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Abstract Transthyretin is a transport protein whose misfolding has been implicated in the development of cardiac amyloidosis. Here, we examine the clinical correlates of transthyretin levels, the differences in transthyretin levels according to the pathogenic V142I TTR variant carrier status, and the association of transthyretin levels with outcomes among 35,206 UK Biobank participants who underwent plasma profiling and were free from prevalent cardiovascular disease and chronic renal disease. Transthyretin levels are lower in females, decrease with increasing C-reactive protein levels, and increase with body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, albumin levels, triglyceride levels, and creatinine levels. V142I non-carriers [n = 35,167, mean: −0.1 (0.3)] have higher adjusted transthyretin levels compared with the carriers [n = 39, mean: −0.5 (0.3)] (p:

Background Septal myectomy and alcohol septal ablation (ASA) are septal reduction therapies for patients with symptomatic obstructive hypertrophic cardiomyopathy. Operator and hospital volume may influence outcomes, but contemporary data on this relationship are limited. Methods and Results This retrospective cohort study used data from the Vizient Clinical Data Base (2016–2022). Patients with undergoing septal myectomy and ASA were identified using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) codes and stratified into low‐, medium‐, and high‐volume groups based on annualized operator and hospital volumes. The outcomes were 30‐day in‐hospital mortality and 90‐day readmission, analyzed using multivariable adjusted logistic and Cox models. Among 5725 patients with hypertrophic cardiomyopathy (3990 septal myectomy; 1735 ASA), most operators and hospitals performed

Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundworm Heligmosomoides polygyrus, and altered the host tissue transcriptome at the site of infection with the large intestinal whipworm Trichuris muris, with a notable enhancement of type-1 inflammatory and interferon-driven gene pathways. In the absence of infection, PAC intake promoted the expansion of Turicibacter within the gut microbiota, increased fecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-γ-valerolactones in the cecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected with T. muris, suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the cecum dwelling T. muris), and infection may abrogate the beneficial effects of health-promoting phytochemicals.

Objective: Extradural hematomas (EDHs) are contact injuries resulting from blunt trauma to the skull. It may be unilateral or bilateral. Bilateral acute extradural hematoma (EDH) was rarely reported before the advent of computed tomography. Mortality rates vary from 10.0%-40.0% and are an index of alertness and efficiency of health care and hospital set-up. EDH is an injury with preventable mortality in most cases. Bilateral acute extradural hematomas no longer confer high mortality of pre-CT era because of early diagnosis on CT, and prompt neurosurgical intervention. We present our experience with Bilateral EDH cases with an aim to investigate clinical, GCS score, and radiological features and also to analyse outcomes in these patients. Material and methods: We analyzed cases of EDH who presented at our centre from January 2023 to December 2023 and further investigated ten cases of bilateral EDH. All the patients were examined clinically and a plain computerized tomography scan of the head was performed. The clinical details of all patients, GCS at admission and discharge, radiological findings on CT and neurosurgical intervention performed, and GOS (Glasgow outcome score) were noted. Results: Road traffic accident was the reason for traumatic brain injury in all the cases. The GCS at admission was between 13–15 in 2 patients, 8–12 in 6 and 3–7 in 2 patients. Bilateral EDH was found in all of our patients .9 out of 10 cases were males. On CT head underlying fracture was seen in all cases. The localization of epidural hematomas in CT scans was bifrontal in four of the cases. All cases were treated with surgical management. The GOS Score was 5 in eight of the patients. Conclusion: Posttraumatic bilateral acute extradural hematoma is a rare entity, but now does not show the high mortality previously seen in the preCT era. This is due to early radiological diagnosis on CT and profuse monitoring combined with expeditious operative procedures.

Phosphodiesterase 3A (PDE3A) gene mutations have recently been associated with hypertension and brachydactyly syndrome (HTNB). This report shows how the recent recognition of the role of the PDE3A gene in HTNB facilitated the diagnosis of HTNB in a 20-year-old female who could not be diagnosed at her initial presentation at 6 years of age.

This case study explores the physiological phenomenon of height decrease with aging, scientifically known as age-related height loss or shrinkage. It delves into the mechanisms underlying this process, including changes in intervertebral discs, bone density, and posture. The genesis of this inquiry is whether height decreases with age to determine the eligibility of police personnel for regularization in the service.

