UBC-Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude.

Key Points: Sherpa have lived in the Nepal Himalaya for 25-40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH.

Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice.

Background: A low estimated glomerular filtration rate (eGFR) and an increased urinary albumin-to-creatinine ratio (ACR) are well-recognised prognostic markers of cardiovascular (CV) risk, but their individual and combined relationship with CV disease and total mortality among insulin-treated type 2 diabetes (T2D) patients in routine clinical care is unclear.

Methods: We analysed data for insulin users with T2D from UK general practices between 2007 and 2014 and examined the association between mortality rates and chronic kidney disease [categorised by low eGFR (< 60 mL/min/1.73 m), high eGFR (≥60 mL/min/1.

Sequencing of human genomes with nanopore technology.

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels.

New HPLC-MS method for rapid and simultaneous quantification of doxycycline, diethylcarbamazine and albendazole metabolites in rat plasma and organs after concomitant oral administration.

A sensitive and relatively fast, cost-effective high-performance liquid chromatographic method coupled with mass spectrometer (HPLC-MS) is herein reported for the first time for a simultaneous quantification of plasma and organs concentration of three therapeutic agents that are widely used in treatment of lymphatic filariasis (LF), namely, doxycycline (DOX), diethylcarbamazine (DEC) and albendazole (ABZ) metabolites. The method was developed and validated as per ICH and FDA guidelines and successfully employed to quantify DOX, DEC and ABZ metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)) in the plasma and organs of Sprague Dawley rats after oral concomitant administration of the above mentioned therapeutic agents. Importantly, a simple, one-step protein precipitation and extraction method was used to extract the four compounds efficiently with a recovery in the range of 79.

Tier 3 specialist weight management service and pre-bariatric multicomponent weight management programmes for adults with obesity living in the UK: A systematic review.

Background: NHS England has recommended a multidisciplinary weight management services (MWMS-Tier 3 services) for patients requiring specialized management of obesity, including bariatric surgery, but clinical and measurable health-related outcomes from these services remains fragmented. We therefore undertook a systematic review to explore the evidence base of effect on body weight loss and comorbidities outcomes of Tier 3 or UK pre-bariatric MWMPs.

Methods: AMED, CINAHL, EMBASE, HMIC, MEDLINE, PsycINFO, PubMed, HDAS search and Google Scholar were searched from January 2000 to September 2017 in a free-text fashion and crossed-references of included studies to identify potential illegibility.

Measuring the performance of the Mental Health Continuum-Short Form (MHC-SF) in a primary care youth mental health service.

Objectives: Mental health is regarded as more than the absence of mental health difficulties, with clinical and research focus moving towards measurement of well-being. The Mental Health Continuum-Short Form (MHC-SF) was developed to assess overall and emotional, social and psychological well-being. Little is known about the use of the MHC-SF with young people engaging with mental health services.

Potential Diagnostic Imaging of Alzheimer's Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques.

Amyloid-β plaques, consisting of aggregated amyloid-β peptides, are one of the pathological hallmarks of Alzheimer's disease. Copper complexes formed using positron-emitting copper radionuclides that cross the blood-brain barrier and bind to specific molecular targets offer the possibility of noninvasive diagnostic imaging using positron emission tomography. New thiosemicarbazone-pyridylhydrazone based ligands that incorporate pyridyl-benzofuran functional groups designed to bind amyloid-β plaques have been synthesized.

Imminent fracture risk assessments in the UK FLS setting: implications and challenges.

With the recognition that a sentinel fracture leads to a high imminent risk of fracture, we discuss the implications and challenges of using imminent fracture risk in the secondary fracture prevention setting.

Toxic doses of caffeine are needed to increase skeletal muscle contractility.

Discrepant results have been reported regarding an intramuscular mechanism underlying the ergogenic effect of caffeine on neuromuscular function in humans. Here, we reevaluated the effect of caffeine on muscular force production in humans and combined this with measurements of the caffeine dose-response relationship on force and cytosolic free [Ca] ([Ca]) in isolated mouse muscle fibers. Twenty-one healthy and physically active men (29 ± 9 yr, 178 ± 6 cm, 73 ± 10 kg, mean ± SD) took part in the present study.

