The use of electronic voting systems in large group lectures: Challenges and opportunities

We describe pedagogical, technical and operational issues associated with the introduction of an electronic voting system into large first-year undergraduate lectures. The rationale for doing so is to transform the lecture experience from a one-way transmission of information in to a two-way conversation between lecturer and students, mediated by the technology. We discuss some of the logistics involved, such as choice of handset, cost and siting within a lecture theatre as well as the aspects of pedagogy, such as the requirements of a good question for these interactive episodes. We present a number of possible use scenarios and evaluate student and staff experiences of the process

Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesio11See Editorial by Haas,P. 1188.

Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion.BackgroundSeveral entities or variants within focal segmental glomerulosclerosis (FSGS) have been described, but their changes with time and interrelationships are undetermined.MethodsChanges with time were studied in two series of segmental sclerosing lesions in the nephrotic syndrome, one of 22 specimens from ten patients in a trial, the other of 176 specimens from 121 consecutive patients.ResultsThe earliest lesions were probably all at the tubular origin, equivalent to the tip variant of FSGS. In some patients, lesions remained at this site, but progression to renal failure was accompanied by morphologic progression, with development of lesions at various sites, equivalent to FSGS, not otherwise specified (NOS). Progression was more likely if there were large lesions, abnormal mesangium, and extensive acute tubular damage. Patients with lesions at the tubular origin at presentation had a shorter duration of symptoms and less chronic renal damage than those with multiple lesions, were more likely to have a complete response of the nephrotic syndrome, and were less likely to progress to renal failure. Recurrent nephrotic syndrome occurred in 12 of 14 allografts at risk, and was usually accompanied by lesions at the tubular origin, then multiple lesions.ConclusionAt least some patients with FSGS (NOS) have evolved from the tip variant. The tip variant has been considered a distinct entity. Another interpretation is that it includes two conditions, one an early form of classic FSGS, and the other closely related to minimal change nephropathy (MCN), equivalent to the glomerular tip lesion as originally defined

Hydrogen at extreme pressures (Review Article)

Here we review recent experimental and theoretical studies of hydrogen approaching metallization regime. Ex-perimental techniques have made great advances over the last several years making it possible to reach previously unachievable conditions of pressure and temperature and to probe hydrogen at these conditions. Theoretical me-thods have also greatly improved; exemplified through the prediction of new structural and ordered quantum states. Recently, a new solid phase of hydrogen, phase IV, has been discovered in a high-pressure high-temperature do-main. This phase is quite unusual structurally and chemically as it represents an intermediate state between common molecular and monatomic configurations. Moreover, it shows remarkable fluxional characteristics related to its quantum nature, which makes it unique among the solid phases, even of light elements. However, phase IV shows the presence of a band gap and exhibits distinct phonon and libron characteristic of classical solids. The quantum behavior of hydrogen in the limit of very high pressure remains an open question. Prospects of studying hydrogen at more extreme conditions by static and combined static-dynamic methods are also presented

CD248+ stromal cells are associated with progressive chronic kidney disease

Stromal fibroblasts are the primary cells of the kidney that produce fibrotic matrix. CD248 is a stromal marker expressed on fibroblasts and pericytes within the human kidney. Here, we tested whether CD248 expression in the kidney colocalizes with fibrosis and if it is associated with known determinants of chronic kidney disease (CKD). CD248 expression was located and quantified in situ by immunohistochemistry in kidney biopsies from 93 patients with IgA nephropathy and compared with 22 archived biopsies encompassing normal kidney tissue as control. In normal kidney tissue, CD248 was expressed by resident pericytes, stromal fibroblasts, and was upregulated in human CKD. The expression was linked to known determinants of renal progression. This relationship was maintained in a multivariate analysis with CD248 expression linked to renal survival. CD248 was expressed by a population of α-smooth muscle actin (SMA)+ myofibroblasts and α-SMA− stromal cells but not expressed on CD45+ leukocytes. Thus, CD248 defines a subset of stromal cells, including but not limited to some myofibroblasts, linked to albuminuria and tubulointerstitial damage during tissue remodeling in CKD

Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans

Background: While it has long been recognized that smooth muscle Na/K ATPase (NKA) modulates vascular tone and blood pressure (BP), the role of its accessory protein phopholemman (PLM) has not been characterized. The aim of this study was to test the hypothesis that PLM phosphorylation regulates vascular tone in vitro and this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in man. Methods: Mouse studies: PLM knock-in mice (PLM3SA), in which PLM is rendered unphosphorylatable, were used to assess the role of PLM phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type (WT) and transgenic mice. Human studies: We searched human genomic databases for mutations in PLM in the region of the phosphorylation sites and performed analyses within two human data cohorts (UK Biobank and GoDARTS) to assess the impact of an identified SNP on BP. This SNP was expressed in HEK cells and its effect on PLM phosphorylation determined using Western Blotting. Results: PLM phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of PLM phosphorylation in the PLM3SA mouse profoundly enhanced vascular responses to PE both in vitro and in vivo. In ageing WT mice PLM was hypophosphorylated and this correlated with the development of ageing-induced essential hypertension. In man we identified a non-synonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in PLM. In HEK cells the R70C mutation prevented PLM phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men. Conclusions: These studies demonstrate the importance of PLM phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for ageing-induced essential hypertension in man

Detection of Highly Pathogenic Avian Influenza Virus H5N1 Clade 2.3.4.4b in Great Skuas:A Species of Conservation Concern in Great Britain

The UK and Europe have seen successive outbreaks of highly pathogenic avian influenza across the 2020/21 and 2021/22 autumn/winter seasons. Understanding both the epidemiology and transmission of these viruses in different species is critical to aid mitigating measures where outbreaks cause extensive mortalities in both land- and waterfowl. Infection of different species can result in mild or asymptomatic outcomes, or acute infections that result in high morbidity and mortality levels. Definition of disease outcome in different species is of great importance to understanding the role different species play in the maintenance and transmission of these pathogens. Further, the infection of species that have conservation value is also important to recognise and characterise to understand the impact on what might be limited wild populations. Highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b has been detected in great skuas (Stercorarius skua) across different colonies on islands off the shore of Scotland, Great Britain during summer 2021. A large number of great skuas were observed as developing severe clinical disease and dying during the epizootic and mortalities were estimated to be high where monitored. Of eight skuas submitted for post-mortem examination, seven were confirmed as being infected with this virus using a range of diagnostic assays. Here we overview the outbreak event that occurred in this species, listed as species of conservation concern in Great Britain and outline the importance of this finding with respect to virus transmission and maintenance

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

Background. In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. Methods. An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. Results. We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3mg/dl (114.9 μmol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m2 and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. Conclusions. The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropath

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression