Nanoscale protein architecture of the kidney glomerular basement membrane

In multicellular organisms, proteins of the extracellular matrix (ECM) play structural and functional roles in essentially all organs, so understanding ECM protein organization in health and disease remains an important goal. Here, we used sub-diffraction resolution stochastic optical reconstruction microscopy (STORM) to resolve the in situ molecular organization of proteins within the kidney glomerular basement membrane (GBM), an essential mediator of glomerular ultrafiltration. Using multichannel STORM and STORM-electron microscopy correlation, we constructed a molecular reference frame that revealed a laminar organization of ECM proteins within the GBM. Separate analyses of domains near the N- and C-termini of agrin, laminin, and collagen IV in mouse and human GBM revealed a highly oriented macromolecular organization. Our analysis also revealed disruptions in this GBM architecture in a mouse model of Alport syndrome. These results provide the first nanoscopic glimpse into the organization of a complex ECM. DOI: http://dx.doi.org/10.7554/eLife.01149.00

Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children.

BACKGROUND: Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections. METHODS: Plasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case-control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann-Whitney tests, log-rank tests for survival, and repeated measures ANOVA. RESULTS: In Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p \u3c 0.01; haemopexin, p \u3c 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p \u3c 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p \u3c 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p \u3c 0.05). CONCLUSIONS: These data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology

Low-calorie diets for people with isolated impaired fasting glucose

Standard lifestyle interventions prove ineffective in preventing type 2 diabetes among individuals with isolated impaired fasting glucose, a highly prevalent prediabetes phenotype globally. Here, we propose low-calorie diets as a promising strategy for diabetes prevention in this high-risk population

Cost-effectiveness of a lifestyle intervention in high-risk individuals for diabetes in a low- and middle-income setting:Trial-based analysis of the Kerala Diabetes Prevention Program

BACKGROUND: Data on the cost-effectiveness of lifestyle-based diabetes prevention programs are mostly from high-income countries, which cannot be extrapolated to low- and middle-income countries. We performed a trial-based cost-effectiveness analysis of a lifestyle intervention targeted at preventing diabetes in India. METHODS: The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial of 1007 individuals conducted in 60 polling areas (electoral divisions) in Kerala state. Participants (30-60 years) were those with a high diabetes risk score and without diabetes on an oral glucose tolerance test. The intervention group received a 12-month peer-support lifestyle intervention involving 15 group sessions delivered in community settings by trained lay peer leaders. There were also linked community activities to sustain behavior change. The control group received a booklet on lifestyle change. Costs were estimated from the health system and societal perspectives, with 2018 as the reference year. Effectiveness was measured in terms of the number of diabetes cases prevented and quality-adjusted life years (QALYs). Three times India's gross domestic product per capita (US$6108) was used as the cost-effectiveness threshold. The analyses were conducted with a 2-year time horizon. Costs and effects were discounted at 3$2.0 (intervention group: US$303.6; control group: US$301.6), incremental societal cost of US$6.2 (intervention group: US$367.8; control group: US$361.5), absolute risk reduction of 2.1$95.2, and the cost per QALY gained was US$50.0. From a societal perspective, the corresponding figures were US$295.1 and US$155.0. For the number of diabetes cases prevented, the probability for the intervention to be cost-effective was 84.0% and 83.1% from the health system and societal perspectives, respectively. The corresponding figures for QALY gained were 99.1% and 97.8%. The results were robust to discounting and sensitivity analyses. CONCLUSIONS: A community-based peer-support lifestyle intervention was cost-effective in individuals at high risk of developing diabetes in India over 2 years. TRIAL REGISTRATION: The trial was registered with Australia and New Zealand Clinical Trials Registry ( ACTRN12611000262909 ). Registered 10 March 2011

The coalition for conservation genetics: working across organizations to build capacity and achieve change in policy and practice

The Coalition for Conservation Genetics (CCG) brings together four eminentorganizations with the shared goal of improving the integration of geneticinformation into conservation policy and practice. We provide a historicalcontext of conservation genetics as a field and reflect on current barriers toconserving genetic diversity, highlighting the need for collaboration acrosstraditional divides, international partnerships, and coordinated advocacy. Wethen introduce the CCG and illustrate through examples how a coalitionapproach can leverage complementary expertise and improve the organiza-tional impact at multiple levels. The CCG has proven particularly successfulat implementing large synthesis-type projects, training early-career scientists,and advising policy makers. Achievements to date highlight the potential forthe CCG to make effective contributions to practical conservation policy andmanagement that no one“parent”organization could achieve on its own.Finally, we reflect on the lessons learned through forming the CCG, and ourvision for the futur

A peer-support lifestyle intervention for preventing type 2 diabetes in India: A cluster-randomized controlled trial of the Kerala Diabetes Prevention Program.

BACKGROUND: The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score. METHODS AND FINDINGS: The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30-60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66-1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater reduction in IDRS score (mean difference: -1.50 points, p = 0.022) and alcohol use (RR 0.77, p = 0.018) and a greater increase in fruit and vegetable intake (≥5 servings/day) (RR 1.83, p = 0.008) and physical functioning score of the HRQoL scale (mean difference: 3.9 score, p = 0.016). The cost of delivering the peer-support intervention was US$22.5 per participant. There were no adverse events related to the intervention. We did not adjust for multiple comparisons, which may have increased the overall type I error rate. CONCLUSIONS: A low-cost community-based peer-support lifestyle intervention resulted in a nonsignificant reduction in diabetes incidence in this high-risk population at 24 months. However, there were significant improvements in some cardiovascular risk factors and physical functioning score of the HRQoL scale. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12611000262909

Bringing together approaches to reporting on within species genetic diversity

1. Genetic diversity is one of the three main levels of biodiversity recognised in the Convention on Biological Diversity (CBD). Fundamental for species adaptation to environmental change, genetic diversity is nonetheless under-reported within global and national indicators. When it is reported, the focus is often narrow and confined to domesticated or other commercial species. 2. Several approaches have recently been developed to address this shortfall in reporting on genetic diversity of wild species. While multiplicity of approaches is helpful in any development process, it can also lead to confusion among policy makers and heighten a perception that conservation genetics is too abstract to be of use to organisations and governments. 3. As the developers of five of the different approaches, we have come together to explain how various approaches relate to each other and propose a scorecard, as a unifying reporting mechanism for genetic diversity. 4. Policy implications. We believe the proposed combined approach captures the strengths of its components and is practical for all nations and subnational governments. It is scalable and can be used to evaluate species conservation projects as well as genetic conservation projects.ISSN:0021-8901ISSN:1365-266

Global commitments to conserving and monitoring genetic diversity are now necessary and feasible

Global conservation policy and action have largely neglected protecting and monitoring genetic diversity—one of the three main pillars of biodiversity. Genetic diversity (diversity within species) underlies species’ adaptation and survival, ecosystem resilience, and societal innovation. The low priority given to genetic diversity has largely been due to knowledge gaps in key areas, including the importance of genetic diversity and the trends in genetic diversity change; the perceived high expense and low availability and the scattered nature of genetic data; and complicated concepts and information that are inaccessible to policymakers. However, numerous recent advances in knowledge, technology, databases, practice, and capacity have now set the stage for better integration of genetic diversity in policy instruments and conservation efforts. We review these developments and explore how they can support improved consideration of genetic diversity in global conservation policy commitments and enable countries to monitor, report on, and take action to maintain or restore genetic diversity

Supermarket/Hypermarket Opportunistic Screening for Atrial Fibrillation (SHOPS-AF) using sensors embedded in the handles of supermarket trolleys: A feasibility study

BackgroundAtrial fibrillation (AF) increases the risk of death, stroke, heart failure, cognitive decline, and healthcare costs but is often asymptomatic and undiagnosed. There is currently no national screening programme for AF. The advent of validated hand-held devices allows AF to be detected in non-healthcare settings, enabling screening to be undertaken within the community. Method and ResultsIn this novel observational study, we embedded a MyDiagnostick single lead ECG sensor into the handles of shopping trolleys in four supermarkets in the Northwest of England: 2155 participants were recruited. Of these, 231 participants either activated the sensor or had an irregular pulse, suggesting AF. Some participants agreed to use the sensor but refused to provide their contact details, or consent to pulse assessment. In addition, some data were missing, resulting in 203 participants being included in the final analyses. Fifty-nine participants (mean age 73.6 years, 43% female) were confirmed or suspected of having AF; 20 were known to have AF and 39 were previously undiagnosed. There was no evidence of AF in 115 participants and the remaining 46 recordings were non-diagnostic, mainly due to artefact. Men and older participants were significantly more likely to have newly diagnosed AF. Due to the number of non-diagnostic ECGs (n=46), we completed three levels of analyses, excluding all non-diagnostic ECGs, assuming all non-diagnostic ECGs were masking AF, and assuming all non-diagnostic ECGs were not AF. Based on the results of the three analyses, the sensor's sensitivity (95% CI) ranged from 0.70 - 0.93; specificity from 0.15 - 0.97; positive predictive values (PPV) and negative predictive values (NPV) ranged from 0.24 - 0.56 and 0.55-1.00, respectively. These values should be interpreted with caution, as the ideal reference standard on 1934 participants was imperfect. ConclusionThe study demonstrates that the public will engage with AF screening undertaken as part of their daily routines using hand-held devices. Sensors can play a key role in identifying asymptomatic patients in this way, but the technology must be further developed to reduce the quantity of non-diagnostic ECGs