bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR7 agonist attenuates acetylcholine‐induced, Ca2+‐dependent ionic currents in swine tracheal submucosal gland cells
Authors: Gamo Shunichi , Tamada Tsutomu , Murakami Koji , Muramatsu Soshi , Aritake Hidemi , Nara Masayuki , Kazama Itsuro , Okazaki Tatsuma , Sugiura Hisatoshi , Ichinose Masakazu 
Published: September 2018

New Findings
What is the central question of this study?Does Toll‐like receptor 7 (TLR7) have any direct effects on Ca2+‐dependent physiological function of tracheal submucosal gland cells?
What is the main finding and its importance?TLR7 is co‐localized with SERCA2 in tracheal submucosal gland cells and causes a rapid attenuation of acetylcholine (ACh)‐induced, Ca2+‐dependent ionic currents through the activation of SERCA2‐dependent Ca2+ clearance. TLR7 is abundantly expressed in the airways of both swine and healthy human subjects, but is significantly downregulated in chronic obstructive pulmonary disease (COPD) airways. These findings suggest that a dysfunction of TLR7 in COPD removes the brake on ACh‐induced serous secretion during viral infections, resulting in prolonged airway hypersecretion, and that it is one of the triggers of COPD exacerbations.
AbstractAirway surface fluids are mainly secreted from submucosal glands (SMGs) and play important roles in the defence of airways via the activation of mucociliary transport. Toll‐like receptor 7 (TLR7) recognizes and eliminates single stranded RNA (ssRNA) viruses through the induction of innate immunity. However, there is no obvious connection between TLR7 and mucus secretion, aside from TLR7 recognizing ssRNA viruses, which are often associated with airway hypersecretion in chronic obstructive pulmonary disease (COPD). Here, we investigated whether TLR7 has any direct effects on the Ca2+‐dependent physiological function of tracheal SMG cells. Patch‐clamp analyses revealed that TLR7 ligand inhibited the acetylcholine (ACh)‐induced ionic currents in isolated tracheal SMG cells. Intracellular calcium assays and pharmacological analyses revealed that TLR7 attenuated the transient rises in the intracellular calcium concentration evoked by ACh by activating sarco/endoplasmic reticulum Ca2+‐ATPase 2 (SERCA2). Immunofluorescence staining and immunohistochemical staining revealed that TLR7 was co‐localized with SERCA2. These findings suggest that the activation of TLR7 during viral infections contributes to the rapid attenuation of ACh‐induced ionic currents through an increase in SERCA2‐dependent Ca2+ clearance in healthy airway SMG cells. Our study also revealed that TLR7 expression was significantly downregulated in COPD airways. Based on these findings, we speculate that a dysfunction of TLR7 may not only have an adverse effect on the elimination of these viruses but also remove the brake on ACh‐induced serous secretion, resulting in prolonged hypersecretion and acting as one of the triggers of COPD exacerbations.
Complex and spatially segregated auditory inputs of the mouse superior colliculus
Authors: Bednárová Veronika , Grothe Benedikt , Myoga Michael H. 
Published: September 2018

Key points
Although the visual circuits in the superior colliculus (SC) have been thoroughly examined, the auditory circuits lack equivalent scrutiny.
SC neurons receiving auditory inputs in mice were characterized and three distinguishable types of neurons were found.
The auditory pathways from external nuclei of the inferior colliculus (IC) were characterized, and a novel direct inhibitory connection and an excitation that drives feed‐forward inhibitory circuits within the SC were found.
The direct excitatory and inhibitory inputs exhibited distinct arbourization patterns in the SC.
These findings suggest functional differences between excitatory and inhibitory sensory information that targets the auditory SC.
AbstractThe superior colliculus (SC) is a midbrain structure that integrates auditory, somatosensory and visual inputs to drive orientation movements. While much is known about how visual information is processed in the superficial layers of the SC, little is known about the SC circuits in the deep layers that process auditory inputs. We therefore characterized intrinsic neuronal properties in the auditory‐recipient layer of the SC (stratum griseum profundum; SGP) and confirmed three electrophysiologically defined clusters of neurons, consistent with literature from other SC layers. To determine the types of inputs to the SGP, we expressed Channelrhodopsin‐2 in the nucleus of the brachium of the inferior colliculus (nBIC) and external cortex of the inferior colliculus (ECIC) and optically stimulated these pathways while recording from SGP neurons. Probing the connections in this manner, we described a monosynaptic excitation that additionally drives feed‐forward inhibition via circuits intrinsic to the SC. Moreover, we found a profound long‐range monosynaptic inhibition in 100% of recorded SGP neurons, a surprising finding considering that only about 15% of SGP‐projecting neurons in the nBIC/ECIC are inhibitory. Furthermore, we found spatial differences in the cell body locations as well as axon trajectories between the monosynaptic excitatory and inhibitory inputs, suggesting that these inputs may be functionally distinct. Taking this together with recent anatomical evidence suggesting an auditory excitation from the nBIC and a GABAergic multimodal inhibition from the ECIC, we propose that sensory integration in the SGP is more multifaceted than previously thought.
TRPV1 and BDKRB2 receptor polymorphisms can influence the exercise pressor reflex
Authors: Notay Karambir , Klingel Shannon L. , Lee Jordan B. , Doherty Connor J. , Seed Jeremy D. , Swiatczak Michal , Mutch David M. , Millar Philip J. 
Published: September 2018