Abstract Objective: We aimed to assess risk of COVID-19 infection & seroprotection status in healthcare workers (HCWs) in both hospital and community settings following an intensive vaccination drive in India. Setting: Tertiary Care Hospital Methods: We surveyed COVID-19 exposure risk, personal protective equipment (PPE) compliance, vaccination status, mental health & COVID-19 infection rate across different HCW cadres. Elecsys® test for COVID-19 spike (Anti-SARS-CoV-2S; ACOVs) and nucleocapsid (Anti-SARS-CoV-2; ACOV) responses following vaccination and/or COVID-19 infection were measured in a stratified sample of 386 HCW. Results: We enrolled 945 HCWs (60.6% male, age 35.9 ± 9.8 years, 352 nurses, 211 doctors, 248 paramedics & 134 support staff). Hospital PPE compliance was 90.8%. Vaccination coverage was 891/945 (94.3%). ACOVs neutralizing antibody was reactive in 381/386 (98.7%). ACOVs titer (U/ml) was higher in the post-COVID-19 infection group (N =269; 242.1 ± 35.7 U/ml) than in the post-vaccine or never infected subgroup (N = 115, 204.1 ± 81.3 U/ml). RT PCR + COVID-19 infections were documented in 224/945 (23.7%) and 6 HCWs had disease of moderate severity, with no deaths. However, 232/386 (60.1%) of HCWs tested positive for nucleocapsid ACOV antibody, suggesting undocumented or subclinical COVID-19 infection. On multivariate logistic regression, only female gender [aOR 1.79, 95% CI 1.07–3.0, P = .025] and COVID-19 family contact [aOR 5.1, 95% CI 3.84–9.5, P < .001] were predictors of risk of developing COVID-19 infection, independent of association with patient-related exposure. Conclusion: Our HCWs were PPE compliant and vaccine motivated, with immunization coverage of 94.3% and seroprotection rate of 98.7%. There was no relationship between HCW COVID-19 infection to exposure characteristics in the hospital. Vaccination reduced disease severity and prevented death in HCW.

Background Ambulatory follow‐up for all patients with heart failure (HF) is recommended within 7 to 14 days after hospital discharge to improve HF outcomes. We examined postdischarge ambulatory follow‐up of patients with comorbid diabetes and HF from a low‐income population in primary and specialty care. Methods and Results Adults with diabetes and first hospitalizations for HF, covered by Alabama Medicaid in 2010 to 2019, were included and the claims analyzed for ambulatory care use (any, primary care, cardiology, or endocrinology) within 60 days after discharge using restricted mean survival time regression and negative binomial regression. Among 9859 Medicaid‐covered adults with diabetes and first hospitalization for HF (mean age, 53.7 years; SD, 9.2 years; 47.3% Black; 41.8% non‐Hispanic White; 10.9% Hispanic/Other [Other included non‐White Hispanic, American Indian, Pacific Islander and Asian adults]; 65.4% women, 34.6% men), 26.7% had an ambulatory visit within 0 to 7 days, 15.2% within 8 to 14 days, 31.3% within 15 to 60 days, and 26.8% had no visit; 71% saw a primary care physician and 12% a cardiology physician. Black and Hispanic/Other adults were less likely to have any postdischarge ambulatory visit (P

Objective: Oversampling of Asian American individuals in the National Health and Nutrition Examination Survey (NHANES) provides a unique opportunity to assess the population-level cardiovascular health (CVH) in the fastest-growing racial group in the US. Methods: The Life's Essential 8 (LE8) score and its components were calculated in self-reported Asian American individuals ≥20 years of age and free of cardiovascular disease in the NHANES cycles from 2011-March 2020. Multivariable adjusted linear and logistic regression models were used for analysis. Results: Among 2,059 Asian American individuals, the weighted mean LE8 score was 69.1 (0.4) with US-born [69.0 (0.8)] and foreign-born individuals [69.1 (0.4)] having similar CVH. From 2011 to March 2020, CVH in the overall population [69.7 (0.8) to 68.1 (0.8); Ptrend: 0.009] and foreign-born individuals [69.7 (0.8) to 67.7 (0.8); Ptrend: 0.005] declined. Decreasing trends were noted in the body mass index score irrespective of stratification and in the blood pressure scores in the overall population and foreign-born Asian American individuals. Compared with US-born individuals, the odds of ideal levels of smoking [ORadj:

BackgroundMarfan syndrome is a potentially fatal inherited autosomal dominant condition impacting the cardiovascular and the skeletal system with an estimated 25% cases caused by sporadic genetic variations. Given the genetic inheritance pattern, an autopsy of probands with Marfan syndrome–associated mortality is critical to establish the phenotypic expression and clinical implications of the particular genetic variant, especially for first-degree relatives. We present the findings of a Marfan syndrome proband decedent presenting with sudden onset abdominal pain and unexplained retroperitoneal abdominal hemorrhage.MethodsAn autopsy was performed to inform the blood relatives of the phenotypic expression and penetrance of the potentially heritable condition. A clinical laboratory improvement amendment (CLIA)-certified clinical grade genetic sequencing was performed to identify pathogenic variants in genes associated with aortopathy.ResultsThe autopsy showed intra-abdominal and retroperitoneal hemorrhage due to infarction of the right kidney caused by dissection of the right renal artery. Genetic testing identified a heterozygous pathogenic FBN1 gene variant. The specific variant is FBN1 NM_000138.4 c.2953G > A p.(Gly985Arg).ConclusionsWe report a case of a previously undiagnosed Marfan syndrome death due to a de novo FBN1 variant, c.2953G > A.

