High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension.

Objectives: Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important.

Methods: Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa.

Atypical Presentation and Treatment Response in a Child with Familial Hypercholesterolemia Having a Novel LDLR Mutation.

Familial hypercholesterolemia (FH) is an autosomal codominantly inherited disease. The severity of clinical presentation depends on the zygosity of the mutations in the LDLR, APOB, or PCSK9 genes. The homozygous form (HoFH) is associated with high mortality rate by third decade of life, while individuals with HeFH begin to suffer from premature cardiovascular disease in fourth or fifth decade of life.

Familial partial lipodystrophy presenting as metabolic syndrome.

We report the first described case of a heterozygous p.R545H (c.1634 G > A) missense mutation in the LMNA gene with clinical features compatible with Dunnigan-type 2 familial partial lipodystrophy (FPLD2).

Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations.

Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain.

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection.

The RNA modification N6-methyladenosine (mA) post-transcriptionally regulates RNA function. The cellular machinery that controls mA includes methyltransferases and demethylases that add or remove this modification, as well as mA-binding YTHDF proteins that promote the translation or degradation of mA-modified mRNA. We demonstrate that mA modulates infection by hepatitis C virus (HCV).

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Objective: Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic.

Approach And Results: We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.

Repetitive Transcranial Magnetic Stimulation for Depression Due to Cerebrovascular Disease: A Systematic Review.

Objective: This study aims to perform a systematic review evaluating the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in improving depression resulting from cerebrovascular disease including vascular depression (VD) and poststroke depression (PSD).

Methods: A literature search of multiple scientific databases was conducted for English studies published from January 1980 to June 2016. Studies were included if the sample consisted of 50% or more adult humans with VD or PSD and had 3 or more subjects, the intervention applied was rTMS, and depression was assessed pre- and post intervention using a formal outcome measure.

High content image analysis of focal adhesion-dependent mechanosensitive stem cell differentiation.

Human mesenchymal stem cells (hMSCs) receive differentiation cues from a number of stimuli, including extracellular matrix (ECM) stiffness. The pathways used to sense stiffness and other physical cues are just now being understood and include proteins within focal adhesions. To rapidly advance the pace of discovery for novel mechanosensitive proteins, we employed a combination of in silico and high throughput in vitro methods to analyze 47 different focal adhesion proteins for cryptic kinase binding sites.

The ONDRISeq panel: custom-designed next-generation sequencing of genes related to neurodegeneration.

The Ontario Neurodegenerative Disease Research Initiative (ONDRI) is a multimodal, multi-year, prospective observational cohort study to characterise five diseases: (1) Alzheimer's disease (AD) or amnestic single or multidomain mild cognitive impairment (aMCI) (AD/MCI); (2) amyotrophic lateral sclerosis (ALS); (3) frontotemporal dementia (FTD); (4) Parkinson's disease (PD); and (5) vascular cognitive impairment (VCI). The ONDRI Genomics subgroup is investigating the genetic basis of neurodegeneration. We have developed a custom next-generation-sequencing-based panel, ONDRISeq that targets 80 genes known to be associated with neurodegeneration.

Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young.

Objectives: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, reportedly accounting for 2% to 5% of all cases of diabetes. In samples from Canadian patients referred for molecular genetic confirmation of a clinically suspected MODY, we determined the prevalence of likely disease-causing DNA variants in known MODY genes.

Methods: Between 1999 and 2015, our centre received requests from colleagues for DNA sequencing of 96 samples from unrelated Canadian patients with clinically suspected MODY.

The Role of pH Regulation in Cancer Progression.

Frequently observed phenotypes of tumours include high metabolic activity, hypoxia and poor perfusion; these act to produce an acidic microenvironment. Cellular function depends on pH homoeostasis, and thus, tumours become dependent on pH regulatory mechanisms. Many of the proteins involved in pH regulation are highly expressed in tumours, and their expression is often of prognostic significance.

Use of the physical environment to support everyday activities for people with dementia: A systematic review.