MtrA Response Regulator Controls Cell Division and Cell Wall Metabolism and Affects Susceptibility of Mycobacteria to the First Line Antituberculosis Drugs.

The biological processes regulated by the essential response regulator MtrA and the growth conditions promoting its activation in , a slow grower and pathogen, are largely unknown. Here, using a gain-of-function mutant, MtrA, which functions in the absence of the cognate MtrB sensor kinase, we show that the MtrA regulon includes several genes involved in the processes of cell division and cell wall metabolism. The expression of selected MtrA targets and intracellular MtrA levels were compromised under replication arrest induced by genetic manipulation and under stress conditions caused by toxic radicals.

Jupiter's Mesoscale Waves Observed at 5 m by Ground-based Observations and JIRAM.

We characterize the origin and evolution of a mesoscale wave pattern in Jupiter's North Equatorial Belt (NEB), detected for the first time at 5 m using a 2016-17 campaign of "lucky imaging" from the VISIR instrument on the Very Large Telescope and the NIRI instrument on the Gemini observatory, coupled with -band imaging from Juno's JIRAM instrument during the first seven Juno orbits. The wave is compact, with a 1°.1-1°.

Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer.

PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer.

Longitudinal Maternal Vitamin D Status during Pregnancy Is Associated with Neonatal Anthropometric Measures.

Findings on maternal 25-hydroxyvitamin D (25[OH]D) and neonatal anthropometry are inconsistent, and may at least be partly due to variations in gestational week (GW) of 25(OH)D measurement and the lack of longitudinal 25(OH)D measurements across gestation. The aim of the current study was to examine the associations of longitudinal measures of maternal 25(OH)D and neonatal anthropometry at birth. This study included 321 mother⁻offspring pairs enrolled in the National Institute of Child Health and Human Development Fetal Growth Studies⁻Singletons.

Oral delivery of the anti-tumor necrosis factor α domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys.

Objective: V565 is a novel oral anti-tumor necrosis factor (TNF)-α domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys.

Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center's experience.

Objective: Transthyretin (ATTR) amyloidosis is an under-recognized, progressive disease manifesting as cardiomyopathy and/or polyneuropathy. Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID), has demonstrated transthyretin stabilization in vitro and slowing of polyneuropathy progression in the hereditary ATTR subtype (ATTRm). However, the use of diflunisal has only been described in a small cohort of patients with ATTR cardiac amyloidosis (CA).

Observational Study of a Wearable Sensor and Smartphone Application Supporting Unsupervised Exercises to Assess Pain and Stiffness.

Background: Evaluation of pain and stiffness in patients with arthritis is largely based on participants retrospectively reporting their self-perceived pain/stiffness. This is subjective and may not accurately reflect the true impact of therapeutic interventions. We now have access to sensor-based systems to continuously capture objective information regarding movement and activity.

Phenome-wide association studies across large population cohorts support drug target validation.

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints.

The UK Biobank resource with deep phenotyping and genomic data.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain.

Costs of Quality and Safety in Radiology.

With the movement toward at-risk population health management-related payment models, a core factor for the success and survival of health care organizations has become understanding and decreasing costs. In medical specialties such as radiology, understanding models for procedure-based costing will become increasingly important. Using bottom-up models for procedure-based costing, such as time-driven activity-based costing, is more advantageous than using the inaccurate ratio of costs to charges approach; however, these approaches are more resource intensive when compared to top-down approaches.

Optimizing Performance by Preventing Disruptive Behavior in Radiology.

Disruptive behaviors impede delivery of high-value health care by negatively impacting patient outcomes and increasing costs. Health care is brimming with potential triggers of disruptive behavior. Given omnipresent environmental and cultural factors such as constrained resources, stressful environments, commercialization, fatigue, unrealistic expectation of perfectionism, and burdensome documentation, a burnout epidemic is raging, and medical providers are understandably at tremendous risk to succumb and manifest these unprofessional behaviors.

Cryptic genetic variation and adaptation to waterlogging in Caledonian Scots pine, L.

Local adaptation occurs as the result of differential selection among populations. Observations made under common environmental conditions may reveal phenotypic differences between populations with an underlying genetic basis; however, exposure to a contrasting novel environment can trigger release of otherwise unobservable (cryptic) genetic variation. We conducted a waterlogging experiment on a common garden trial of Scots pine, (L.