Key points
The mechanisms responsible for the high inter‐individual variability in blood pressure responses to exercise remain unclear.
Common genetic variants of genes related to the vascular transduction of sympathetic outflow have been investigated, but variants influencing skeletal muscle afferent feedback during exercise have not been explored.
Single nucleotide polymorphisms in TRPV1 rs222747 and BDKRB2 rs1799722 receptors present in skeletal muscle were associated with differences in the magnitude of the blood pressure response to static handgrip exercise but not mental stress.
The combined effects of TRPV1 rs222747 and BDKRB2 rs1799722 on blood pressure and heart rate responses during exercise were additive, and primarily found in men.
Genetic differences in skeletal muscle metaboreceptors may be a risk factor for exaggerated blood pressure responses to exercise.
AbstractExercise blood pressure (BP) responses demonstrate high inter‐individual variability, which could relate to differences in metabolically sensitive afferent feedback from the exercising muscle. We hypothesized that single‐nucleotide polymorphisms (SNPs) in genes encoding metaboreceptors present in group III/IV skeletal muscle afferents can influence the exercise pressor response. Two hundred men and women underwent measurements of continuous BP and heart rate at baseline and during 2 min of static handgrip exercise (30% maximal volitional contraction), post‐exercise circulatory occlusion and mental stress (serial subtraction; internal control). Participants were genotyped for SNPs in TRPV1 (rs222747; G/C), ASIC3 (rs2288645; G/A), BDKRB2 (rs1799722; C/T), PTGER2 (rs17197; A/G) and P2RX4 (rs25644; A/G). Exercise systolic BP (19 ± 10 vs. 22 ± 10 mmHg, P = 0.03) was lower in GG versus GC/CC minor allele carriers for TRPV1 rs222747, while exercise diastolic BP (14 ± 7 vs. 17 ± 7 mmHg, P = 0.007) and heart rate (12 ± 8 vs. 15 ± 9 beats min−1, P = 0.03) were lower in CC versus CT/TT minor allele carriers for BDKRB2 rs1799722. Individuals carrying both minor alleles for TRPV1 rs222747 and BDKRB2 rs1799722 had greater systolic (22 ± 11 vs. 17 ± 10 mmHg, P = 0.04) and diastolic (18 ± 7 vs. 14 ± 7 mmHg, P = 0.01) BP responses than those with no minor alleles; these differences were larger in men. No differences in BP or heart rate responses were detected during static handgrip with ASIC3 rs2288645, PTGER2 rs17197 or P2RX4 rs25644. None of the selected SNPs were associated with differences during mental stress. These findings demonstrate that variants in TRPV1 and BDKRB2 receptors can contribute to BP differences during static exercise in an additive manner.
Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults
Authors: Reidy Paul T. , McKenzie Alec I. , Mahmassani Ziad , Morrow Vincent R. , Yonemura Nikol M. , Hopkins Paul N. , Marcus Robin L. , Rondina Matthew T. , Lin Yu Kuei , Drummond Micah J. 
Published: September 2018

