A mass media campaign are needed to counter misconceptions about back pain and promote higher value care.

Back pain is saddled by misconceptions that contribute to low-value care and poor outcomes. Many patients and clinicians mistakenly view the spine as fragile, believe that pain equates to damage, and over-emphasise the role and value of rest, imaging, medication, and surgery.1 Guideline-based care will not be embraced if such misconceptions are not countered. Here we provide four arguments for accessible, engaging and convincing education to the public and health professionals

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

A novel isolator-based system promotes viability of human embryos during laboratory processing

In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.This is thepublished version. It first appeared at http://link.springer.com/article/10.1007%2Fs10875-016-0232-2

Are caregiving responsibilities associated with non-attendance at breast screening?

<p>Abstract</p> <p>Background</p> <p>Previous research showed that deprived individuals are less likely to attend breast screening and those providing intense amounts of informal care tend to be more deprived than non-caregivers. The aim of this study was to examine the relationship between informal caregiving and uptake of breast screening and to determine if socio-economic gradients in screening attendance were explained by caregiving responsibilities.</p> <p>Methods</p> <p>A database of breast screening histories was linked to the Northern Ireland Longitudinal Study, which links information from census, vital events and health registration datasets. The cohort included women aged 47 - 64 at the time of the census eligible for breast screening in a three-year follow-up period. Cohort attributes were recorded at the Census. Multivariate logistic regression was used to examine the relationship between informal caregiving and uptake of screening using STATA version 10.</p> <p>Results</p> <p>37,211 women were invited for breast screening of whom 27,909 (75%) attended; 23.9% of the cohort were caregivers. Caregivers providing <20 hours of care/week were more affluent, while those providing >50 hours/week were more deprived than non-caregivers. Deprived women were significantly less likely to attend breast screening; however, this was not explained by caregiving responsibilities as caregivers were as likely as non-caregivers to attend (Odds Ratio 0.97; 95% confidence intervals 0.88, 1.06).</p> <p>Conclusions</p> <p>While those providing the most significant amounts of care tended to be more deprived, caregiving responsibilities themselves did not explain the known socio-economic gradients in breast screening attendance. More work is required to identify why more deprived women are less likely to attend breast screening.</p

Human metabolic profiles are stably controlled by genetic and environmental variation

A comprehensive variation map of the human metabolome identifies genetic and stable-environmental sources as major drivers of metabolite concentrations. The data suggest that sample sizes of a few thousand are sufficient to detect metabolite biomarkers predictive of disease

HIV treatment is associated with a twofold higher probability of raised triglycerides: pooled analyses in 21 023 individuals in sub-Saharan Africa

Background Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TGs) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations. Methods Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models. Findings Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51–2.77, I2 = 45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies. Interpretation Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SS

Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling