APOL1 risk alleles are associated with exaggerated age-related changes in glomerular number and volume in African-American adults: an autopsy study

APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N-glom,) and mean glomerular volume (V-glom,) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N-glom and increases in V-glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of >= 30 kg/m(2), enhanced the expression of age-related changes in N-glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans

Optimising recruitment into trials using an internal pilot

Abstract Background Recruitment to trials can be difficult. Despite careful planning and research that outlines ways to improve recruitment, many trials do not achieve their target on time and require extensions of funding or time. Methods We describe a trial in which an internal pilot with embedded qualitative research was used to improve recruitment processes and inform recruitment projections for the main trial. At the end of the pilot, it was clear that the sample size would not be met on time. Three steps were taken to optimise recruitment: (1) adjustments were made to the recruitment process using information from the qualitative work done in the pilot and advice from a patient and public involvement group, (2) additional recruiting sites were included based on site feasibility assessments and (3) a projection equation was used to estimate recruitment at each site and overall trial recruitment. Results Qualitative work during the pilot phase allowed us to develop strategies to optimise recruitment during the main trial, which were incorporated into patient information packs, the standard operating procedures and training sessions with recruiters. From our experience of feasibility assessments, we developed a checklist of recommended considerations for feasibility assessments. For recruitment projections, we developed a four-stage projection equation that estimates the number of participants recruited using a conversion rate of the number randomised divided by the number screened. Conclusions This work provides recommendations for feasibility assessments and an easy-to-use projection tool, which can be applied to other trials to help ensure they reach the required sample size. Trial registration ISRCTN, ISRCTN92545361. Registered on 6 September 2016

Understanding employers' graduate recruitment and selection practices. BIS Research Paper 231.

This research examined the approach to graduate recruitment adopted by employers and how this has evolved in recent years. In particular the study aimed to explore patterns in graduate recruitment, behaviours of graduate employers and interactions between graduate employers and universities. It therefore provides a picture of long-term trends in practice from pre-recruitment activities through to entry, induction and beyond, and before, during and after the recession; and indicates the ways in which employers’ thinking about recruitment and selection have, and are, changing and developing. The research was driven by a need to update the evidence and understanding of recruitment practice as the population of graduates has increased dramatically and become more heterogeneous; the labour market has changed, emerging from difficult economic conditions; and there is increasing policy interest in diversity and particularly in social mobility.Department for Business, Innovation and Skills

Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition

Specific criteria have been established to define the occurrence of myocardial infarction (MI) and stroke in cardiovascular clinical trials, but there is not a consistent definition for heart failure. Heart failure events appear to occur at a rate that is similar to stroke and MI in trials of hypertension, hyperlipidaemia, diabetes, and coronary heart disease, yet a consistent approach to defining heart failure events has not yet been realized. The wide range of definitions used in clinical trials makes it difficult to interpret new data in the context of existing literature. This inconsistency has led to challenges in determining the incidence of heart failure in cardiovascular studies and the effects of interventions on these endpoints. This paper examines issues related to defining heart failure events in cardiovascular clinical trials and presents a definition to formally address this issu

Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed

A quasi-elastic light scattering study of smooth muscle myosin in the presence of ATP

We have investigated the hydrodynamic properties of turkey gizzard smooth muscle myosin in solution using quasi-elastic light scattering (QELS). The effects of ionic strength (0.05–0.5 M KCl) and light chain phosphorylation on the conformational transition of myosin were examined in the presence of ATP at 20 degrees C. Cumulant analysis and light scattering models were used to describe the myosin system in solution. A nonlinear least squares fitting procedure was used to determine the model that best fits the data. The conformational transition of the myosin monomer from a folded form to an extended form was clearly demonstrated in a salt concentration range of 0.15–0.3 M KCl. Light chain phosphorylation regulates the transition and promotes unfolding of the myosin. These results agree with the findings obtained using sedimentation velocity and electron microscopy (Onishi and Wakabayashi, 1982; Trybus et al., 1982; Trybus and Lowey, 1984). In addition, we present evidence for polymeric myosin coexisting with the two monomeric myosin species over a salt concentration range from 0.05 to 0.5 M KCl. The size of the polymeric myosin varied with salt concentration. This observation supports the hypothesis that, in solution, a dynamic equilibrium exists between the two conformations of myosin monomer and filaments