Introduction: The role of immune mediated injury in pathogenesis of Ankylosing Spondylitis (AS) is well established. HLA B27, a Major Histocompatibility Complex (MHC) class I molecule is one of the major genetic risk factors associated with the disease. Various techniques are used for testing HLA-B27 which includes Polymerase Chain Reaction (PCR) based tests, Enzyme Linked Immunosorbent Assay (ELISA) and flowcytometry. Flowcytometry has gained popularity due to ease of procedure, shortened turnaround time and cost-effectiveness. Aim: The aim of the present study was to assess the sensitivity and specificity of flowcytometry for HLA-B27 detection, taking PCR assay as the gold standard along with its association with demographic, clinicopathological and radiological parameters. Materials and Methods: This was a prospective study conducted in Department at Pathology of Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, India, for a period of 18 months from January 2020 to June 2021. The study included 51 patients for which HLA-B27 typing was done cases by flowcytometry and Sequence Specific Allele (SSA) PCR/Real time PCR on peripheral blood samples. The association of HLA-B27 with clinical features {Inflammatory Back Pain (IBP), arthritis, psoriasis, uveitis, dactylitis, Inflammatory Bowel Disease (IBD), cervicitis, urethritis, diarrhoea) along with MRI findings (sacroiliitis)}, laboratory findings {C-reactive protein and Erythrocyte Sedimentation Rate (ESR)} was evaluated. The performance analysis parameters of flowcytometry were evaluated both by excluding and including the cases in grey zone taking PCR as gold standard. Statistical testing was conducted with SPSS 20.0. Chi-square test or Fisher’s-exact test were used and a p-value of less than 0.05 was taken as significant. Results: A significant association of HLA-B27 was seen only with IBP (p-value= 0.001) and sacroiliitis (p-value= 0.03). Of the 22 (43.1%) patients positive for HLA-B27 by PCR, 18(81.8%) patients were positive while the remaining 4(18.1%) were in grey zone by flowcytometry. Of the 29(56.9%) patients testing negative by PCR, 27(93.1%) patients were negative, one (3.4%) was in grey zone and one (3.4%- false positive) tested positive for HLA-B27 by flowcytometry. Sensitivity and specificity of flowcytometry for detection of HLA-B27 was found to be 100% and 96.4% respectively when grey zone cases were excluded. Conclusion: The study brings to light that flowcytometry is a fairly specific and sensitive method for HLA-B27 detection with a high Negative Predictive Value (NPV) (100%) and Positive Predictive Value (PPV) (94.7%). In the COVID-19 era, it reiterates the importance of flowcytometry for HLA-B27 especially when PCR is overburdened.

Abstract Low concentrations of natriuretic peptides (NPs) have been associated with greater risk for Type 2 diabetes (T2D). African American individuals (AA) have lower NP levels and are disproportionately burdened by T2D. The purpose of this study was to test the hypothesis that higher post‐challenge insulin in AA adults is associated with lower plasma N‐terminal pro‐atrial natriuretic peptide (NT‐proANP). A secondary purpose was to explore associations between NT‐proANP and adipose depots. Participants were 112 AA and European American (EA) adult men and women. Measures of insulin were obtained from an oral glucose tolerance test and hyperinsulinemic‐euglycemic glucose clamp. Total and regional adipose depots were measured from DXA and MRI. Multiple linear regression analysis was used to assess associations of NT‐proANP with measures of insulin and adipose depots. Lower NT‐proANP concentrations in AA participants was not independent of 30‐min insulin area under the curve (AUC). NT‐proANP was inversely associated with 30‐min insulin AUC in AA participants, and with fasting insulin and HOMA‐IR in EA participants. Thigh subcutaneous adipose tissue and perimuscular adipose tissue were positively associated with NT‐proANP in EA participants. Higher post‐challenge insulin may contribute to lower ANP concentrations in AA adults.

Objective: This study assessed cardiovascular health (CVH) in young adults using the 2022 AHA Life's Essential 8 (LE8) score and compared it with the Life's Simple 7 (LS7) score. Methods: Individuals aged 18 to 44 years without a history of cardiovascular disease in the National Health and Nutrition Examination Survey (NHANES) cycles were included. Data from 2007-2008 to 2017-2018 were combined to create 3 groups (2007-2010, 2011-2014, and 2015-2018) for analysis. The LE8 score and its components were computed in the overall population and stratified by sex and race/ethnicity. Trends for the LE8 score were analyzed using adjusted linear regression models. Results: Among 12,197 young adults, representing an estimated 89.4 million individuals, from the NHANES 2007-2018, the CVH in the overall population and across all subgroups was stable (Ptrend >0.05). The blood lipid score improved across all subgroups (Ptrend:

The COVID 19 pandemic ravaged the globe with a remarkable ferocity and has not entirely abated till now with cases flaring up at various places at different times. The expected course is for it to become endemic with recurring exacerbations. Over the past two years, we have become wiser to its pathology, diagnosis, and treatment. However, it is imperative for us to regularly and consistently reassess our protocols to assimilate the current and ever-growing knowledge in this direction. Doing so will help us to use our resources judiciously, improve patient care, and enhance the overall benefit to stakeholders. In this article, we aim draw the researchers' attention to few issues which may not be at the forefront at this point in time but important nevertheless. These include the use of personal protective equipment (PPE), universal gloving, isolation criteria, and handling of dead bodies, among others. We hope that a reassessment of the challenges involved in the said procedures will help us to be better prepared to face and tackle potential future waves and the multiple challenges that would potentially ensue post-spikes in infection incidences.

Background Dual antiplatelet therapy after percutaneous coronary intervention reduces myocardial infarctions but increases bleeding. The risk of bleeding may be higher among Black patients for unknown reasons. Bleeding risk scores have not been validated among Black patients. We assessed the difference in bleeding risk between Black and White patients along with the performance of the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy, Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients, and Academic Research Consortium for High Bleeding Risk scores among both groups. Methods and Results This was a single‐center prospective study of patients who underwent percutaneous coronary intervention (2014–2019) and were followed for 1 year. The outcome was postdischarge Bleeding Academic Research Consortium 2 to 5 bleeding. Incidence rates were reported. Cox proportional hazards models measured the effect of self‐reported Black race on bleeding and determined the predictors of bleeding among 19 a priori variables. The 3 risk scores were assessed among Black and White patients separately using the Harrell concordance index. Of 1529 included patients, 342 (22.4%) self‐reported as being Black race. Unadjusted bleeding rates were 22.7 per 100 person‐years among Black patients versus 16.3 among White patients (hazard ratio, 1.41 [95% CI, 1.00–2.00], P=0.052). Predictors of bleeding were age, glomerular filtration rate

Abstract Aims We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA‐PEFF and H2FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study. Methods and results Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable‐adjusted Cox regression analyses. The median HFA‐PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0–6.0], 4.0 (IQR: 2.0–4.0), and 3.0 (IQR: 2.0–4.0), respectively. The median H2FPEF scores in the three studies were 5.5 (IQR: 4.0–7.0), 6.0 (IQR: 4.0–7.0), and 3.0 (IQR: 2.0–5.0), respectively. A low HFA‐PEFF and H2FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA‐PEFF and H2FPEF score can rule‐in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA‐PEFF and H2FPEF score was 1.26 (95% confidence interval: 0.98–1.63) and 1.01 (95% confidence interval: 0.88–1.15), respectively. A higher H2FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01). Conclusions The HFA‐PEFF and the H2FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations.

Objective: There has been a substantial decline in patients presenting for emergent and routine cardiovascular care in the United States after the onset of the coronavirus disease 2019 (COVID-19) pandemic. We sought to assess the risk of adverse clinical outcomes among patients undergoing coronary artery bypass graft (CABG) surgery during the 2020 COVID-19 pandemic period and compare the risks with those undergoing CABG before the pandemic in the year 2019. Methods: A retrospective cross-sectional analysis of the TriNetX Research Network database was performed. Patients undergoing CABG between January 20, 2019, and September 15, 2019, contributed to the 2019 cohort, and those undergoing CABG between January 20, 2020, and September 15, 2020, contributed to the 2020 cohort. Propensity-score matching was performed, and the odds of mortality, acute kidney injury, stroke, acute respiratory distress syndrome, and mechanical ventilation occurring by 30 days were evaluated. Results: The number of patients undergoing CABG in 2020 declined by 35.5% from 5534 patients in 2019 to 3569 patients in 2020. After propensity-score matching, 3569 patient pairs were identified in the 2019 and the 2020 cohorts. Compared with those undergoing CABG in 2019, the odds of mortality by 30 days were 0.96 (95% confidence interval [CI], 0.69-1.33; P = .80) in those undergoing CABG in 2020. The odds for stroke (odds ratio [OR], 1.201; 95% CI, 0.96-1.39), acute kidney injury (OR, 0.76; 95% CI, 0.59-1.08), acute respiratory distress syndrome (OR, 1.01; 95% CI, 0.60-2.42), and mechanical ventilation (OR, 1.11; 95% CI, 0.94-1.30) were similar between the 2 cohorts. Conclusions: The number of patients undergoing CABG in 2020 has substantially declined compared with 2019. Similar odds of adverse clinical outcomes were seen among patients undergoing CABG in the setting of COVID-19 compared with those in 2019.

Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self‐identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable‐adjusted regression modeling. Multivariable‐adjusted genotype‐stratified differences in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and BNP (B‐type natriuretic peptide) levels were assessed. Genotype‐stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; −1.24±0.82), diastolic BP (0.51±0.33; −0.41±0.46), mean arterial pressure (0.48±0.38; −0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80–1.09]; OR, 0.79 [95% CI, 0.61–1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; −1.26±0.81), diastolic BP (0.52±0.33; −0.33±0.45), mean arterial pressure (0.50±0.38; −0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84–1.23]; OR, 0.87 [95% CI, 0.67–1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94–1.93]; OR, 0.95 [95% CI, 0.64–1.39]) in the study cohorts. The NT‐proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups. Conclusions Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Abstract Children and adolescents account for ~ 13% of total COVID-19 cases in the United States. However, little is known about the nature of the illness in children. The reopening of schools underlines the importance of understanding the epidemiology of pediatric COVID-19 infections. We sought to assess the clinical characteristics and outcomes in pediatric COVID-19 patients. We conducted a retrospective cross-sectional analysis of pediatric patients diagnosed with COVID-19 from healthcare organizations in the United States. The study outcomes (hospitalization, mechanical ventilation, critical care) were assessed using logistic regression. The subgroups of sex and race were compared after propensity score matching. Among 12,306 children with lab-confirmed COVID-19, 16.5% presented with respiratory symptoms (cough, dyspnea), 13.9% had gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), 8.1% had dermatological symptoms (rash), 4.8% had neurological (headache), and 18.8% had other non-specific symptoms (fever, malaise, myalgia, arthralgia and disturbances of smell or taste). In the study cohort, the hospitalization frequency was 5.3%, with 17.6% needing critical care services and 4.1% requiring mechanical ventilation. Following propensity score matching, the risk of all outcomes was similar between males and females. Following propensity score matching, the risk of hospitalization was greater in non-Hispanic Black (RR 1.97 [95% CI 1.49–2.61]) and Hispanic children (RR 1.31 [95% CI 1.03–1.78]) compared with non-Hispanic Whites. In the pediatric population infected with COVID-19, a substantial proportion were hospitalized due to the illness and developed adverse clinical outcomes.

