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Falls are extremely common in occupational settings. Intrinsic factors such as overexertion and extrinsic factors such as the supporting surface are causative factors of falls. The impact of prolonged exposure to a slippery surface on postural stability has not been previously studied. The purpose of the study was to analyze the effect of extended exposure to a dry and a slippery surface on postural stability. Eighteen males (age: 21.17 ± 3.38 years; height: 1.77 ± 0.08 m; mass: 89.81 ± 14.23 kg) were recruited and subjected to one-hour walking on a dry surface and a slippery surface on two different days. Participants' balance was assessed using a force platform in stable and unstable conditions at 0, 30, and 60 min. Postural sway variables were analyzed using a 2 (surface) × 3 (time) repeated-measures ANOVA. Significant time main effects were observed in the stable condition with greater balance decrements at 30 and 60 min. Greater balance decrements were observed on the slippery surface compared to the dry surface in the unstable condition. The balance decrements can be attributed to overexertion due to the physiological workload of prolonged walking and to the potential gait modifications due to walking on the slippery surface.

Background : Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. Methods and Results: We conducted an exome-wide association study of LV mass (LVM) adjusted to height 2.7 , LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein ( MYRIP ), trafficking protein particle complex 11 ( TRAPPC11 ), and solute carrier family 27 member 6 ( SLC27A6 )] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. MYRIP knockdowns showed a significant decrease in atrial natriuretic factor ( NPPA ) and brain natriuretic peptide ( NPPB ) expression. Knockdowns of the heart long chain fatty acid (FA) transporter SLC27A6 resulted in downregulated caveolin 3 ( CAV3 ) expression, which has been linked to hypertrophic phenotypes in animal models. Finally, TRAPPC11 knockdown was linked to deficient calcium handling. Conclusions : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a past co-authorship with the authors CG, MI, KS, and DR., (Copyright © 2021 Irvin, Aggarwal, Claas, de las Fuentes, Do, Gu, Matter, Olson, Patki, Schwander, Smith, Srinivasasainagendra, Tiwari, Turner, Nickerson, Rao, Broeckel and Arnett.)

Abstract: Krings, BM, Shepherd, BD, Swain, JC, Turner, AJ, Chander, H, Waldman, HS, McAllister, MJ, Knight, AC, and Smith, JW. Impact of fat grip attachments on muscular strength and neuromuscular activation during resistance exercise. J Strength Cond Res 35(2S): S152-S157, 2021-The purpose of this study was to examine the acute effects of Fat Gripz (FG) on muscular activation and strength. Resistance trained men (n = 15; age = 22.4 ± 2.3 years; mass = 83.2 ± 11.1 kg) performed 2 experimental trials in a randomized order. Subjects completed 1 repetition maximum (1RM) testing with an Olympic barbell (OB) and with FG attached to an OB during the exercises of deadlift, bent-over row, upright row, concentration curl, and completed maximum repetitions of pull-ups until failure. Surface electromyography (EMG) was used to measure muscle activity from 8 upper extremity muscles (trapezius, medial deltoid, biceps brachii, triceps brachii, flexor carpi radialis, flexor carpi ulnaris, extensor carpi radialis, and extensor carpi ulnaris), while performing maximal voluntary isometric contractions during 1RM trials and while performing maximum number of pull-ups. When using the FG, 1RM strength was significantly decreased for each exercise, and the maximal number of pull-ups completed was significantly lower. Electromyography muscle activity was significantly increased in the forearm and shoulder muscles, but significantly decreased in the upper arm muscles with the use of FG during deadlift, bent-over row, and pull-ups. However, there were no differences for EMG activity for upright row and concentration curl. Differences in maximal strength, pull-up performance, and EMG activity with FG use may be due to the different muscle length positions. Although FG training may increase neuromuscular activation, decrements in muscular strength may result in prescribing low training loads that may not be ideal for building muscular strength., (Copyright © 2019 National Strength and Conditioning Association.)

The neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signalling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signalling to reduce METH self-administration and reinstatement of METH-seeking behaviours. Male and female Sprague-Dawley rats underwent surgery for jugular catheterisation and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking. Oxytocin treatment robustly attenuated METH intake in both sexes, and SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV decreased the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8. Our data suggest that vagus nerve signalling is required for the inhibitory effects of peripherally administered oxytocin on METH self-administration and reinstatement, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has implications for the use of oxytocin as a therapy for METH use disorder for both sexes.

