Outcomes after angiography with sodium bicarbonate and acetylcysteine

Background: Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. Methods: Using a 2-by-2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated acute kidney injury was a secondary end point. Results: The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between-group differences in the rates of contrast-associated acute kidney injury. Conclusions: Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast-associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466.

Genetic variability and diversity of grain nutritional and quality traits of unexplored traditional rice landraces for developing biofortified varieties

Characterization of grain nutritional and quality traits was done in a total of 192 exotic and indigenous rice genotypes were genetically characterized for 16 grain nutritional and quality traits. Substantial genetic variability was observed for all the traits. The coefficient of variation was maximum for flavonoid content (87.10%) and minimum for kernel breadth (11.90%). The estimated coefficient of skewness and kurtosis indicated the presence of genetic interaction among the traits. Based on grain shape 4, 37, 31, 65 and 55 rice genotypes were classified as short slender, short bold, medium slender, long slender and long bold respectively. Further, kernel length was negatively associated with zinc, iron, phenolics and flavonoid contents. Amylose content was positively associated with protein, phenolics and flavonoid contents suggesting that such relationship could serve as grain indices for indirect selection of genotypes. Four genotypes- Oryza officinalis, Oryza latifolia, IC435559 and IC135877 were identified as donors for zinc and iron contents. The genotypes- IC74637, IC301547, IC301589 and IC301625 were identified as potential donors for both phenolics and flavonoid. Five genotypes viz., IC379109, IC331668, Mancha (M:1028), Dubraj (D:1251) and Laxmibhog (L:708) were identified for grain yield, quality and nutritional traits. The identified donors will be useful to develop nutrient dense biofortified varieties

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Left ventricular function, congestion, and effect of empagliflozin on heart failure risk after myocardial infarction

Background Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). Objective To evaluate the association between left ventricular ejection fraction (LVEF), congestion, or both on outcomes and the impact of empagliflozin in reducing HF risk post-MI. Methods In the EMPACT-MI trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both to empagliflozin 10 mg daily or placebo and followed for a median of 17.9 months. Results Among 6522 patients, the mean baseline LVEF was 41%+9%; 2648 patients (40.6%) presented with LVEF<45% alone, 1483 (22.7%) presented with congestion alone, and 2181 (33.4%) presented with both. Among patients in the placebo arm, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (hazard ratio [HR] 1.49; 95%CI, 1.31-1.69; P<0.0001), first HF hospitalization (HR, 1.64; 95%CI, 1.37-1.96; P<0.0001), and total HF hospitalizations (rate ratio [RR], 1.89; 95%CI, 1.51-2.36; P<0.0001). Presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR 1.52, 1.94, and RR 2.03, respectively). Empagliflozin reduced the risk for first (HR 0.77, 95%CI 0.60-0.98) and total (RR 0.67, 95%CI 0.50-0.89) HF hospitalization, irrespective of LVEF or congestion or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. Conclusions In patients with AMI, severity of LV dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion

Effect of empagliflozin on heart failure outcomes after acute myocardial infarction: insights from the EMPACT-MI trial

Background: Empagliflozin reduces the risk of heart failure events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, and in those with prevalent heart failure irrespective of ejection fraction. While EMPACT-MI showed empagliflozin does not reduce the risk of the composite of hospitalization of heart failure and all-cause mortality, the impact of empagliflozin on first and recurrent heart failure events in patients after myocardial infarction is unknown. Methods: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for heart failure based on newly developed left ventricular ejection fraction of <45% and/or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for heart failure outcomes. Results: Over a median of follow-up of 17.9 months, the risk for first heart failure hospitalization and total heart failure hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 (3.6%) vs. 153 (4.7%) patients with events, HR 0.77 [95% CI 0.60, 0.98], P=0.031 for first heart failure hospitalization and 148 vs. 207 events, RR 0.67 [95% CI 0.51, 0.89], P=0.006 for total heart failure hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total heart failure hospitalizations. Post-discharge need for new use of diuretics, renin-angiotensin modulators, and mineralocorticoid receptor antagonists were less in patients randomized to empagliflozin than placebo (all p<0.05). Conclusions: In patients after acute myocardial infarction with left ventricular dysfunction or congestion, empagliflozin reduced the risk of heart failure

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

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

Genetic variability and diversity of grain nutritional and quality traits of unexplored traditional rice landraces for developing biofortified varieties.

Not AvailableCharacterization of grain nutritional and quality traits was done in a total of 192 exotic and indigenous rice genotypes were genetically characterized for 16 grain nutritional and quality traits. Substantial genetic variability was observed for all the traits. The coefficient of variation was maximum for flavonoid content (87.10%) and minimum for kernel breadth (11.90%). The estimated coefficient of skewness and kurtosis indicated the presence of genetic interaction among the traits. Based on grain shape 4, 37, 31, 65 and 55 rice genotypes were classified as short slender, short bold, medium slender, long slender and long bold respectively. Further, kernel length was negatively associated with zinc, iron, phenolics and flavonoid contents. Amylose content was positively associated with protein, phenolics and flavonoid contents suggesting that such relationship could serve as grain indices for indirect selection of genotypes. Four genotypes- Oryza officinalis, Oryza latifolia, IC435559 and IC135877 were identified as donors for zinc and iron contents. The genotypes- IC74637, IC301547, IC301589 and IC301625 were identified as potential donors for both phenolics and flavonoid. Five genotypes viz., IC379109, IC331668, Mancha (M:1028), Dubraj (D:1251) and Laxmibhog (L:708) were identified for grain yield, quality and nutritional traits. The identified donors will be useful to develop nutrient dense biofortified varieties

A New Syndrome of Patent Foramen Ovale Inducing Vasospastic Angina and Migraine

Patent foramen ovale (PFO) is the most common congenital cardiac abnormality and is usually considered a benign finding. This case series suggests a potential link between PFO and vasospastic angina. It also demonstrates PFO closure as a potential therapeutic intervention for individuals with PFO who suffer from refractory vasospastic angina