Key points
Insulin sensitivity (as determined by a hyperinsulinaemic‐euglyceamic clamp) decreased 15% after reduced activity. Despite not fully returning to baseline physical activity levels, insulin sensitivity unexpectedly, rebounded above that recorded before 2 weeks of reduced physical activity by 14% after the recovery period.
Changes in insulin sensitivity in response to reduced activity were primarily driven by men but, not women.
There were modest changes in ceramides (nuclear/myofibrillar fraction and serum) following reduced activity and recovery but, in the absence of major changes to body composition (i.e. fat mass), ceramides were not related to changes in inactivity‐induced insulin sensitivity in healthy older adults.
AbstractOlder adults are at risk of physical inactivity as they encounter debilitating life events. It is not known how insulin sensitivity is affected by modest short‐term physical inactivity and recovery in healthy older adults, nor how insulin sensitivity is related to changes in serum and muscle ceramide content. Healthy older adults (aged 64–82 years, five females, seven males) were assessed before (PRE), after 2 weeks of reduced physical activity (RA) and following 2 weeks of recovery (REC). Insulin sensitivity (hyperinsulinaemic‐euglyceamic clamp), lean mass, muscle function, skeletal muscle subfraction, fibre‐specific, and serum ceramide content and indices of skeletal muscle inflammation were assessed. Insulin sensitivity decreased by 15 ± 6% at RA (driven by men) but rebounded above PRE by 14 ± 5% at REC. Mid‐plantar flexor muscle area and leg strength decreased with RA, although only muscle size returned to baseline levels following REC. Body fat did not change and only minimal changes in muscle inflammation were noted across the intervention. Serum and intramuscular ceramides (nuclear/myofibrillar fraction) were modestly increased at RA and REC. However, ceramides were not related to changes in inactivity‐induced insulin sensitivity in healthy older adults. Short‐term inactivity induced insulin resistance in older adults in the absence of significant changes in body composition (i.e. fat mass) are not related to changes in ceramides.
Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial
Authors: Wen Shi Wu , White Ruth Rennicks , Rybak Natalie , Gaudet Laura M , Robson Stephen , Hague William , Simms-Stewart Donnette , Carroli Guillermo , Smith Graeme , Fraser William D , Wells George , Davidge Sandra T , Kingdom John , Coyle Doug , Fergusson Dean , Corsi Daniel J , Champagne Josee , Sabri Elham , Ramsay Tim , Mol Ben Willem J , Oudijk Martijn A , Walker Mark C 
Published: September 2018

AbstractObjectiveTo determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35.DesignRandomised, phase III, double blinded international, multicentre clinical trial.Setting70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK).Participants2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses.InterventionEligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation.Main outcome measureThe primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks’ gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).ResultsPre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.ConclusionSupplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition.Trial registrationCurrent Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.
Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines
Authors: Hasan Tasnim , Au Eric , Chen Sharon , Tong Allison , Wong Germaine 
Published: September 2018

ObjectiveImmunosuppressed individuals are at a high risk of latent tuberculosis infection (LTBI) and clinical practice guidelines for the screening and management of LTBI in at-risk patients have been developed. We assessed the scope, quality and consistency of clinical practice guidelines on screening for LTBI and the prevention of tuberculosis infection (TB) in high-risk patient populations.DesignWe conducted a systematic review of clinical practice guidelines. Methodological quality of these guidelines was assessed using the Appraisal of Guidelines for Research and Education (AGREE) II instrument. Textual synthesis was used to summarise and compare the recommendations.Data sourcesElectronic databases (MEDLINE, EMBASE, PsycINFO) and guideline registries were searched from inception to December 2017.ResultsThirty-eight guidelines were included. Nineteen focused on patients receiving medical immunosuppression, seven on transplantation, three on patients with HIV and nine were generalised across all at risk populations. Most guidelines (n=32, 84%) used a systematic approach to identify and appraise the evidence. The methodological quality of the guidelines varied with the overall mean AGREE II scores ranging from 35% to 80%. Guidelines performed poorly in terms of editorial independence (average score 35%, range 0%–92%); however, most were robust in defining their scope and purpose (average score 80%, range 56%–100%). Guidelines recommended either or both the tuberculin skin test and the interferon gamma release assay for screening. Treatment of LTBI with isoniazid was consistently recommended.ConclusionClinical practice guidelines on LTBI vary in quality and scope. The recommendations for screening varied across guidelines, while recommendations for treatment were largely consistent. Improving the consistency and quality of guidelines may help to optimise the screening and management of LTBI for improved patient outcomes.
Universal, school-based interventions to promote mental and emotional well-being: what is being done in the UK and does it work? A systematic review
Authors: Mackenzie Karen , Williams Christopher 
Published: September 2018