This Editorial, written by Guest Editors Professor Michael Bader, Professor Anthony J. Turner and Dr Natalia Alenina, proudly introduces the Clinical Science-themed collection on angiotensin-converting enzyme 2 (ACE2), a multifunctional protein - from cardiovascular regulation to coronavirus disease 2019 (COVID-19)., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Crowding in emergency departments (EDs) is increasing in many health systems. Previous studies of the relationship between crowding and care quality are limited by the use of data from single hospitals, a focus on particular patient groups, a focus on a narrow set of quality measures, and use of crowding measures which induce bias from unobserved hospital and patient characteristics. Using data from 139 hospitals covering all major EDss in England, we measure crowding using quasi-exogenous variation in the volume of EDs attendances and examine its impacts on indicators of performance across the entire EDs care pathway. We exploit variations from expected volume estimated using high-dimensional fixed effects capturing hospital-specific variation in attendances by combinations of month and hour-of-the-week. Unexpected increases in attendance volume result in substantially longer waiting times, lower quantity and complexity of care, more patients choosing to leave without treatment, changes in referral and discharge decisions, but only small increases in reattendances and no increase in mortality. Causal bounds under potential omitted variable bias are narrow and exclude zero for the majority of outcomes. Results suggest that physician and patient responses may largely mitigate the impacts of demand increases on patient outcomes in the short-run., (© 2020 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Several studies have established associations between early-life non-cognitive skills and later-life health and health behaviours. However, no study addresses the more important policy concern about how this relationship varies along the health distribution. We use unconditional quantile regression to analyse the effects of adolescent non-cognitive skills across the distributions of the health-related quality of life at age 50 and biomarkers at age 45 years. We examine the effects of measures of conscientiousness, agreeableness and neuroticism recorded at age 16 for 3585 individuals from the National Child Development Study. Adolescent conscientiousness is positively associated with ability to cope with stress and negatively associated with risk of cardiovascular disease in middle-age. Adolescent agreeableness is associated with higher health-related quality of life and lower physiological 'wear and tear', but negatively associated with ability to cope with stress in middle-age. Adolescent neuroticism is associated with lower health-related quality of life, higher physiological 'wear and tear', and a higher risk of cardiovascular disease in middle-age. All of these associations are stronger at the lower end of the health distribution except for the cardiovascular risk biomarkers. These associations are robust to correcting for attrition using inverse probability weighting and consistent with causal bounds assuming proportional selection on observables and unobservables. They suggest policies that improve non-cognitive skills in adolescence could offer most long-term health benefit to those with the poorest health., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Over the past decade, targeting acute kidney injury (AKI) has become a priority to improve patient safety and health outcomes. Illness complicated by AKI is common and is associated with adverse outcomes including high rates of unplanned hospital readmission. Through national patient safety directives, NHS England has mandated the implementation of an AKI clinical decision support system in hospitals. In order to improve care following AKI, hospitals have also been incentivised to improve discharge summaries and general practices are recommended to establish registers of people who have had an episode of illness complicated by AKI. However, to date, there is limited evidence surrounding the development and impact of interventions following AKI., Design: We conducted a quality improvement project in primary care aiming to improve the management of patients following an episode of hospital care complicated by AKI. All 31 general practices within a single NHS Clinical Commissioning Group were incentivised by a locally commissioned service to engage in audit and feedback, education training and to develop an action plan at each practice to improve management of AKI., Results: AKI coding in general practice increased from 28% of cases in 2015/2016 to 50% in 2017/2018. Coding of AKI was associated with significant improvements in downstream patient management in terms of conducting a medication review within 1 month of hospital discharge, monitoring kidney function within 3 months and providing written information about AKI to patients. However, there was no effect on unplanned hospitalisation and mortality., Conclusion: The findings suggest that the quality improvement intervention successfully engaged a primary care workforce in AKI-related care, but that a higher intensity intervention is likely to be required to improve health outcomes. Development of a real-time audit tool is necessary to better understand and minimise the impact of the high mortality rate following AKI., Competing Interests: Competing interests: Between 2014 and 2017, TB was a member of the NHS England Think Kidneys Programme. The authors declare no other competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations., Methods: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509., Findings: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses., Interpretation: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation., Funding: Chugai Pharmaceutical., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study assessed ankle kinematics, surface electromyography, and center-of-pressure (COP) progression relative to the medial border of the foot during a side-cutting task in individuals with and without chronic ankle instability (CAI). Thirty participants (CAI = 15; Controls = 15) performed a side-cutting task on a force platform while 3-dimentional ankle kinematics, COP position, and surface electromyography from the tibialis anterior, medial gastrocnemius, fibularis longus, fibularis brevis, vastus medialis, and semitendinosus were recorded on the testing leg. Ankle kinematics, root-mean-square muscle activity and COP position relative to the medial boarder of the foot were compared between CAI and healthy controls (p < 0.05). Significantly greater ankle internal rotation from 35-54% of the stance phase (p = 0.032) was found for the CAI group compared to controls. Furthermore, significantly greater tibialis anterior muscle activity from 86-94% of the stance phase (p = 0.022) and a more medial COP position from 81-100% (p < 0.05) and of the stance phase was also observed in the CAI group. Less lateral COP progression and increased tibialis anterior activation in the CAI group could reflect a protective movement strategy during anticipated side-cutting to avoid recurrent injury. However, greater ankle internal rotation during mid-stance highlights a potential 'giving way' mechanism in individuals with CAI., Competing Interests: Declaration of Competing Interest All authors listed on this manuscript declare no conflicts of interest. No internal or external funding sources were obtained to complete this study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

End-of-life (EOL) care has become an integral part of intensive care medicine and includes the exploration of possibilities for deceased organ and tissue donation. Donation physicians are specialist doctors with expertise in EOL processes encompassing organ and tissue donation, who contribute significantly to improvements in organ and tissue donation services in many countries around the world. Donation physicians are usually also intensive care physicians, and thus they may be faced with the dual obligation of caring for dying patients and their families in the intensive care unit (ICU), whilst at the same time ensuring organ and tissue donation is considered according to best practice. This dual obligation poses specific ethical challenges that need to be carefully understood by clinicians, institutions and health care networks. These obligations are complementary and provide a unique skillset to care for dying patients and their families in the ICU. In this paper we review current controversies around EOL care in the ICU, including the use of palliative analgesia and sedation specifically with regards to withdrawal of cardiorespiratory support, the usefulness of the so-called doctrine of double effect to guide ethical decision-making, and the management of potential or perceived conflicts of interest in the context of dual professional roles., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin-angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Rhododendrons ( Rhododendron spp.) are ornamental plants in the family Ericaceae that thrive in acidic soils and are challenged by neutral or alkaline soils. This soil requirement limits the locations where rhododendrons can be grown and causes chlorosis, diminished growth, and low survival when rhododendrons are grown in high pH soils. While growth and survival impacts are widely documented, little is known about how high pH soils cause these symptoms in rhododendrons. We hypothesized that high pH stress impacts root form and function, leading to nutrient deficiencies that limit plant growth. We tested this hypothesis in a hydroponic experiment. "Mardi Gras" rhododendron liners were grown in a complete nutrient solution at pH 5.5 (optimum pH) or pH 6.5 (high pH) for 49 days. Biomass accumulation, nutrient uptake and concentration, and root stress were assessed. High pH nutrient solutions diminished leaf and root growth. Plants grown in high pH nutrient solutions developed clusters of short, highly branched roots. Plants grown in optimum pH did not exhibit this morphology. High pH affected the uptake and translocation of most essential nutrients. S and Mn deficiencies likely limited plant growth. High pH had a nuanced effect on root oxidative status. These results suggest that rhododendron root morphology and nutrient uptake are directly affected by high pH and that aboveground symptoms might be a consequence of impaired root function.

