the Kingdom of Saudi Arabia (KSA), and has been developed with the input from in- country academic experts Prof. Annalisa Molini and Mr Luiz Friedrich (Khalifa University, UAE) and Prof. Juan Carlos Santamarina (King Abdullah University of Science and Technology, KSA). It sets out a synthesis of the available evidence base on regional challenges and opportunities for mitigation, adaptation, and resilience measures for both KSA and UAE and the wider Arabian Peninsula associated with climate change and a global transition to an inclusive, desirable, and resilient net-zero future.

OBJECTIVES:The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex. MATERIALS AND METHODS:The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A. RESULTS:PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men. CONCLUSIONS:Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis.