Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data

Objectives To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. Methods Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. Participants Males and females aged 45–74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. Intervention Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. Results One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. Conclusions ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. Registration - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39Peer reviewe

What do the Universal Test and Treat Trials tell us about the path to HIV epidemic control?

Introduction Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population‐based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub‐Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90‐90‐90 campaign. Discussion These three‐year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community‐based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient‐centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population‐level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub‐populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured. Conclusions These trials provide strong evidence that UTT inclusive of universal testing increases population‐level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub‐country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets

Single nucleotide polymorphisms and breast cancer: not yet a success story

Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance. The failure to identify meaningful common genetic variation in relation to breast cancer should give us pause for thought and make us reconsider our current research strategies. The most recent directions of pooling samples to increase statistical power and pursuing whole genome screens may overcome some obstacles while also creating new challenges. Future studies should perhaps also consider alternative designs such as using surrogate (preferably continuous) markers of breast cancer, focusing on high-risk populations, and defining pathologically distinct outcomes

Single nucleotide polymorphisms and breast cancer: not yet a success story

Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance. The failure to identify meaningful common genetic variation in relation to breast cancer should give us pause for thought and make us reconsider our current research strategies. The most recent directions of pooling samples to increase statistical power and pursuing whole genome screens may overcome some obstacles while also creating new challenges. Future studies should perhaps also consider alternative designs such as using surrogate (preferably continuous) markers of breast cancer, focusing on high-risk populations, and defining pathologically distinct outcomes

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Generating samples for association studies based on HapMap data

<p>Abstract</p> <p>Background</p> <p>With the completion of the HapMap project, a variety of computational algorithms and tools have been proposed for haplotype inference, tag SNP selection and genome-wide association studies. Simulated data are commonly used in evaluating these new developed approaches. In addition to simulations based on population models, empirical data generated by perturbing real data, has also been used because it may inherit specific properties from real data. However, there is no tool that is publicly available to generate large scale simulated variation data by taking into account knowledge from the HapMap project.</p> <p>Results</p> <p>A computer program (<it>gs</it>) was developed to quickly generate a large number of samples based on real data that are useful for a variety of purposes, including evaluating methods for haplotype inference, tag SNP selection and association studies. Two approaches have been implemented to generate dense SNP haplotype/genotype data that share similar local <it>linkage disequilibrium </it>(LD) patterns as those in human populations. The first approach takes haplotype pairs from samples as inputs, and the second approach takes patterns of haplotype block structures as inputs. Both quantitative and qualitative traits have been incorporated in the program. Phenotypes are generated based on a disease model, or based on the effect of a quantitative trait nucleotide, both of which can be specified by users. In addition to single-locus disease models, two-locus disease models have also been implemented that can incorporate any degree of epistasis. Users are allowed to specify all nine parameters in a 3 × 3 penetrance table. For several commonly used two-locus disease models, the program can automatically calculate penetrances based on the population prevalence and marginal effects of a disease that users can conveniently specify.</p> <p>Conclusion</p> <p>The program <it>gs </it>can effectively generate large scale genetic and phenotypic variation data that can be used for evaluating new developed approaches. It is freely available from the authors' web site at <url>http://www.eecs.case.edu/~jxl175/gs.html</url>.</p

Tag SNP selection for Finnish individuals based on the CEPH Utah HapMap database

The pattern and nature of linkage disequilibrium in the human genome is being studied and catalogued as part of the International HapMap Project [:2003 Nature 426:789–796]. A key goal of the HapMap Project is to enable identification of tag single nucleotide polymorphisms (SNPs) that capture a substantial portion of common human genetic variability while requiring only a small fraction of SNPs to be genotyped [International HapMap Consortium, 2005: Nature 437:1299–1320]. In the current study, we examined the effectiveness of using the CEU HapMap database to select tag SNPs for a Finnish sample. We selected SNPs in a 17.9-Mb region of chromosome 14 based on pairwise linkage disequilibrium (r 2 ) estimates from the HapMap CEU sample, and genotyped 956 of these SNPs in 1,425 Finnish individuals. An excess of SNPs showed significantly different allele frequencies between the HapMap CEU and the Finnish samples, consistent with population-specific differences. However, we observed strong correlations between the two samples for estimates of allele frequencies, r 2 values, and haplotype frequencies. Our results demonstrate that the HapMap CEU samples provide an adequate basis for tag SNP selection in Finnish individuals, without the need to create a map specifically for the Finnish population, and suggest that the four-population HapMap data will provide useful information for tag SNP selection beyond the specific populations from which they were sampled. Genet. Epidemiol . 2006. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49528/1/20131_ftp.pd

The chronic neuropsychiatric sequelae of COVID?19: The need for a prospective study of viral impact on brain functioning

IntroductionThe increasing evidence of SARS‐CoV‐2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia.MethodsThe Alzheimer's Association and representatives from more than 30 countries—with technical guidance from the World Health Organization—have formed an international consortium to study the short‐and long‐term consequences of SARS‐CoV‐2 on the CNS—including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID‐19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow‐up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology.ConclusionsThe increasing evidence and understanding of SARS‐CoV‐2's impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This program of studies aims to better understand the long‐term consequences that may impact the brain, cognition, and functioning—including the underlying biology that may contribute to AD and other dementias

ICTV virus taxonomy profile: Ophioviridae

The Ophioviridae is a family of filamentous plant viruses, with single-stranded negative, and possibly ambisense, RNA genomes of 11.3-12.5 kb divided into 3-4 segments, each encapsidated separately. Virions are naked filamentous nucleocapsids, forming kinked circles of at least two different contour lengths. The sole genus, Ophiovirus, includes seven species. Four ophioviruses are soil-transmitted and their natural hosts include trees, shrubs, vegetables and bulbous or corm-forming ornamentals, both monocots and dicots. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Ophioviridae, which is available at http://www.ictv.global/report/ophioviridae.Instituto de Biotecnologia y Biologia MolecularFacultad de Ciencias Agrarias y Forestale