Introduction: The EQ-5D-3L (3L) and EQ-5D-5L (5L) are both frequently used measures of health status. Previous studies have found the EQ-5D-5L to have superior measurement properties but no study has compared the two measures in a large general population survey using matched respondents., Methods: Using data from the GP Patient Survey, coarsened exact matching was used to match individuals completing the 3L in 2011 with those completing the 5L in 2012. Measurement properties were assessed for a general population and multimorbid population (chronic conditions ≥ 2), with ceiling effects, informativity and distribution of response compared. Changes in the direction of response, as well as the impact on utility distributions, were quantified., Results: Matching resulted in a cohort of 1,023,218 respondents (2011: 511,609; 2012: 511,609) for analysis. Ceiling effects for the 5L were lower than the 3L (43.8% vs. 54.4%). The 5L had improved informativity and broader spread of responses than the 3L (5L top 50 profiles: 77.4% vs. 3L: 98.8%). Overall, there was an upwards shift in utility values for the 5L versus the 3L as respondents using the 5L reported ill health more frequently but with less severity. Measurement improvements and effects on utility values were more pronounced for the multimorbid population., Conclusion: The 5L had superior measurement properties than the 3L and should be preferred in general population surveys and for use in individuals with multimorbidity. At increasing levels of morbidity, the 5L is currently associated with higher utility values than the 3L.

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2 , Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

Background: Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in Saudi Arabia in 2012 and caused an epidemic in the Middle East. Public Health England (PHE) Manchester is one of the two PHE centres in the UK that perform testing for MERS-CoV. The results of the PHE Manchester MERS surveillance from 2012 to 2019 are presented in this report., Methods: Retrospective data were collected for returning travellers from the Middle East fitting the PHE MERS case definition. Respiratory samples were tested for respiratory viruses and MERS-CoV using an in-house RT-PCR assay., Results: Four hundred and twenty-six (426) samples from 264 patients were tested for MERS Co-V and respiratory viruses. No MERS-CoV infections were identified by PCR. Fifty-six percent of samples were PCR positive for viral or bacterial pathogen with Influenza A as the predominant virus (44%). Sixty-two percent of all patients had a pathogen identified with the highest positivity from sputum samples. Patients with multiple samples demonstrated a 100% diagnostic yield., Conclusions: Although no cases of MERS were identified, the majority of patients had Influenza infection for which oseltamivir treatment was indicated and isolation warranted. Sputum samples were the most useful in diagnosing respiratory viruses with a 100% diagnostic yield from patients with multiple samples., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: School-based social and emotional learning interventions can improve wellbeing and educational attainment in childhood. However, there is no evidence on their effects on health-related quality of life (HRQoL) or on their cost effectiveness., Objective: Our objective was to evaluate the cost effectiveness of the Promoting Alternative Thinking Strategies (PATHS) curriculum., Methods: A prospective economic evaluation was conducted alongside a cluster-randomised controlled trial of the PATHS curriculum implemented in the Greater Manchester area of England. In total, 23 schools (n = 2676 children) were randomised to receive PATHS, and 22 schools (n = 2542 children) were randomised to continue with usual practice. A UK health service perspective and a 2-year time horizon were used. HRQoL data were collected prospectively from all children in the trial via the Child Health Utility Nine-Dimension questionnaire. Micro-costing was undertaken to estimate the intervention costs. Missing data were imputed using multiple imputation., Results: The mean incremental cost of the PATHS curriculum compared with usual practice was £32.01 per child, and mean incremental quality-adjusted life-years (QALYs) were positive (0.0019; 95% confidence interval [CI] 0.0009-0.0029). Assuming a willingness-to-pay threshold of £20,000 per QALY, the expected incremental net benefit of introducing the PATHS curriculum was £5.56 per child (95% CI - 14.68 to 25.81), and the probability of cost effectiveness was 84%. However, this probability fell to 0% when intervention costs included teacher's salary costs., Conclusion: The PATHS curriculum has the potential to be cost effective at standard UK willingness-to-pay thresholds. However, the sensitivity of the cost-effectiveness estimates to key assumptions means decision makers should seek further information before allocating scarce public resources., Trial Registration Number: ISRCTN85087674.

Context: Individuals with chronic ankle instability (CAI) demonstrate altered lower limb movement dynamics during jump landings, which can contribute to recurrent injury. However, the literature examining lower limb movement dynamics during a side-cutting task in individuals with CAI is limited., Objective: To assess lower limb joint kinetics and sagittal-plane joint stiffness during the stance phase of a side-cutting task in individuals with or without CAI., Design: Cohort study., Setting: Motion-capture laboratory., Patients or Other Participants: Fifteen physically active, young adults with CAI (7 men, 8 women; age = 21.3 ± 1.6 years, height = 171.0 ± 11.2 cm, mass = 73.4 ± 15.2 kg) and 15 healthy matched controls (7 men, 8 women; age = 21.5 ± 1.5 years, height = 169.9 ± 10.6 cm, mass = 75.5 ± 13.0 kg)., Intervention(s): Lower limb 3-dimensional kinematic and ground reaction force data were recorded while participants completed 3 successful trials of a side-cutting task. Net internal joint moments, in addition to sagittal-plane ankle-, knee-, and hip-joint stiffness, were computed from 3-dimensional kinematic and ground reaction force data during the stance phase of the side-cutting task and analyzed., Main Outcome Measure(s): Data from each participant's stance phase were normalized to 100% from initial foot contact (0%) to toe-off (100%) to compute means, standard deviations, and Cohen d effect sizes for all dependent variables., Results: The CAI group exhibited a reduced ankle-eversion moment (39%-81% of stance phase) and knee-abduction moment (52%-75% of stance phase) and a greater ankle plantar-flexion moment (3%-16% of stance phase) than the control group ( P range = .009-.049). Sagittal-plane hip-joint stiffness was greater in the CAI than in the control group ( t 28 = 1.978, P = .03)., Conclusions: Our findings suggest that altered ankle-joint kinetics and increased hip-joint stiffness were associated when individuals with CAI performed a side-cutting task. These lower limb kinetic changes may contribute to an increased risk of recurrent lateral ankle sprains in people with CAI. Clinicians and practitioners can use these findings to develop rehabilitation programs for improving maladaptive movement mechanics in individuals with CAI.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC)., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

At the 2017 joint meeting of the International Society for Neurochemistry (ISN) and the European Society for Neurochemistry, 150 years of neurochemistry - the 50th anniversary of ISN, 40 years of European Society for Neurochemistry, and 60 years of the Journal of Neurochemistry (JNC) - was celebrated with a historical symposium that explored the foundations of neurochemical societies, key international figures in the discipline of neurochemistry, and the pre-eminent role of the JNC. The foundations of neurochemistry were laid in Europe, notably France and Germany, in the late 18th and early 19th centuries. Neurochemists in the United Kingdom made globally relevant contributions before and after the Second World War, and Swedish contributions were especially prominent in the 1950s and 1960s. As neurochemistry is a truly international branch of neuroscience, the important contributions of neurochemists in the Americas and the Asia-Pacific were also recognized, as were the seminal roles of the American, Asia-Pacific, and Japanese Societies of Neurochemistry. Although ISN was only formed in 1967, earlier international meetings in Europe and the Americas reflected the growing recognition of the importance of chemistry and biochemistry for understanding and responding to the pathophysiology of clinical conditions and diseases of the central and peripheral nervous systems. JNC was first published in 1956, but the ISN only assumed complete ownership of the journal under tempestuous circumstances in 1970. The ISN-JNC interface and the sterling work of the JNC Editors has meant that the income generated by the journal has allowed the ISN Council to implement diverse programs for supporting neurochemistry internationally, including sustaining regional neurochemical societies, and supporting neurochemists in the developing world and schools of neurochemistry., (© 2019 International Society for Neurochemistry.)

Background: Virtual reality (VR) is becoming a widespread tool in rehabilitation, especially for postural stability. However, the impact of using VR in a "moving wall paradigm" (visual perturbation), specifically without and with anticipation of the perturbation, is unknown., Methods: Nineteen healthy subjects performed three trials of static balance testing on a force plate under three different conditions: baseline (no perturbation), unexpected VR perturbation, and expected VR perturbation. The statistical analysis consisted of a 1 × 3 repeated-measures ANOVA to test for differences in the center of pressure (COP) displacement, 95% ellipsoid area, and COP sway velocity., Results: The expected perturbation rendered significantly lower ( p < 0.05) COP displacements and 95% ellipsoid area compared to the unexpected condition. A significantly higher ( p < 0.05) sway velocity was also observed in the expected condition compared to the unexpected condition., Conclusions: Postural stability was lowered during unexpected visual perturbations compared to both during baseline and during expected visual perturbations, suggesting that conflicting visual feedback induced postural instability due to compensatory postural responses. However, during expected visual perturbations, significantly lowered postural sway displacement and area were achieved by increasing the sway velocity, suggesting the occurrence of postural behavior due to anticipatory postural responses. Finally, the study also concluded that VR could be used to induce different postural responses by providing visual perturbations to the postural control system, which can subsequently be used as an effective and low-cost tool for postural stability training and rehabilitation.

Objectives: This study evaluated center-of-pressure (COP) and time-to-boundary (TTB) measures of postural control during a Lateral Step-Down Test in participants with chronic ankle instability (CAI)., Design: Cohort study., Setting: Biomechanics laboratory., Participants: Physically active adults with CAI (n = 15) and matched controls (n = 15)., Main Outcome Measures: Traditional COP and TTB measures of postural control were computed in the medial/lateral (ML) and anterior/posterior (AP) directions., Results: No significant results were found for the traditional COP measures (p > 0.05). The CAI group exhibited a lower TTB ML absolute minimum on their affected limb compared to the matched limb of the control group (p < 0.001). Additionally, on average the CAI group displayed significantly lower TTB ML mean of minima (p = 0.004) and TTB standard deviation of minima in the ML (p < 0.001) and AP directions (p = 0.002) regardless of limb., Conclusions: Sensorimotor impairments associated with CAI negatively alter spatiotemporal postural control and may cause a maladaptive reorganization of centrally mediated motor control strategies that results in bilateral postural control deficits during the Lateral Step-Down Test. In addition, traditional COP measures did not reveal any postural control deficits suggesting that a spatiotemporal analysis should be used when assessing postural control in participants with CAI., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Targeting the amyloid-β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β- and γ-secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid-degrading enzymes (ADEs) and by a variety of transport processes. The development of late-onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin-degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up-regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc., (© 2019 The British Pharmacological Society.)

While neuromuscular control deficits during inversion perturbations in chronic ankle instability (CAI) cohorts are well documented in the literature, anticipatory motor control strategies to inversion perturbations in CAI are largely unknown. The purpose of this study was to examine neuromuscular control and ankle kinematics in individuals with CAI (n = 15) and matched controls (n = 15) during unexpected and expected single leg drop-landings onto a tilted surface rotated 20° in the frontal plane. Muscle activity from 200 ms pre- to post-landing was recorded from the tibialis anterior (TA), medial gastrocnemius (MG), peroneus longus (PL) and peroneus brevis (PB). Mean muscle activity, co-contraction index (CCI), and peroneal latency was analyzed. Ankle inversion angle at initial contact, time to maximum inversion angle, maximum inversion angle and velocity were also assessed. Significantly longer PL latency, less time to maximum inversion and greater maximum inversion angle was found in CAI compared to controls. Regarding landing condition, significantly greater maximum inversion angle, less inversion at initial contact, longer PB latency, less TA activity and frontal plane CCI during the post-landing phase was found during the unexpected perturbation. Prolonged PL latency and altered ankle kinematics suggests reduced frontal plane ankle stabilization in CAI. However, similar motor control strategies were utilized in both groups during the ankle inversion perturbations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Human IL12RB1 is an autosomal gene that is essential for mycobacterial disease resistance and T cell differentiation. Using primary human tissue and PBMCs, we demonstrate that lung and T cell IL12RB1 expression is allele-biased, and the extent to which cells express one IL12RB1 allele is unaffected by activation. Furthermore following its expression the IL12RB1 pre-mRNA is processed into either IL12RB1 Isoform 1 (IL12Rβ1, a positive regulator of IL12 responsiveness) or IL12RB1 Isoform 2 (a protein of heretofore unknown function). T cells choice to process pre-mRNA into Isoform 1 or Isoform 2 is controlled by intragenic competition of IL12RB1 exon 9-10 splicing with IL12RB1 exon 9b splicing, as well as an IL12RB1 exon 9b-associated polyadenylation site. Heterogeneous nuclear ribonucleoprotein H (hnRNP H) binds near the regulated polyadenylation site, but is not required for exon 9b polyadenylation. Finally, microRNA-mediated knockdown experiments demonstrated that IL12RB1 Isoform 2 promotes T cell IL12 responses. Collectively, our data support a model wherein tissue expression of human IL12RB1 is allele-biased and produces an hnRNP H-bound pre-mRNA, the processing of which generates a novel IL12 response regulator.

Atmospheric methane plays a major role in controlling climate, yet contemporary methane trends (1982-2017) have defied explanation with numerous, often conflicting, hypotheses proposed in the literature. Specifically, atmospheric observations of methane from 1982 to 2017 have exhibited periods of both increasing concentrations (from 1982 to 2000 and from 2007 to 2017) and stabilization (from 2000 to 2007). Explanations for the increases and stabilization have invoked changes in tropical wetlands, livestock, fossil fuels, biomass burning, and the methane sink. Contradictions in these hypotheses arise because our current observational network cannot unambiguously link recent methane variations to specific sources. This raises some fundamental questions: ( i ) What do we know about sources, sinks, and underlying processes driving observed trends in atmospheric methane? ( ii ) How will global methane respond to changes in anthropogenic emissions? And ( iii ), What future observations could help resolve changes in the methane budget? To address these questions, we discuss potential drivers of atmospheric methane abundances over the last four decades in light of various observational constraints as well as process-based knowledge. While uncertainties in the methane budget exist, they should not detract from the potential of methane emissions mitigation strategies. We show that net-zero cost emission reductions can lead to a declining atmospheric burden, but can take three decades to stabilize. Moving forward, we make recommendations for observations to better constrain contemporary trends in atmospheric methane and to provide mitigation support., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: The impact of occupational footwear and workload on postural stability has been studied previously to prevent fall-related workplace injuries., Objective: The purpose of this study was to assess the impact of two types of occupational footwear [steel-toed (SB) and tactical (TB) work boots] on human balance, when exposed to physical workload., Methods: Postural stability was evaluated in eighteen male participants in the following conditions: eyes open (EO), eyes closed (EC), eyes open unstable surface (EOU) and eyes closed unstable surface (ECU). Postural sway parameters were analyzed using a 2×3 repeated measures analysis of variance design [prior to (PRE) and twice post-workload (POST1 & POST2) separated by 10 minutes of rest]., Results: Findings revealed that the use of SB resulted in greater postural stability, which could be attributed to the design characteristics of these footwear and that postural stability was negatively impacted immediately after the workload which could be attributed to the physical exertions during the workload. However, significant differences were limited to ECU with no visual and altered somatosensory feedback., Conclusion: Design features on occupational footwear can aid postural stability while physical exertional tasks can be detrimental. Findings can offer design and work-rest scheduling suggestions to improve work safety.

This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.

Falls and fall-related injuries are a serious health concern in geriatric populations, especially with age-related deficits in postural control and during postural control challenging dual-task situations. Balance training has been reported to be beneficial in reducing falls. However, some of these exercises have their inherent physical challenges that prevent the elderly population from performing them effectively. Other concomitant age-related illness in the elderly pose further challenges in performing these exercises. Hence, the topic of finding alternative types of balance training that are effective and are performed in a safer environment is constantly researched. One such alternative is hydrotherapy that focuses on balance and postural perturbation-based exercises in water-based environments such as aquatic swimming pools or in dedicated hydrotherapy pools. Hydrotherapy for geriatric populations has been reported to be beneficial in improving balance, motor and cognitive tasks with improved motivation and positive attitude towards exercises. Additionally, hydrotherapy also has properties of buoyancy, resistance and temperature, which benefit biomechanical and physiological wellness and offers a safe environment to perform balance training. Hydrotherapy balance training need to be scaled and prescribed according to individual needs and can serve as an effective training and rehabilitation protocol in reducing falls in geriatric population.

