Hyperglycemia Has a Greater Impact on Left Ventricle Function in South Asians Than in Europeans

OBJECTIVE Diabetes is associated with left ventricular (LV) diastolic and systolic dysfunction. South Asians may be at particular risk of developing LV dysfunction owing to a high prevalence of diabetes. We investigated the role of diabetes and hyperglycemia in LV dysfunction in a community-based cohort of older South Asians and white Europeans. RESEARCH DESIGN AND METHODS Conventional and Doppler echocardiography was performed in 999 participants (542 Europeans and 457 South Asians aged 58–86 years) in a population-based study. Anthropometry, fasting bloods, coronary artery calcification scoring, blood pressure, and renal function were measured. RESULTS Diabetes and hyperglycemia across the spectrum of HbA1c had a greater adverse effect on LV function in South Asians than Europeans (N-terminal-probrain natriuretic peptide β ± SE 0.09 ± 0.04, P = 0.01, vs. −0.04 ± 0.05, P = 0.4, P for HbA1c/ethnicity interaction 0.02), diastolic function (E/e′ 0.69 ± 0.12, P < 0.0001, vs. 0.09 ± 0.2, P = 0.6, P for interaction 0.005), and systolic function (s′ −0.11 ± 0.06, P = 0.04, vs. 0.14 ± 0.09, P = 0.1, P for interaction 0.2). Multivariable adjustment for hypertension, microvascular disease, LV mass, coronary disease, and dyslipidemia only partially accounted for the ethnic differences. Adverse LV function in diabetic South Asians could not be accounted for by poorer glycemic control or longer diabetes duration. CONCLUSIONS Diabetes and hyperglycemia have a greater adverse effect on LV function in South Asians than Europeans, incompletely explained by adverse risk factors. South Asians may require earlier and more aggressive treatment of their cardiometabolic risk factors to reduce risks of LV dysfunction

Handling polymorphic algebraic effects

Algebraic effects and handlers are a powerful abstraction mechanism to represent and implement control effects. In this work, we study their extension with parametric polymorphism that allows abstracting not only expressions but also effects and handlers. Although polymorphism makes it possible to reuse and reason about effect implementations more effectively, it has long been known that a naive combination of polymorphic effects and let-polymorphism breaks type safety. Although type safety can often be gained by restricting let-bound expressions---e.g., by adopting value restriction or weak polymorphism---we propose a complementary approach that restricts handlers instead of let-bound expressions. Our key observation is that, informally speaking, a handler is safe if resumptions from the handler do not interfere with each other. To formalize our idea, we define a call-by-value lambda calculus that supports let-polymorphism and polymorphic algebraic effects and handlers, design a type system that rejects interfering handlers, and prove type safety of our calculus.Comment: Added the errata for the ESOP'19 paper (page 28

Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders.

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways

A brief look at the history of the Deaconess Hospital, Edinburgh, 1894–1990

The Deaconess Hospital, Edinburgh, opened in 1894 and was the first establishment of its kind in the UK, maintained and wholly funded as it was by the Reformed Church. Through its 96-year lifetime it changed and evolved to time and circumstance. It was a school: for the training of nurses and deaconesses who took their practical skills all over the world. It was a sanctum: for the sick-poor before the NHS. It was a subsidiary: for the bigger hospitals of Edinburgh after amalgamation into the NHS. It was a specialised centre: as the Urology Department in Edinburgh and the Scottish Lithotripter centre. And now it is currently student accommodation. There is no single source to account for its history. Through the use of original material made available by the Lothian Health Services Archives – including Church of Scotland publications, patient records, a doctor’s casebook and annual reports – we review its conception, purpose, development and running; its fate on joining the NHS, its identity in the latter years and finally its closure

