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ObjectivesThe Modern Innovative Solutions to Improve Outcomes in Asthma, Breathlessness and Chronic Obstructive Pulmonary Disease (COPD) (MABC) service aimed to enhance disease management for chronic respiratory conditions through specialist multidisciplinary clinics, predominantly in the community. This study assesses the outcomes of these clinics.DesignThis study used a prospective, longitudinal, participatory action research approach.SettingThe study was conducted in primary care practices across Hampshire, UK.ParticipantsAdults aged 16 years and above with poorly controlled asthma or COPD, as well as those with undifferentiated breathlessness not under specialist care, were included.InterventionsParticipants received care through the multidisciplinary, specialist-led MABC clinics.Primary and secondary outcome measuresPrimary outcomes included disease activity, quality of life and healthcare utilisation. Secondary outcomes encompassed clinic attendance, diagnostic changes, patient activation, participant and healthcare professional experiences and cost-effectiveness.ResultsA total of 441 participants from 11 general practitioner practices were recruited. Ninety-six per cent of participants would recommend MABC clinics. MABC assessments led to diagnosis changes for 64 (17%) participants with asthma and COPD and treatment adjustments for 252 participants (57%). Exacerbations decreased significantly from 236 to 30 after attending the clinics (p<0.005), with a mean reduction of 0.53 exacerbation events per participant. Reductions were also seen in unscheduled and out-of-hours primary care attendance, emergency department visits and hospital admissions (all p<0.005). Cost savings from reduced exacerbations and healthcare utilisation offset increased medication costs and clinic expenses.ConclusionsSpecialist-supported multidisciplinary teams in MABC clinics improved diagnosis accuracy and adherence to guidelines. High patient satisfaction, disease control improvements and reduced exacerbations resulted in decreased unscheduled healthcare use and cost savings.Trial registration numberNCT03096509.

Hydrogen sulfide (H 2 S) has been shown to have a potential protective role in a number of disease states including diabetes and various kidney disorders; however, the mechanisms involved are still unclear. The aim of this study was to investigate if H 2 S effects the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in human kidney cells. Human mesangial cells and human podocytes were cultured at normal physiological glucose concentration (5.5 mM) and then treated with different H 2 S donors for a 24-h period. Protein was then extracted from the cells, and the expression levels of HO-1 determined by Western blotting. There was a significant increase in HO-1 expression after treatment with the H 2 S donors in both mesangial and podocyte cells. These results suggest that H 2 S has a role in the regulation of HO-1 expression, and the ability to upregulate this antioxidant enzyme maybe a potential mechanism by which H 2 S exerts its protective effects.

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Oxidative stress is a driver of acute and chronic kidney injury. Selonsertib is a clinical stage antagonist of ASK1 (MAP3K5), a serine/threonine kinase that is a mediator of oxidative stress signaling pathways. Selonsertib has demonstrated promising effects on preserving kidney function in the Phase2b Diabetic Kidney Disease (DKD) MOSAIC trial. However, little is known about the biological effects of ASK1 inhibition by selonsertib and its potential mechanism of action in DKD. We identified a plasma proteome signature of selonsertib activity that implicates numerous signaling pathways that regulate fibrosis, inflammation and oxidative stress response demonstrating translation of non-clinical models to the clinic. We further demonstrate that the effects of selonsertib on the plasma proteome are most pronounced in a subset of patients with poor baseline kidney function but who respond well to selonsertib treatment. This observation has implications for the future development of ASK1 inhibitors in a distinct patient population with DKD. Trial registration MOSAIC (NCT04026165 registered July 17, 2019).

The U.S. COVID-19 vaccination program began in December 2020, and ensuring equitable COVID-19 vaccine access remains a national priority.* COVID-19 has disproportionately affected racial/ethnic minority groups and those who are economically and socially disadvantaged (1,2). Thus, achieving not just vaccine equality (i.e., similar allocation of vaccine supply proportional to its population across jurisdictions) but equity (i.e., preferential access and administra-tion to those who have been most affected by COVID-19 disease) is an important goal. The CDC social vulnerability index (SVI) uses 15 indicators grouped into four themes that comprise an overall SVI measure, resulting in 20 metrics, each of which has national and state-specific county rankings. The 20 metric-specific rankings were each divided into lowest to highest tertiles to categorize counties as low, moderate, or high social vulnerability counties. These tertiles were combined with vaccine administration data for 49,264,338 U.S. residents in 49 states and the District of Columbia (DC) who received at least one COVID-19 vaccine dose during December 14, 2020-March 1, 2021. Nationally, for the overall SVI measure, vaccination coverage was higher (15.8%) in low social vulnerability counties than in high social vulnerability counties (13.9%), with the largest coverage disparity in the socioeconomic status theme (2.5 percentage points higher coverage in low than in high vulnerability counties). Wide state variations in equity across SVI metrics were found. Whereas in the majority of states, vaccination coverage was higher in low vulnerability counties, some states had equitable coverage at the county level. CDC, state, and local jurisdictions should continue to monitor vaccination coverage by SVI metrics to focus public health interventions to achieve equitable coverage with COVID-19 vaccine.

The breathtaking rise in the number of start-up banks is finally showing signs of leveling off. So far this year, 216 applications to insure a new bank or thrift have been filed with the Federal Deposit Insurance Corp. At this rate, 355 applications would be filed this year, 4% below last year. Since 1992, applications for insurance have increased an average of nearly 34% a year, according to the FDIC. Florida, with 21 applications pending, and Georgia, with 18, are still by far the leaders in projected start-ups. But the rate of growth is much smaller than in the past few years.

United Bancshares of El Dorado said last week that it had terminated its $23 million deal for another Arkansas company, Mountain Bancshares of Yellville. United has $2.4 billion of assets and owns 13 banks in Arkansas, Texas, and Louisiana. Mountain has $115 million of assets.

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible. Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.