A chronic disease outreach program for Aboriginal communities

Background. Our objective is to describe a program to improve awareness and management of hypertension, renal disease, and diabetes in 3 remote Australian Aboriginal communities. Methods. The program espouses that regular integrated checks for chronic disease and their risk factors are essential elements of regular adult health care. Programs should be run by local health workers, following algorithms for testing and treatment, with backup, usually from a distance, from nurse coordinators. Constant evaluation is essential to develop community health profiles and adapt program structure. Results. Participation ranged from 65% to 100% of adults. Forty-one percent of women and 72% of men were current smokers. Body weight varied markedly by community. Although excessive in all, rates of chronic diseases also differed markedly among communities. Rates increased with age, but the greatest numbers of people with morbidities were middle age and young adults. Multiple morbidities were common by middle age. Hypertension and renal disease were early features, whereas diabetes was a variable and later manifestation of this integrated chronic disease syndrome. Adherence to testing and treatment protocols improved markedly over time. Substantial numbers of new diagnoses were made. Blood pressure improved in people in whom antihypertensive agents were started or increased. Components of a systematic activity plan became more clearly defined with time. Treatment of people in the community with the greatest disease burden posed a large additional workload. Lack of health workers and absenteeism were major impediments to productivity. Conclusion. We cannot generalize about body habitus, and chronic disease rates among Aboriginal adults. Pilot data are needed to plan resources based on the chronic disease burden in each community. Systematic screening is useful in identifying high-risk individuals, most at an early treatable stage. Community-based health profiles provide critical information for the development of rational health policy and needs-based health services

The STAR care pathway for patients with pain at 3 months after total knee replacement:a multicentre, pragmatic randomised controlled trial

BACKGROUND: Approximately 20% of people experience chronic pain after total knee replacement, but effective treatments are not available. We aimed to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for chronic pain after total knee replacement. METHODS: We did an unmasked, parallel group, pragmatic, superiority, randomised, controlled trial at eight UK National Health Service (NHS) hospitals. People with chronic pain at 3 months after total knee replacement surgery were randomly assigned (2:1) to the Support and Treatment After Replacement (STAR) care pathway plus usual care, or to usual care alone. The STAR intervention aimed to identify underlying causes of chronic pain and enable onward referrals for targeted treatment through a 3-month post-surgery assessment with an extended scope practitioner and telephone follow-up over 12 months. Co-primary outcomes were self-reported pain severity and pain interference in the replaced knee, assessed with the Brief Pain Inventory (BPI) pain severity and interference scales at 12 months (scored 0–10, best to worst) and analysed on an as-randomised basis. Resource use, collected from electronic hospital records and participants, was valued with UK reference costs. Quality-adjusted life-years (QALYs) were calculated from EQ-5D-5L responses. This trial is registered with ISRCTN, ISRCTN92545361. FINDINGS: Between Sept 6, 2016, and May 31, 2019, 363 participants were randomly assigned to receive the intervention plus usual care (n=242) or to receive usual care alone (n=121). Participants had a median age of 67 years (IQR 61 to 73), 217 (60%) of 363 were female, and 335 (92%) were White. 313 (86%) patients provided follow-up data at 12 months after randomisation (213 assigned to the intervention plus usual care and 100 assigned to usual care alone). At 12 months, the mean between-group difference in the BPI severity score was −0·65 (95% CI −1·17 to −0·13; p=0·014) and the mean between-group difference in the BPI interference score was −0·68 (−1·29 to −0·08; p=0·026), both favouring the intervention. From an NHS and personal social services perspective, the intervention was cost-effective (greater improvement with lower cost), with an incremental net monetary benefit of £1256 (95% CI 164 to 2348) at £20 000 per QALY threshold. One adverse reaction of participant distress was reported in the intervention group. INTERPRETATION: STAR is a clinically effective and cost-effective intervention to improve pain outcomes over 1 year for people with chronic pain at 3 months after total knee replacement surgery. FUNDING: National Institute for Health Research

Podocyte number in children and adults: associations with glomerular size and numbers of other glomerular resident cells

Increases in glomerular size occur with normal body growth and in many pathologic conditions. In this study, we determined associations between glomerular size and numbers of glomerular resident cells, with a particular focus on podocytes. Kidneys from 16 male Caucasian-Americans without overt renal disease, including 4 children (= 18 years old), were collected at autopsy in Jackson, Mississippi. We used a combination of immunohistochemistry, confocal microscopy, and design-based stereology to estimate individual glomerular volume (IGV) and numbers of podocytes, nonepithelial cells (NECs; tuft cells other than podocytes), and parietal epithelial cells (PECs). Podocyte density was calculated. Data are reported as medians and interquartile ranges (IQRs). Glomeruli from children were small and contained 452 podocytes (IQR=335-502), 389 NECs (IQR=265-498), and 146 PECs (IQR=111-206). Adult glomeruli contained significantly more cells than glomeruli from children, including 558 podocytes (IQR=431-746;