Functional Big-step Semantics

When doing an interactive proof about a piece of software, it is important that the underlying programming language’s semantics does not make the proof unnecessarily difficult or unwieldy. Both smallstep and big-step semantics are commonly used, and the latter is typically given by an inductively defined relation. In this paper, we consider an alternative: using a recursive function akin to an interpreter for the language. The advantages include a better induction theorem, less duplication, accessibility to ordinary functional programmers, and the ease of doing symbolic simulation in proofs via rewriting. We believe that this style of semantics is well suited for compiler verification, including proofs of divergence preservation. We do not claim the invention of this style of semantics: our contribution here is to clarify its value, and to explain how it supports several language features that might appear to require a relational or small-step approach. We illustrate the technique on a simple imperative language with C-like for-loops and a break statement, and compare it to a variety of other approaches. We also provide ML and lambda-calculus based examples to illustrate its generality

Transformations between WISE, 2MASS, SDSS and BVRI photometric systems: I. Transformation equations for dwarfs

We present colour transformations for the conversion of the W1 and W2 magnitudes of WISE photometric system to the Johnson-Cousins' BVRI, SDSS (gri), and 2MASS (JHK_s) photometric systems, for dwarfs. The W3 and W4 magnitudes were not considered due to their insufficient signal to noise ratio (S/N). The coordinates of 825 dwarfs along with their BVRI, gri, and JHK_s data, taken from Bilir et al. (2008) were matched with the coordinates of stars in the preliminary data release of WISE (Wright et al., 2010) and a homogeneous dwarf sample with high S/N ratio have been obtained using the following constraints: 1) the data were dereddened, 2) giants were identified and excluded from the sample, 3) sample stars were selected according to data quality, 4) transformations were derived for sub samples of different metallicity range, and 5) transformations are two colour dependent. These colour transformations, coupled with known absolute magnitudes at shorter wavelenghts, can be used in space density evaluation for the Galactic (thin and thick) discs, at distances larger than the ones evaluated with JHK_s photometry.Comment: 16 pages, including 5 figures and 7 tables, accepted for publication in MNRA

The N-terminal intrinsically disordered domain of mgm101p is localized to the mitochondrial nucleoid.

The mitochondrial genome maintenance gene, MGM101, is essential for yeasts that depend on mitochondrial DNA replication. Previously, in Saccharomyces cerevisiae, it has been found that the carboxy-terminal two-thirds of Mgm101p has a functional core. Furthermore, there is a high level of amino acid sequence conservation in this region from widely diverse species. By contrast, the amino-terminal region, that is also essential for function, does not have recognizable conservation. Using a bioinformatic approach we find that the functional core from yeast and a corresponding region of Mgm101p from the coral Acropora millepora have an ordered structure, while the N-terminal domains of sequences from yeast and coral are predicted to be disordered. To examine whether ordered and disordered domains of Mgm101p have specific or general functions we made chimeric proteins from yeast and coral by swapping the two regions. We find, by an in vivo assay in S.cerevisiae, that the ordered domain of A.millepora can functionally replace the yeast core region but the disordered domain of the coral protein cannot substitute for its yeast counterpart. Mgm101p is found in the mitochondrial nucleoid along with enzymes and proteins involved in mtDNA replication. By attaching green fluorescent protein to the N-terminal disordered domain of yeast Mgm101p we find that GFP is still directed to the mitochondrial nucleoid where full-length Mgm101p-GFP is targeted

The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project: An open-label pragmatic randomised control trial comparing the efficacy of differing therapeutic agents for primary care detoxification from either street heroin or methadone [ISRCTN07752728]

BACKGROUND: Heroin is a synthetic opioid with an extensive illicit market leading to large numbers of people becoming addicted. Heroin users often present to community treatment services requesting detoxification and in the UK various agents are used to control symptoms of withdrawal. Dissatisfaction with methadone detoxification [8] has lead to the use of clonidine, lofexidine, buprenorphine and dihydrocodeine; however, there remains limited evaluative research. In Leeds, a city of 700,000 people in the North of England, dihydrocodeine is the detoxification agent of choice. Sublingual buprenorphine, however, is being introduced. The comparative value of these two drugs for helping people successfully and comfortably withdraw from heroin has never been compared in a randomised trial. Additionally, there is a paucity of research evaluating interventions among drug users in the primary care setting. This study seeks to address this by randomising drug users presenting in primary care to receive either dihydrocodeine or buprenorphine. METHODS/DESIGN: The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project is a pragmatic randomised trial which will compare the open use of buprenorphine with dihydrocodeine for illicit opiate detoxification, in the UK primary care setting. The LEEDS project will involve consenting adults and will be run in specialist general practice surgeries throughout Leeds. The primary outcome will be the results of a urine opiate screening at the end of the detoxification regimen. Adverse effects and limited data to three and six months will be acquired

Diagnostic accuracy of the Abbott ID NOW SARS-CoV-2 rapid test for the triage of acute medical admissions

Background: Decisions to isolate patients at risk of having coronavirus disease 2019 (COVID-19) in the emergency department (ED) must be rapid and accurate to ensure prompt treatment and maintain patient flow whilst minimising nosocomial spread. Reverse transcription polymerase chain reaction (RT-PCR) assays are too slow to achieve this, and near-patient testing is being used increasingly to facilitate triage. The ID NOW severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) assay is an isothermal nucleic acid amplification near-patient test which targets the RNA-dependent RNA-polymerase gene. Aim: To assess the diagnostic performance of ID NOW as a COVID-19 triage tool for medical admissions from the ED of a large acute hospital. Methods: All adult acute medical admissions from the ED between 31st March and 31st July 2021 with valid ID NOW and RT-PCR results were included. The diagnostic accuracy of ID NOW [sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)] was calculated against the laboratory reference standard. Discrepant results were explored further using cycle threshold values and clinical data. Findings: Two percent (124/6050) of medical admissions were SARS-CoV-2 positive on RT-PCR. Compared with PCR, ID NOW had sensitivity and specificity of 83.1% [95% confidence interval (CI) 75.4–88.7] and 99.5% (95% CI 99.3–99.6), respectively. PPV and NPV were 76.9% (95% CI 69.0–83.2) and 99.6% (95% CI 99.5–99.8), respectively. The median time from arrival in the ED to ID NOW result was 59 min. Conclusion: ID NOW provides a rapid and reliable adjunct for the safe triage of patients with COVID-19, and can work effectively when integrated into an ED triage algorithm

The ‘SELection End points in Communities of bacTeria’ (SELECT) Method: A Novel Experimental Assay to Facilitate Risk Assessment of Selection for Antimicrobial Resistance in the Environment

This is the final version. Available on open access from NIEHS via the DOI in this recordBackground: Antimicrobial resistance (AMR) is one of the most significant health threats to society. A growing body of research demonstrates selection for AMR likely occurs at environmental concentrations of antibiotics. However, no standardized experimental approaches for determining selective concentrations of antimicrobials currently exist, preventing appropriate environmental and human health risk assessment of AMR. Objectives: We aimed to design a rapid, simple, and cost-effective novel experimental assay to determine selective effect concentrations of antibiotics and to generate the largest experimental data set of selective effect concentrations of antibiotics to date. Methods: Previously published methods and data were used to validate the assay, which determines the effect concentration based on reduction of bacterial community (wastewater) growth. Risk quotients for test antibiotics were generated to quantify risk. Results: The assay (SELection End points in Communities of bacTeria, or the SELECT method) was used to rapidly determine selective effect concentrations of antibiotics. These were in good agreement with quantitative polymerase chain reaction effect concentrations determined within the same experimental system. The SELECT method predicted no effect concentrations were minimally affected by changes in the assay temperature, growth media, or microbial community used as the inoculum. The predicted no effect concentrations for antibiotics tested ranged from 0.05μg/L for ciprofloxacin to 1,250μg/L for erythromycin. Discussion: The lack of evidence demonstrating environmental selection for AMR, and of associated human health risks, is a primary reason for the lack of action in the mitigation of release of antibiotics into the aquatic environment. We present a novel method that can reliably and rapidly fill this data gap to enable regulation and subsequent mitigation (where required) to lower the risk of selection for, and human exposure to, AMR in aquatic environments. In particular, ciprofloxacin and, to a lesser extent, azithromycin, cefotaxime, and trimethoprim all pose a significant risk for selection of AMR in the environment. https://doi.org/10.1289/EHP6635Biotechnology and Biological Sciences Research Council (BBSRC)AstraZeneca Collaborative Awards in Science and Engineering studentshipNatural Environment Research Council (NERC)Nuffield Foundatio