Difficulty with everyday activities is a key symptom and defining feature of dementia, relating to subjective reports of well-being and overall quality of life. One way to support individuals in their daily activities is by modifying the physical environment to make it easier to interact with during activity performance. This systematic review explores the range of studies available using physical environmental strategies to support performance in everyday activities for people with dementia.

Clinical Genomics: Challenges and Opportunities.

Next-generation sequencing (NGS) approaches are highly applicable to clinical studies. We review recent advances in sequencing technologies, as well as their benefits and tradeoffs, to provide an overview of clinical genomics from study design to computational analysis. Sequencing technologies enable genomic, transcriptomic, and epigenomic evaluations.

Building a Knowledge to Action Program in Stroke Rehabilitation.

The knowledge to action (KTA) process proposed by Graham et al (2006) is a framework to facilitate the development and application of research evidence into clinical practice. The KTA process consists of the knowledge creation cycle and the action cycle. The Evidence Based Review of Stroke Rehabilitation is a foundational part of the knowledge creation cycle and has helped guide the development of best practice recommendations in stroke.

Identification and Characterization of Unique Subgroups of Chronic Pain Individuals with Dispositional Personality Traits.

Objective. The current study attempted to identify and characterize distinct CP subgroups based on their level of dispositional personality traits. The secondary objective was to compare the difference among the subgroups in mood, coping, and disability.

Does skill specialisation influence individual differences in drag flicking speed and accuracy?

Research has revealed that individual soccer goalkeepers respond differently to penalty shots, depending on their specific perceptual and motor capabilities. However, it remains unclear whether analogous differences exist between individual penalty takers, and if specialising in penalty taking affects the occurrence of differences between individuals. The present study examined individual differences in penalty shot speed and accuracy for specialists in penalty taking versus non-specialists.

How are service users instructed to measure home furniture for provision of minor assistive devices?

Purpose: Measurements play a vital role in providing devices that meet the individual needs of users. There is increasing evidence of devices being abandoned. The reasons for this are complex but one key factor that plays a role in non-use of equipment is the lack of fit between the device, environment and person.

Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia.

Background: Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types.

Combined Cubital and Carpal Tunnel Release Results in Symptom Resolution Outside of the Median or Ulnar Nerve Distributions.

Background: Resolution of symptoms including pain, numbness, and tingling outside of the median nerve distribution has been shown to occur following carpal tunnel release. We hypothesized that a similar effect would be found after combined release of the ulnar nerve at the elbow with simultaneous release of the median nerve at the carpal tunnel.

Methods: 20 patients with combined cubital and carpal tunnel syndrome were prospectively enrolled.

Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia.

Regions of hypoxia in tumours can be modelled in vitro in 2D cell cultures with a hypoxic chamber or incubator in which oxygen levels can be regulated. Although this system is useful in many respects, it disregards the additional physiological gradients of the hypoxic microenvironment, which result in reduced nutrients and more acidic pH. Another approach to hypoxia modelling is to use three-dimensional spheroid cultures.

The use of virtual reality for balance among individuals with chronic stroke: a systematic review and meta-analysis.

Background: Virtual reality (VR) is becoming a popular alternative to traditional upper and lower limb rehabilitation following a stroke.

Objective: To conduct a systematic review and meta-analysis on the effectiveness of VR interventions for improving balance in a chronic stroke (≥6 months) population.

Data Sources: A literature search of Pubmed, Scopus, CINAHL, Embase, Psycinfo, and Web of Science databases was conducted.

The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer.

The availability of bromodomain and extra-terminal inhibitors (BETi) has enabled translational epigenetic studies in cancer. BET proteins regulate transcription by selectively recognizing acetylated lysine residues on chromatin. BETi compete with this process leading to both downregulation and upregulation of gene expression.

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result.

A meta-review of stress, coping and interventions in dementia and dementia caregiving.

Background: There has been a substantial number of systematic reviews of stress, coping and interventions for people with dementia and their caregivers. This paper provides a meta-review of this literature 1988-2014.

Method: A meta-review was carried out of systematic reviews of stress, coping and interventions for people with dementia and their caregivers, using SCOPUS, Google Scholar and CINAHL Plus databases and manual searches.