The hydroxyl radical (OH) is the primary oxidant in the troposphere, and the impact of its fluctuations on the methane budget has been disputed in recent years, however measurements of OH are insufficient to characterize global interannual fluctuations relevant for methane. Here, we use a 6,000-y control simulation of preindustrial conditions with a chemistry-climate model to quantify the natural variability in OH and internal feedbacks governing that variability. We find that, even in the absence of external forcing, maximum OH changes are 3.8 ± 0.8% over a decade, which is large in the context of the recent methane growth from 2007-2017. We show that the OH variability is not a white-noise process. A wavelet analysis indicates that OH variability exhibits significant feedbacks with the same periodicity as the El Niño-Southern Oscillation (ENSO). We find intrinsically generated modulation of the OH variability, suggesting that OH may show periods of rapid or no change in future decades that are solely due to the internal climate dynamics (as opposed to external forcings). An empirical orthogonal function analysis further indicates that ENSO is the dominant mode of OH variability, with the modulation of OH occurring primarily through lightning [Formula: see text] La Niña is associated with an increase in convection in the Tropical Pacific, which increases the simulated occurrence of lightning and allows for more OH production. Understanding this link between OH and ENSO may improve the predictability of the oxidative capacity of the troposphere and assist in elucidating the causes of current and historical trends in methane., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Decompensation, a critical phase in the response to hemorrhage, is characterized by profound sympathoinhibition and the overriding of baroreflex mediated compensation. As sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) maintain vasomotor tone and are essential for sympathetic baroreceptor reflex function, the RVLM is the likely mediator. However, how decompensation occurs is a mystery. Our previous work demonstrated that the inhibitory neuropeptide somatostatin (SST), evokes potent sympathoinhibition. Here we test the hypothesis that, in response to hypovolemia, SST in the RVLM evokes sympathoinhibition, driving decompensation and suppressing baroreflex compensation. We evaluated neuronal activation at sites that contain SST mRNA and project to the RVLM and, in SST2A expressing neurons in the RVLM. We determined the effects on cardiovascular and sympathetic responses to haemorrhage, of bilateral blockade of SST2 receptors in both the RVLM and A1 regions. Haemorrhage in conscious rats evoked c-Fos immunoreactivity in the amygdala, periaqueductal gray, and parabrachial nuclei, regions previously associated with hemorrhage, shown to contain SST and project to the RVLM. Although c-Fos labeling was found throughout the ventrolateral medulla, only a small subset of RVLM SST2A receptor expressing neurons were activated, consistent with the idea that these neurons are inhibited during hemorrhage. However, SST2 receptor antagonists bilaterally injected in the RVLM or the A1 region did not affect the decompensation response to hemorrhage. Thus somatostatin in the RVLM does not mediate decompensation. The physiological role associated with somatostatin-induced sympathoinhibition in the RVLM together with the central mechanisms responsible for decompensation remain elusive.

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients., Patients and Methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively., Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25)., Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC., Clinical Trial Registration: ClinicialTrials.gov identifier: CNCT02193633.

Objectives: To develop an algorithm to predict the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L) utility scores from the Dermatology Life Quality Index (DLQI) in psoriasis., Methods: This mapping study used data from the British Association of Dermatologists Biologic Interventions Register-a pharmacovigilance register comprising patients with moderate to severe psoriasis on systemic therapies. Conceptual overlap between the EQ-5D-3L and DLQI was assessed using Spearman rank correlation coefficients and exploratory factor analysis. Six regression methods to predict the EQ-5D-3L index (direct mapping) and two regression methods to predict EQ-5D-3L domain responses (response mapping) were tested. Random effects models were explored to account for repeated observations from the same individual. Estimated and actual EQ-5D-3L utility scores were compared using 10-fold cross-validation (in-sample) to evaluate predictive performance. Final models were selected using root mean squared error, mean absolute error, and mean error., Results: The data set comprised 22,085 observations for which DLQI and EQ-5D-3L were recorded on the same day. A moderate correlation was found between the measures (r = -0.47). Exploratory factor analysis showed that two EQ-5D-3L domains (pain/discomfort and depression/anxiety) were associated with all six DLQI domains. The best-performing model used ordinary least squares with DLQI items, age, and sex as explanatory variables (with squared, cubic, and interaction terms). A tool was produced to allow users to map their data to the EQ-5D-3L, and includes algorithms that require fewer variables (e.g., total DLQI scores)., Conclusions: This study produced mapping algorithms that can generate EQ-5D-3L utility scores from DLQI data for economic evaluations of health interventions for patients with psoriasis., (Copyright © 2018 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: The DBA/2J mouse has been described as a model for congenital experimental glaucoma. It develops anterior segment anomalies with synechiae and pigment dispersion leading to raised intraocular pressure and glaucomatous damage. However, there are serious practical considerations when using this model in longitudinal studies., Methods: We followed 118 mice from 12-48 weeks of age in a pharmaceutical trial. Here we report on the findings in control animals (n = 37). Intraocular pressure was measured weekly, electrophysiology and optical coherence tomography every 6 weeks. A subset also had invasive intraocular pressure measurements performed prior to euthanasia., Results: Although intraocular pressure eventually rose by 9 months in most animals, tonometry was complicated by corneal calcification in the majority of animals rendering intraocular pressure measurement unreliable. Invasive intraocular pressure did not correlate with non-invasive measures. Loss of scotopic threshold response and thinning of inner retinal layers on optical coherence tomography was observed over time, suggesting glaucomatous damage, but this occurred in some animals without raised intraocular pressure. Poor pupil dilation significantly affected electrophysiology, optical coherence tomography and fundus imaging; 22% of animals developed major systemic complications leading to high dropout rate., Conclusions: The DBA/2J experimental glaucoma model shows variability in expression, and its pathological changes cause major difficulties in assessing disease progression. From our experience, the model presents significant challenges for drug studies in glaucoma, as there are many confounding factors: difficulty with accurate intraocular pressure measurement, in vivo imaging, and electrophysiology recording and a high dropout rate. In addition, there may be an underlying neurodegenerative process independent of intraocular pressure., (© 2017 Royal Australian and New Zealand College of Ophthalmologists.)

Four subcluster L2 mycobacteriophages, Finemlucis, Miley16, Wilder, and Zakai, that infect Mycobacterium smegmatis mc 2 155 were isolated. The four phages are closely related to each other and code for 12 to 14 tRNAs and 130 to 132 putative protein-coding genes, including tyrosine integrases, cro , immunity repressors, and excise genes involved in the establishment of lysogeny., (Copyright © 2017 Herren et al.)

Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomerular filtration rate. or electrolyte excretion rates between the Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex-treated fetuses was significantly lower (12.9 ± 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 ± 1.0 nl/min). This resetting of TGF sensitivity persisted after birth ( P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TGF sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TGF response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults., (Copyright © 2017 the American Physiological Society.)

Parkinson's disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient's movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815., (© 2017 International Society for Neurochemistry.)

Methane is the second strongest anthropogenic greenhouse gas and its atmospheric burden has more than doubled since 1850. Methane concentrations stabilized in the early 2000s and began increasing again in 2007. Neither the stabilization nor the recent growth are well understood, as evidenced by multiple competing hypotheses in recent literature. Here we use a multispecies two-box model inversion to jointly constrain 36 y of methane sources and sinks, using ground-based measurements of methane, methyl chloroform, and the C 13 /C 12 ratio in atmospheric methane (δ 13 CH 4 ) from 1983 through 2015. We find that the problem, as currently formulated, is underdetermined and solutions obtained in previous work are strongly dependent on prior assumptions. Based on our analysis, the mathematically most likely explanation for the renewed growth in atmospheric methane, counterintuitively, involves a 25-Tg/y decrease in methane emissions from 2003 to 2016 that is offset by a 7% decrease in global mean hydroxyl (OH) concentrations, the primary sink for atmospheric methane, over the same period. However, we are still able to fit the observations if we assume that OH concentrations are time invariant (as much of the previous work has assumed) and we then find solutions that are largely consistent with other proposed hypotheses for the renewed growth of atmospheric methane since 2007. We conclude that the current surface observing system does not allow unambiguous attribution of the decadal trends in methane without robust constraints on OH variability, which currently rely purely on methyl chloroform data and its uncertain emissions estimates., Competing Interests: The authors declare no conflict of interest.

The accumulation of cerebral amyloid βpeptide (Aβ) is a key precipitating factor for neuronal cell death in Alzheimer's Disease (AD). However, brain Aβ levels are modifiable since there is a balance between its formation from the Amyloid Precursor Protein (APP) and its removal by clearance mechanisms, which can be either through proteolysis or by protein binding and subsequent transport). Among the major enzymes degrading brain Aβ are several zinc-proteases: neprilysin (NEP), its homologues NEP2 and the Endothelin Converting Enzymes (ECE-1 and -2) and also the Insulin-Degrading Enzyme (IDE). During the ageing process, and under certain pathological conditions (e.g. ischemia and stroke), the expression and activity of these enzymes decline, which leads to a deficit of Aβ clearance and its accumulation in the brain. Some of these changes in the enzyme properties are due to their reduced expression and/or structural modification by reactive oxygen species. In this review paper we shall discuss some mechanisms of regulation of Amyloid-Degrading Enzymes (ADEs) and possible therapeutic approaches which might prevent their decline with age and after pathology.

We present a gridded inventory of US anthropogenic methane emissions with 0.1° × 0.1° spatial resolution, monthly temporal resolution, and detailed scale-dependent error characterization. The inventory is designed to be consistent with the 2016 US Environmental Protection Agency (EPA) Inventory of US Greenhouse Gas Emissions and Sinks (GHGI) for 2012. The EPA inventory is available only as national totals for different source types. We use a wide range of databases at the state, county, local, and point source level to disaggregate the inventory and allocate the spatial and temporal distribution of emissions for individual source types. Results show large differences with the EDGAR v4.2 global gridded inventory commonly used as a priori estimate in inversions of atmospheric methane observations. We derive grid-dependent error statistics for individual source types from comparison with the Environmental Defense Fund (EDF) regional inventory for Northeast Texas. These error statistics are independently verified by comparison with the California Greenhouse Gas Emissions Measurement (CALGEM) grid-resolved emission inventory. Our gridded, time-resolved inventory provides an improved basis for inversion of atmospheric methane observations to estimate US methane emissions and interpret the results in terms of the underlying processes.

This paper examines the synthetic control method in contrast to commonly used difference-in-differences (DiD) estimation, in the context of a re-evaluation of a pay-for-performance (P4P) initiative, the Advancing Quality scheme. The synthetic control method aims to estimate treatment effects by constructing a weighted combination of control units, which represents what the treated group would have experienced in the absence of receiving the treatment. While DiD estimation assumes that the effects of unobserved confounders are constant over time, the synthetic control method allows for these effects to change over time, by re-weighting the control group so that it has similar pre-intervention characteristics to the treated group. We extend the synthetic control approach to a setting of evaluation of a health policy where there are multiple treated units. We re-analyse a recent study evaluating the effects of a hospital P4P scheme on risk-adjusted hospital mortality. In contrast to the original DiD analysis, the synthetic control method reports that, for the incentivised conditions, the P4P scheme did not significantly reduce mortality and that there is a statistically significant increase in mortality for non-incentivised conditions. This result was robust to alternative specifications of the synthetic control method. © 2015 The Authors. Health Economics published by John Wiley & Sons Ltd., (© 2015 The Authors. Health Economics published by John Wiley & Sons Ltd.)

