An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages

Violence and post-traumatic stress disorder in Sao Paulo and Rio de Janeiro, Brazil: the protocol for an epidemiological and genetic survey

Background: violence is a public health major concern, and it is associated with post-traumatic stress disorder and other psychiatric outcomes. Brazil is one of the most violent countries in the world, and has an extreme social inequality. Research on the association between violence and mental health may support public health policy and thus reduce the burden of disease attributable to violence. the main objectives of this project were: to study the association between violence and mental disorders in the Brazilian population; to estimate the prevalence rates of exposure to violence, post-traumatic stress disorder, common metal disorder, and alcohol hazardous use and dependence: and to identify contextual and individual factors, including genetic factors, associated with the outcomes.Methods/design: one phase cross-sectional survey carried out in São Paulo and Rio de Janeiro, Brazil. A multistage probability to size sampling scheme was performed in order to select the participants (3000 and 1500 respectively). the cities were stratified according to homicide rates, and in São Paulo the three most violent strata were oversampled. the measurements included exposure to traumatic events, psychiatric diagnoses (CIDI 2.1), contextual (homicide rates and social indicators), and individual factors, such as demographics, social capital, resilience, help seeking behaviours. the interviews were carried between June/2007 February/2008, by a team of lay interviewers. the statistical analyses will be weight-adjusted in order to take account of the design effects. Standardization will be used in order to compare the results between the two centres. Whole genome association analysis will be performed on the 1 million SNP (single nucleotide polymorphism) arrays, and additional association analysis will be performed on additional phenotypes. the Ethical Committee of the Federal University of São Paulo approved the study, and participants who matched diagnostic criteria have been offered a referral to outpatient clinics at the Federal University of São Paulo and Federal University of Rio de Janeiro

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Peer reviewe

Rapid bioerosion in a tropical upwelling coral reef

Coral reefs persist in an accretion-erosion balance, which is critical for understanding the natural variability of sediment production, reef accretion, and their effects on the carbonate budget. Bioerosion (i.e. biodegradation of substrate) and encrustation (i.e. calcified overgrowth on substrate) influence the carbonate budget and the ecological functions of coral reefs, by substrate formation/consolidation/erosion, food availability and nutrient cycling. This study investigates settlement succession and carbonate budget change by bioeroding and encrusting calcifying organisms on experimentally deployed coral substrates (skeletal fragments of Stylophora pistillata branches). The substrates were deployed in a marginal coral reef located in the Gulf of Papagayo (Costa Rica, Eastern Tropical Pacific) for four months during the northern winter upwelling period (December 2013 to March 2014), and consecutively sampled after each month. Due to the upwelling environmental conditions within the Eastern Tropical Pacific, this region serves as a natural laboratory to study ecological processes such as bioerosion, which may reflect climate change scenarios. Time-series analyses showed a rapid settlement of bioeroders, particularly of lithophagine bivalves of the genus Lithophaga/ Leiosolenus (Dillwyn, 1817), within the first two months of exposure. The observed enhanced calcium carbonate loss of coral substrate (>30%) may influence seawater carbon chemistry. This is evident by measurements of an elevated seawater pH (>8.2) and aragonite saturation state (Ωarag >3) at Matapalo Reef during the upwelling period, when compared to a previous upwelling event observed at a nearby site in distance to a coral reef (Marina Papagayo). Due to the resulting local carbonate buffer effect of the seawater, an influx of atmospheric CO2 into reef waters was observed. Substrates showed no secondary cements in thin-section analyses, despite constant seawater carbonate oversaturation (Ωarag >2.8) during the field experiment. Micro Computerized Tomography (μCT) scans and microcast-embeddings of the substrates revealed that the carbonate loss was primarily due to internal macrobioerosion and an increase in microbioerosion. This study emphasizes the interconnected effects of upwelling and carbonate bioerosion on the reef carbonate budget and the ecological turnovers of carbonate producers in tropical coral reefs under environmental change.Sistema Nacional de Áreas de Conservación/[028-2013-SINAC]/SINAC/Costa RicaSistema Nacional de Áreas de Conservación/[72-2013-SINAC]/SINAC/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias del Mar y Limnología (CIMAR

Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

This corrects the article DOI: 10.1038/ncomms5999