Objective Aim of this study is to evaluate the effect of craniospinal interventions on cerebrospinal fluid (CSF) flow hydrodynamics and study the correlation of postoperative changes in flow alteration with clinical outcome. Materials and Methods Fifty patients who underwent various craniospinal procedures were studied using conventional and phase-contrast magnetic resonance imaging (PCMRI) protocol. CSF flow quantification was performed at cerebral aqueduct, foramen magnum, C2–3, and D12–L1 vertebral levels with site showing maximal alteration of CSF flow dynamics considered as the region of interest. Velocity encoding was kept at 20 cm/s. Patients with pathology atcraniovertebral junction were considered separately (group I) from others (group II) due to different flow dynamics. Follow-up scans were performed after an interval of 1 month for temporal evaluation of changes in CSF flow dynamics. Results Patients in both groups showed a significant change in peak CSF velocity postoperatively (mean change of 1.34 cm/s in group I and 0.28 cm/s in group II) with bidirectional improvement in flow on cine-phase-contrast qualitative images. Regional pain (82%) and headache (46%) were seen in most of the patients preoperatively. Postoperatively clinical symptoms improved in 59.5%, static in 26.2%, and worsened in 14.3%. In both the groups, an improvement in clinical symptomatology had significant correlation with mean changes in peak CSF velocity postoperatively (p = 0.04 in both groups). Conclusion PCMRI can effectively evaluate changes in CSF flow noninvasively both pre- and postoperatively. This may have potential role in determining clinical outcome and prognosis of patients undergoing procedures in craniospinal axis.

Objective: To evaluate the race-stratified state-level prevalence of health determinants and the racial disparities in coronavirus disease 2019 (COVID-19) cumulative incidence and mortality in the United States. Patients and Methods: The age-adjusted race-stratified prevalence of comorbidities (hypertension, diabetes, dyslipidemia, and obesity), preexisting medical conditions (pulmonary disease, heart disease, stroke, kidney disease, and malignant neoplasm), poor health behaviors (smoking, alcohol abuse, and physical inactivity), and adverse socioeconomic factors (education, household income, and health insurance) was computed in 435,139 American adult participants from the 2017 Behavioral Risk Factor Surveillance System survey. Correlation was assessed between health determinants and the race-stratified COVID-19 crude mortality rate and infection-fatality ratio computed from respective state public health departments in 47 states. Results: Blacks had a higher prevalence of comorbidities (63.3%; 95% CI, 62.4% to 64.2% vs 55.1%; 95% CI, 54.7% to 55.5%) and adverse socioeconomic factors (47.0%; 95% CI, 46.0% to 47.9% vs 30.9%; 95% CI, 30.6% to 31.3%) than did whites. The prevalence of preexisting medical conditions was similar in blacks (30.4%; 95% CI, 28.8% to 32.1%) and whites (30.8%; 95% CI, 30.2% to 31.4%). The prevalence of poor health behaviors was higher in whites (57.2%; 95% CI, 56.3% to 58.0%) than in blacks (50.2%; 95% CI,46.2% to 54.2%). Comorbidities and adverse socioeconomic factors were highest in the southern region, and poor health behaviors were highest in the western region. The cumulative incidence rate (per 100,000 persons) was 3-fold higher in blacks (1546.4) than in whites (540.4). The crude mortality rate (per 100,000 persons) was 2-fold higher in blacks (83.2) than in whites (33.2). However, the infection-fatality ratio (per 100 cases) was similar in whites (6.2) and blacks (5.4). Within racial groups, the geographic distribution of health determinants did not correlate with the state-level COVID-19 mortality and infection-fatality ratio (P>.05 for all). Conclusion: Racial disparities in COVID-19 are largely driven by the higher cumulative incidence of infection in blacks. There is a discordance between the geographic dispersion of COVID-19 mortality and the regional distribution of health determinants.

