Genetic therapies for cardiomyopathy: survey of attitudes of the patient community for the CureHeart project.

Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway.

The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria.

The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients).

CSDE1 promotes miR-451 biogenesis.

MicroRNAs are sequentially processed by RNase III enzymes Drosha and Dicer. miR-451 is a highly conserved miRNA in vertebrates which bypasses Dicer processing and instead relies on AGO2 for its maturation. miR-451 is highly expressed in erythrocytes and regulates the differentiation of erythroblasts into mature red blood cells.

Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy.

Background: A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect.

Methods: We estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits.

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

Background: Left ventricular maximum wall thickness (LVMWT) is an important biomarker of left ventricular hypertrophy and provides diagnostic and prognostic information in hypertrophic cardiomyopathy (HCM). Limited information is available on the genetic determinants of LVMWT.

Methods: We performed a genome-wide association study of LVMWT measured from the cardiovascular magnetic resonance examinations of 42 176 European individuals.

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci.

Connexin 43 Gene Ablation Does Not Alter Human Pluripotent Stem Cell Germ Lineage Specification.

During embryonic germ layer development, cells communicate with each other and their environment to ensure proper lineage specification and tissue development. Connexin (Cx) proteins facilitate direct cell-cell communication through gap junction channels. While previous reports suggest that gap junctional intercellular communication may contribute to germ layer formation, there have been limited comprehensive expression analyses or genetic ablation studies on Cxs during human pluripotent stem cell (PSC) germ lineage specification.

Robust estimates of heritable coronary disease risk in individuals with type 2 diabetes.

Type 2 diabetes (T2D) is an important heritable risk factor for coronary artery disease (CAD), the risk of both diseases being increased by metabolic syndrome (MS). With the availability of large-scale genome-wide association data, we aimed to elucidate the genetic burden of CAD risk in T2D predisposed individuals within the context of MS and their shared genetic architecture. Mendelian randomization (MR) analyses supported a causal relationship between T2D and CAD [odds ratio (OR) = 1.

Medical Advice for Commercial Air Travel.

Air travel is generally safe, but the flight environment poses unique physiologic challenges such as relative hypoxia that may trigger adverse myocardial or pulmonary outcomes. To optimize health outcomes, communication must take place between the traveler, family physician, and airline carrier when there is any doubt about fitness for air travel. Travelers should carry current medications in their original containers and a list of their medical conditions and allergies; they should adjust timing of medications as needed based on time zone changes.

Pannexin 1 Influences Lineage Specification of Human iPSCs.

Every single cell in the body communicates with nearby cells to locally organize activities with their neighbors and dysfunctional cell-cell communication can be detrimental during cell lineage commitment, tissue patterning and organ development. Pannexin channels (PANX1, PANX2, and PANX3) facilitate purinergic paracrine signaling through the passage of messenger molecules out of cells. PANX1 is widely expressed throughout the body and has recently been identified in human oocytes as well as 2 and 4-cell stage human embryos.

Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants.

Manhattan++: displaying genome-wide association summary statistics with multiple annotation layers.

Background: Over the last 10 years, there have been over 3300 genome-wide association studies (GWAS). Almost every GWAS study provides a Manhattan plot either as a main figure or in the supplement. Several software packages can generate a Manhattan plot, but they are all limited in the extent to which they can annotate gene-names, allele frequencies, and variants having high impact on gene function or provide any other added information or flexibility.

Lack of genetic support for shared aetiology of Coronary Artery Disease and Late-onset Alzheimer's disease.

Epidemiological studies suggest a positive association between coronary artery disease (CAD) and late-onset Alzheimer's disease (LOAD). This large-scale genetic study brings together 'big data' resources to examine the causal impact of genetic determinants of CAD on risk of LOAD. A two-sample Mendelian randomization approach was adopted to estimate the causal effect of CAD on risk of LOAD using summary data from 60,801 CAD cases from CARDIoGRAMplusC4D and 17,008 LOAD cases from the IGAP Consortium.

Association analyses based on false discovery rate implicate new loci for coronary artery disease.

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach.

Molecular phylogeny and patterns of diversification in syngnathid fishes.

The family Syngnathidae is a large and diverse clade of morphologically unique bony fishes, with 57 genera and 300 described species of seahorses, pipefishes, pipehorses, and seadragons. They primarily inhabit shallow coastal waters in temperate and tropical oceans, and are characterized by a fused jaw, male brooding, and extraordinary crypsis. Phylogenetic relationships within the Syngnathidae remain poorly resolved due to lack of generic taxon sampling, few diagnostic morphological characters, and limited molecular data.

Elevated Biomarkers of Inflammation and Coagulation in Patients with HIV Are Associated with Higher Framingham and VACS Risk Index Scores.

Background: Biomarkers of inflammation and altered coagulation are of increasing interest as predictors of chronic disease and mortality in HIV patients, as well as the use of risk stratification scores such as the Framingham index and the Veterans Aging Cohort Study (VACS) score.

Methods: Demographic and laboratory data for 252 HIV patients were assessed for their relationship with 5 biomarkers: hsCRP, D-dimer, Cystatin C, IL-6 and TNF-alpha. Analysis of variance was used to model the association between the number of elevated biomarkers patients had and their Framingham 10 year cardiovascular risk and VACS scores.

CDR-restricted engineering of native human scFvs creates highly stable and soluble bifunctional antibodies for subcutaneous delivery.

While myriad molecular formats for bispecific antibodies have been examined to date, the simplest structures are often based on the scFv. Issues with stability and manufacturability in scFv-based bispecific molecules, however, have been a significant hindrance to their development, particularly for high-concentration, stable formulations that allow subcutaneous delivery. Our aim was to generate a tetravalent bispecific molecule targeting two inflammatory mediators for synergistic immune modulation.

Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain.

Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity.

Clinical pharmacokinetic assessment of an anti-MAdCAM monoclonal antibody therapeutic by LC-MS/MS.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been shown to be a viable tool for preclinical pharmacokinetic (PK) analysis of monoclonal antibody (mAb) therapeutics. This work describes free and total PK assays for the mAb PF-00547,659 in serum of ulcerative colitis patients in a First-In-Human study [Vermeire, S. et al.

Planning and incorporating public health preparedness into the medical curriculum.

As part of a 2010 conference entitled "Patients and Populations: Public Health in Medical Education," faculty from four U.S. medical schools (Case Western Reserve University, Harvard Medical School, the University of Colorado School of Medicine, and the University of Vermont College of Medicine), collaborated on a workshop to help other medical educators develop scenario-based learning experiences as practical, engaging, and effective mechanisms for teaching public health principles to medical school students.

The complexity, relative value, and financial worth of curbside consultations in an academic infectious diseases unit.

Background: Curbside consultations are common in clinical practice. The complexity, relative value, and revenue loss associated with curbside consultations are not well defined.

Methods: Curbside consultations performed during a 1-year period were studied.

The Vermont model for rural HIV care delivery: eleven years of outcome data comparing urban and rural clinics.

Context: Provision of human immunodeficiency virus (HIV) care in rural areas has encountered unique barriers.

Purpose: To compare medical outcomes of care provided at 3 HIV specialty clinics in rural Vermont with that provided at an urban HIV specialty clinic.

Methods: This was a retrospective cohort study.