ObjectivesThe present review aimed to assess the quality, content and evidence of efficacy of universally delivered (to all pupils aged 5–16 years), school-based, mental health interventions designed to promote mental health/well-being and resilience, using a validated outcome measure and provided within the UK in order to inform UK schools-based well-being implementation.DesignA systematic review of published literature set within UK mainstream school settings.Data sourcesEmbase, CINAHL, MEDLINE, PsycINFO, PsychArticles, ASSIA and Psychological and Behavioural Sciences published between 2000 and April 2016.Eligibility criteriaPublished in English; universal interventions that aimed to improve mental health/emotional well-being in a mainstream school environment; school pupils were the direct recipients of the intervention; pre-post design utilised allowing comparison using a validated outcome measure.Data extraction and synthesis12 studies were identified including RCTs and non-controlled pre-post designs (5 primary school based, 7 secondary school based). A narrative synthesis was applied with study quality check.1ResultsEffectiveness of school-based universal interventions was found to be neutral or small with more positive effects found for poorer quality studies and those based in primary schools (pupils aged 9–12 years). Studies varied widely in their use of measures and study design. Only four studies were rated ‘excellent’ quality. Methodological issues such as small sample size, varying course fidelity and lack of randomisation reduced overall study quality. Where there were several positive outcomes, effect sizes were small, and methodological issues rendered many results to be interpreted with caution. Overall, results suggested a trend whereby higher quality studies reported less positive effects. The only study that conducted a health economic analysis suggested the intervention was not cost-effective.ConclusionsThe current evidence suggests there are neutral to small effects of universal, school-based interventions in the UK that aim to promote emotional or mental well-being or the prevention of mental health difficulties. Robust, long-term methodologies need to be pursued ensuring adequate recording of fidelity, the use of validated measures sensitive to mechanisms of change, reporting of those lost to follow-up and any adverse effects. Further high-quality and large-scale research is required across the UK in order to robustly test any long-term benefits for pupils or on the wider educational or health system.
Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials
Authors: Yamamoto Jennifer M , Benham Jamie L , Nerenberg Kara A , Donovan Lois E 
Published: September 2018

ObjectiveTo determine in women with subclinical hypothyroidism diagnosed in pregnancy whether levothyroxine treatment compared with control, impacts important obstetrical or childhood outcomes (specifically IQ) in randomised controlled trials.DesignSystematic review and meta-analysis.Study eligibility criteriaRandomised trials which met all the following were included: (1) reported original data of women with subclinical hypothyroidism diagnosed in pregnancy (by any prespecified study definition); (2) randomised to either levothyroxine or control (placebo or no treatment); (3) reported obstetrical outcomes and/or childhood neurodevelopmental outcomes and (4) published from 1980 to January 2018 in either English or French language.Data sourcesMedline, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov.Outcome measuresObstetrical, neonatal and childhood outcomes including: miscarriage, gestational hypertension, pre-eclampsia, preterm delivery, mode of delivery, neonatal intensive care unit admission, birth weight, gestational age at delivery, childhood IQ and neurodevelopmental scores.Risk of bias assessmentCochrane Risk of Bias Tool (Modified) for Quality Assessment of Randomised Controlled TrialsResultsThree trials of low to unclear risk of bias with 1837 participants were included. Two studies were meta-analysed for maternal and neonatal outcomes and two studies for childhood IQ. No statistically significant differences were found for any clinical outcomes with levothyroxine therapy compared with control.LimitationsOnly three trials were identified for inclusion.ConclusionsThis review, based on three randomised trials in women with subclinical hypothyroidism diagnosed in pregnancy, found no evidence of benefit of levothyroxine therapy on obstetrical, neonatal, childhood IQ or neurodevelopmental outcomes. Current trial evidence does not support the treatment of subclinical hypothyroidism diagnosed in pregnancy.PROSPERO registration numberCRD4201707980.
Explaining variations in test ordering in primary care: protocol for a realist review
Authors: Duddy Claire , Wong Geoffrey 
Published: September 2018

IntroductionStudies have demonstrated the existence of significant variation in test-ordering patterns in both primary and secondary care, for a wide variety of tests and across many health systems. Inconsistent practice could be explained by differing degrees of underuse and overuse of tests for diagnosis or monitoring. Underuse of appropriate tests may result in delayed or missed diagnoses; overuse may be an early step that can trigger a cascade of unnecessary intervention, as well as being a source of harm in itself.Methods and analysisThis realist review will seek to improve our understanding of how and why variation in laboratory test ordering comes about. A realist review is a theory-driven systematic review informed by a realist philosophy of science, seeking to produce useful theory that explains observed outcomes, in terms of relationships between important contexts and generative mechanisms.An initial explanatory theory will be developed in consultation with a stakeholder group and this ‘programme theory’ will be tested and refined against available secondary evidence, gathered via an iterative and purposive search process. This data will be analysed and synthesised according to realist principles, to produce a refined ‘programme theory’, explaining the contexts in which primary care doctors fail to order ‘necessary’ tests and/or order ‘unnecessary’ tests, and the mechanisms underlying these decisions.Ethics and disseminationEthical approval is not required for this review. A complete and transparent report will be produced in line with the RAMESES standards. The theory developed will be used to inform recommendations for the development of interventions designed to minimise ‘inappropriate’ testing. Our dissemination strategy will be informed by our stakeholders. A variety of outputs will be tailored to ensure relevance to policy-makers, primary care and pathology practitioners, and patients.Prospero registration numberCRD42018091986