The amyloid precursor protein (APP) and acetylcholinesterase (AChE) are multi-faceted proteins with a wide range of vital functions, both crucially linked with the pathogenesis of Alzheimer's disease (AD). APP is the precursor of the Aβ peptide, the pathological agent in AD, while AChE is linked to its pathogenesis either by increasing cholinergic deficit or exacerbating Aβ fibril formation and toxicity. As such, both proteins are the main targets in AD therapeutics with AChE inhibitors being currently the only clinically available AD drugs. In our studies we have demonstrated an important inter-relation in functioning of these proteins. Both can be released from the cell membrane and we have shown that AChE shedding involves a metalloproteinase-mediated mechanism which, like the α-secretase dependent cleavage of APP, is stimulated by cholinergic agonists. Overexpression of the neuronal specific isoform APP695 in neuronal cells substantially decreased levels of the AChE mRNA, protein and catalytic activity accompanied by a similar decrease in mRNA levels of the AChE membrane anchor, PRiMA (proline rich membrane anchor). We further established that this regulation does not involve APP processing and its intracellular domain (AICD) but requires the E1 region of APP, specifically its copper-binding domain. On the contrary, siRNA knock-down of APP in cholinergic SN56 cells resulted in a significant upregulation of AChE mRNA levels. Hence APP may influence AChE physiology while released AChE may regulate amyloidogenesis through multiple mechanisms suggesting novel therapeutic targets., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Scientific journals that are owned by a learned society, like the Journal of Neurochemistry (JNC), which is owned by the International Society for Neurochemistry (ISN), benefit the scientific community in that a large proportion of the income is returned to support the scientific mission of the Society. The income generated by the JNC enables the ISN to organize conferences as a platform for members and non-members alike to share their research, supporting researchers particularly in developing countries by travel grants and other funds, and promoting education in student schools. These direct benefits and initiatives for ISN members and non-members distinguish a society journal from pure commerce. However, the world of scholarly publishing is changing rapidly. Open access models have challenged the business model of traditional journal subscription and hence provided free access to publicly funded scientific research. In these models, the manuscript authors pay a publication cost after peer review and acceptance of the manuscript. Over the last decade, numerous new open access journals have been launched and traditional subscription journals have started to offer open access (hybrid journals). However, open access journals follow the general scheme that, of all participating parties, the publisher receives the highest financial benefit. The income is generated by researchers whose positions and research are mostly financed by taxpayers' or funders' money, and by reviewers and editors, who frequently are not reimbursed. Last but not least, the authors pay for the publication of their work after a rigorous and sometimes painful review process. JNC itself has an open access option, at a significantly reduced cost for Society members as an additional benefit. This article provides first-hand insights from two former Editors-in-Chief, Kunihiko Suzuki and Leslie Iversen, about the history of JNC's ownership and about the difficulties and battles fought along the way to its current success and reputation. Scientific journals that are owned by a learned society, like the Journal of Neurochemistry (JNC) which is owned by the International Society for Neurochemistry (ISN), benefit the scientific community in that a large proportion of the income is returned to support the scientific mission of the Society. The income generated by the JNC enables the ISN to organize conferences as a platform for members and non-members alike to share their research, supporting researchers particularly in developing countries by travel grants and other funds, and to promote education in student schools. These direct benefits and initiatives for ISN members and non-members distinguish a society journal from pure commerce. However, the world of scholarly publishing is changing rapidly. Open access models have challenged the business model of traditional journal subscription and hence provide free access to publicly funded scientific research. In these models, the manuscript authors pay a publication cost after peer review and acceptance of the manuscript. Over the last decade, numerous new open access journals have been launched and traditional subscription journals have started to offer open access (hybrid journals). However, open access journals pertain to the general scheme that, of all participating parties, the publisher receives the highest financial benefit. The income is generated by researchers whose positions and research are mostly financed by tax payers' or funders' money, reviewers and editors, who frequently are not reimbursed. Last but not least, the authors pay for the publication of their work after a rigorous and sometimes painful review process. JNC itself has an open access option, at a significantly reduced cost for Society members as an additional benefit. This article provides first-hand insights from a long-standing Editor-in-Chief, Kunihiko Suzuki, about the history of JNC's ownership and about difficulties and battles fought on the way to its current success and reputation today. This article is part of the 60th Anniversary special issue., (© 2016 International Society for Neurochemistry.)

This review reflects on the origins, development, publishing trends, and scientific directions of the Journal of Neurochemistry over its 60 year lifespan as seen by key contributors to the Journal's production. The Journal first appeared in May 1956 with just two issues published in that inaugural year. By 1963, it appeared monthly and, by 2002, 24 hard copy issues were published yearly. In 2014, the Journal became online only. For much of its time, the Journal was managed through two separate editorial offices each with their respective Chief Editor (the 'Western' and 'Eastern' hemispheres). The Journal was restructured to operate through a single editorial office and Editor-in-Chief from 2013. Scientifically, the Journal progressed through distinct scientific eras with the first two decades generally centered around developments in methodology followed by a period when publications delved deeper into underlying mechanisms. By the late 1980s, the Journal had entered the age of genetics and beyond, with an increasing focus on neurodegenerative diseases. Reviews have played a regular part in the success of J Neurochem with focused special and virtual issues being a highlight of recent years. Today, 60 years and onwards, J Neurochem continues to be a leading source of top-quality, original and review articles in neuroscience. We look forward to its continued success at the forefront of neurochemistry in the decades to come. This article celebrates 60 years of publication of Journal of Neurochemistry including personal reminiscences from some of the Chief Editors, past and present, as well as input from some of the key contributors to the Journal over this period. We highlight the scientific, technological, and publishing developments along the way, with reference to key papers published in the Journal. The support of the Journal toward the aims and objectives of the International Society for Neurochemistry (ISN) is also emphasized. This article is part of the 60th Anniversary special issue., (© 2016 International Society for Neurochemistry.)