Abstract Background Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. Methods In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012–2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015–2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. Results The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13–0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74). Conclusion Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Objective: Recently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair. Methods: To define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers. Results: Lack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2−/− mice showed lower expression of lipoxygenases (−5, −12, −15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (−1 and −2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2−/− mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction. Conclusions: Lack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation–resolution processes, obesogenic aging, and renal homeostasis. Keywords: Inflammation, Leukocytes, Myocardial infarction, Nonresolving inflammation, Obesogenic aging, Resolution of inflammation

Introduction: Job satisfaction among nurses is an indicator of excellent working environment and management of the institution. The study of job satisfaction has relevance to nursing from economic, humanitarian, and professional perspectives. Aim and Objective: This study aimed to understand the job satisfaction among nursing officers (NOs) at a tertiary care hospital. Methodology: A cross-sectional questionnaire-based study was conducted using the Minnesota Satisfaction Questionnaire short form. Results: The study was conducted in the different areas of tertiary care hospital. The study population comprised NOs employed in tertiary care hospital. Nearly half of the participants were in the age group of 21–30 years. Among the nursing professionals, more than two-third of them were NOs 620 (73.4%), followed by senior NOs, assistant nursing superintendent (NS), deputy NS, and NS with least in count comprising 0.1%. It was found that mostly all of the nursing professionals were either moderately satisfied or highly satisfied with their profession. Discussion: Chi-square test was performed to find the relationship between the job satisfaction and age group factor, which indicated that there was a significant association between the variables (P < 0.01). There was no significant difference was observed in the satisfaction level of intrinsic factors among the nurses. Age, area of posting, and the educational qualification had a significant influence on satisfaction level of nurses. It was also observed that length of service did not have any significant influence on the satisfaction level among the nursing staffs. Conclusion: The study found that most of the nurses were satisfied but some factors were commonly related with dis-satisfaction.

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.

Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs‐CRP (high‐sensitivity C‐reactive protein), N‐terminal pro‐B‐type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25‐hydroxyvitamin‐D [25‐OH‐D] ≤25 ng/mL) receiving low‐dose (400 IU/d) versus high‐dose (4000 IU/d) vitamin D3 for 6 months. A meta‐analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25‐OH‐D increased in the high‐dose relative to the low‐dose vitamin D group (+15.5 versus +4.6 ng/mL, P

Background Obese patients have lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels. The prognostic implications of achieving NT‐proBNP levels ≤1000 pg/mL in obese patients with heart failure (HF) receiving biomarker‐guided therapy are not completely known. We evaluated the prognostic implications of obesity and having NT‐proBNP levels (≤1000 pg/mL) in the GUIDE‐IT (Guiding Evidence‐Based Therapy Using Biomarker‐Intensified Treatment in HF) trial participants. Methods and Results The risk of adverse cardiovascular events (HF hospitalization or cardiovascular mortality) was assessed using multivariable‐adjusted Cox proportional hazard models based on having NT‐proBNP ≤1000 pg/mL (taken as a time‐varying covariate), stratified by obesity status. The study outcome was also assessed on the basis of the body mass index at baseline. The predictive ability of NT‐proBNP for adverse cardiovascular events was assessed using the likelihood ratio test. Compared with nonobese patients, obese patients were mostly younger, Black race, and more likely to be women. NT‐proBNP levels were 59.0% (95% CI, 39.5%–83.5%) lower among obese individuals. The risk of adverse cardiovascular events was lower in obese (hazard ratio [HR], 0.48; 95% CI, 0.29–0.59) and nonobese (HR, 0.32; 95% CI, 0.19–0.57) patients with HF who had NT‐proBNP levels ≤1000 pg/mL, compared with those who did not. There was no interaction between obesity and having NT‐proBNP ≤1000 pg/mL on the study outcome (P>0.10). Obese patients had a greater risk of developing adverse cardiovascular events (HR, 1.39; 95% CI, 1.01–1.90) compared with nonobese patients. NT‐proBNP was the strongest predictor of adverse cardiovascular event risk in both obese and nonobese patients. Conclusions On‐treatment NT‐proBNP level ≤1000 pg/mL has favorable prognostic implications, irrespective of obesity status. NT‐proBNP levels were the strongest predictor of cardiovascular events in both obese and nonobese individuals in this trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840.

The role of dietary components in immune function has acquired considerable attention in recent years. An important focus area is to unravel the role of bioactive dietary compounds in relation to enteric disease and their impact on gut mucosal immunity. Proanthocyanidins (PAC) are among the most common and most consumed dietary polyphenols, and are characterised by their variable molecular structures and diverse bioactivities. In particular, their anti-oxidative effects and ability to modulate gut microbiota have been widely described. However, there is limited evidence on the mechanism of action of PAC on the immune system, nor is it clearly established how PAC may influence susceptibility to enteric infections. Establishing the sites of action of PAC and their metabolites within the gut environment is fundamental to determine the applicability of PAC against enteric pathogens. Some mechanistic studies have shown that PAC have direct modulatory effects on immune cell signalling, isolated pathogens, and gut mucosal barrier integrity. Boosting the recruitment of immune cells and suppressing the amount of pro-inflammatory cytokines are modulating factors regulated by PAC, and can either be beneficial or detrimental in the course of re-establishing gut homeostasis. Herein, we review how PAC may alter distinct immune responses towards enteric bacterial, viral and parasitic infections, and how the modulation of gut microbiota may act as a mediating factor. Furthermore, we discuss how future studies could help unravel the role of PAC in preventing and/or alleviating intestinal inflammation and dysbiosis caused by enteric disease.

Objectives Healthcare personnel (HCP) are at an increased risk of acquiring COVID-19 infection especially in resource-restricted healthcare settings, and return to homes unfit for self-isolation, making them apprehensive about COVID-19 duty and transmission risk to their families. We aimed at implementing a novel multidimensional HCP-centric evidence-based, dynamic policy with the objectives to reduce risk of HCP infection, ensure welfare and safety of the HCP and to improve willingness to accept and return to duty.Setting Our tertiary care university hospital, with 12 600 HCP, was divided into high-risk, medium-risk and low-risk zones. In the high-risk and medium-risk zones, we organised training, logistic support, postduty HCP welfare and collected feedback, and sent them home after they tested negative for COVID-19. We supervised use of appropriate personal protective equipment (PPE) and kept communication paperless.Participants We recruited willing low-risk HCP, aged

World Health Organization (WHO) has identified antimicrobial resistance as one of the top 10 threats to public health. The agency has formulated a global action plan to tackle antimicrobial resistance by reducing incidence of infectious diseases, increasing knowledge and awareness and promoting rational use of antimicrobials amongst other measures. While the core elements of successful antimicrobial stewardship (AMS) programs are much publicized, there application in resource limited settings is fraught with several challenges. The key limiting factors include lack of clear political commitment, inadequate funding, overcrowded healthcare systems, lax legal and regulatory frameworks, non-uniform access to diagnostics, absence of electronic health record systems, limited knowledge and awareness especially with existence of multiple systems of medicines, issues with access to quality assured medicines, in-house pharmacies, and shortage of trained manpower. Since these implementation-impeding issues may differ considerably from those experienced in developed economies, intervention efforts in low- and middle-income countries (LMICs) need to address the context and focus on the root causes prevailing locally. In this article, we review the evidence highlighting the magnitude of these challenges and suggest feasible models with effective application. We also share the evidence from our center where we have contextualized the core elements to resource constrained settings. These domains include delivering prospective audit and feedback, prescriber education, development of evidence-based and implementable guidelines, and optimization of surgical antibiotic prophylaxis. However, there is a tremendous need for scaling up, extending outreach and honing these models while at the same time, addressing the existing strategic challenges that curtail the full potential of global antimicrobial stewardship.

Background: Establishment of a cancer registry is the first step in cancer control, and population-based cancer registries (PBCRs) are considered the gold standard for providing information on cancer incidence and mortality at population level. Materials and Methods: Earlier surveys reported a high prevalence of cancer in Punjab state. To address this issue and to provide reliable data on cancer incidence and mortality, four PBCRs were set up in Punjab and Chandigarh in year 2013 covering a total population of 4.5 million with PBCR Chandigarh and SAS Nagar, predominantly urban (covering 2.9 million population) and Mansa and Sangrur, predominantly rural (covering 2.6 million population). Results: Among males, Chandigarh and SAS Nagar have the age-standardized incidence rates (ASRs) of 93.5 and 73.5/100,000, respectively, whereas PBCR Mansa and Sangrur have age-standardized incidence rates (ASIRs) of only 45.3 and 43.7/100,000, respectively. Similarly, in females, PBCR Chandigarh and SAS Nagar have the ASIRs of 105.0 and 104.5/100,000, respectively, which was almost 2 times that seen at PBCR Mansa (55.8/100,000) and Sangrur (52.8/100,000). The incidence of breast cancer in females was 4–5 times higher in urban registries as compared to rural ones, whereas incidence of lung cancer was 4–7 times higher in urban registries. The most common cancer was lung cancer among males and breast cancer among females at PBCR Chandigarh and SAS Nagar, whereas it was esophagus among males and cervical cancer among females at PBCR Mansa and Sangrur. Conclusion: There were wider urban–rural differences with respect to incidence and pattern of cancers among the four registries which may be due to urbanization, lifestyle, and environmental factors which need to be explored further. Cancer incidence and pattern of cancer in Punjab are comparable with rest of the country.

BackgroundRecent trends of hospitalizations and in‐hospital mortality are not well defined in sarcoidosis. We examined aforementioned trends and prevalence of cardiovascular manifestations and explored rates of implantable cardioverter‐defibrillator implantation in hospitalizations with sarcoidosis. Methods and ResultsUsing data from the National Inpatient Sample, a retrospective population cohort from 2005 to 2014 was studied. To identify sarcoidosis, an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis code was used. We excluded hospitalizations with myocardial infarction, coronary artery disease, and ischemic cardiomyopathy. Cardiovascular manifestations were defined by the presence of diagnosis codes for conduction disorders, arrhythmias, heart failure, nonischemic cardiomyopathy, and pulmonary hypertension. A total of 609 051 sarcoidosis hospitalizations were identified, with an age of 55±14 years, 67% women, and 50% black. The number of sarcoidosis hospitalizations increased from 2005 through 2014 (138 versus 175 per 100 000, Ptrend

Introduction: Cytodiagnosis of CNS Space Occupying Lesions (SOLs) by squash smear preparation is a rapid, inexpensive and fairly accurate diagnostic tool. Most of the studies till date have proved its utility in intraoperative consultation. Aim: This study was undertaken to evaluate accuracy of squash smear cytology and to highlight as well as analyze the diagnostic pitfalls. Materials and Methods: This study was conducted in department of pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences. Intraoperative squash smears of two hundred and twenty two cases of CNS SOLs were studied. Cytological diagnoses were correlated with histopathological evaluation which was taken as gold standard. Discordant smears were reviewed and causes were analyzed. Results: An accuracy of 83.78% was achieved by squash smear cytology. The discrepancies due to interpretational errors were seen in 61.1% cases and sampling errors accounted for 38.9% cases. Cyto-histological discordance was noted more in oligodendrogliomas and grading of gliomas. Conclusion: Squash smear cytology is a fairly reliable diagnostic tool in intraoperative neuropathological consultation. Thorough sampling of tissue submitted, clinicoradiological correlation while reporting and awareness about the diagnostic pitfalls help in achieving reasonable accuracy

Multiple novel oral anticoagulants and left atrial appendage closure devices (WATCHMAN) have been tested against dose-adjusted vitamin K antagonists in randomized controlled trials for stroke prophylaxis in non-valvular atrial fibrillation. No direct comparisons of these strategies are available from randomized controlled trials. We conducted the current analyses by combining efficacy and safety characteristics of all FDA approved stroke prophylaxis treatment strategies for patients with non-valvular atrial fibrillation.We searched SCOPUS from 1945 till October 2015 for randomized controlled trials comparing these strategies and reporting efficacy and safety outcomes. Six randomized controlled trials were identified and included in the final analyses and review. We followed PRISMA guidelines for network meta-analyses while reporting the current analyses. We collected data on ischemic stroke, major bleeding, and the composite primary safety endpoint as defined by various randomized controlled trials. Network meta-analyses were conducted using consistency and inconsistency models for efficacy and safety outcomes. Surface under the cumulative ranking curve were then utilized to cluster rank these treatments for safety and efficacy.Six randomized controlled trials with 59,627 patients comparing six treatment strategies were eligible for the analyses. All prophylaxis strategies had comparable rates of ischemic stroke. Apixaban was associated with the least number of primary safety endpoint events as compared with all other treatments. In the cluster analyses assessing safety and efficacy, apixaban, edoxaban and dabigatran ranked best followed by vitamin K antagonists and rivaroxaban, whereas the WATCHMAN left atrial appendage closure device ranked last.Dose-adjusted vitamin K antagonists, novel oral anticoagulants, and the WATCHMAN left atrial appendage closure devices are equally efficacious for ischemic stroke prevention but these treatments have different safety profiles. More randomized controlled trials are needed to directly compare these strategies.

Background Significant controversy exists regarding the best approach for nonculprit vessel revascularization in patients with multivessel coronary artery disease presenting with ST‐segment elevation myocardial infarction. We conducted a systematic investigation to pool data from current randomized controlled trials (RCTs) to assess optimal treatment strategies in this patient population. Methods and Results A comprehensive search of SCOPUS from inception through May 2015 was performed using predefined criteria. We compared efficacy and safety outcomes of different approaches by categorizing the studies into 3 groups: (1) complete revascularization (CR) versus culprit lesion revascularization (CL) at index hospitalization, (2) CR at index hospitalization versus staged revascularization (SR) of nonculprit vessels at a separate hospitalization, and (3) comparison of SR versus CL. Eight eligible RCTs met the inclusion criteria: (1) CR versus CL (6 RCTs, n=1727) (2) CR versus SR (3 RCTs, n=311), and (3) SR versus CL (1 RCT, n=149). We observed significantly lower rates of major adverse cardiovascular events, revascularization, and repeat percutaneous coronary interventions among patients treated with CR and SR compared with a CL approach (P

The mRNA processing body (P-body) is a cellular structure that regulates the stability of cytoplasmic mRNA. MARF1 is a murine oocyte RNA-binding protein that is associated with maintenance of mRNA homeostasis and genomic stability. In this study, autoantibodies were used to identify Limkain B (LMKB), the human orthologue of MARF1, as a P-body component. Indirect immunofluorescence demonstrated that Ge-1 (a central component of the mammalian core-decapping complex) co-localized with LMKB in P-bodies. Two-hybrid and co-immunoprecipitation assays were used to demonstrate interaction between Ge-1 and LMKB. The C-terminal 120 amino acids of LMKB mediated interaction with Ge-1 and the N-terminal 1094 amino acids of Ge-1 were required for interaction with LMKB. LMKB is the first protein identified to date that interacts with this portion of Ge-1. LMKB was expressed in human B and T lymphocyte cell lines; depletion of LMKB increased expression of IFI44L, a gene that has been implicated in the cellular response to Type I interferons. The interaction between LMKB/MARF1, a protein that contains RNA-binding domains, and Ge-1, which interacts with core-decapping proteins, suggests that LMKB has a role in the regulation of mRNA stability. LMKB appears to have different functions in different cell types: maintenance of genomic stability in developing oocytes and possible dampening of the inflammatory response in B and T cells.

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1-deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.