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Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92-0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients.

BackgroundIn low- and middle-income countries twin births have a high risk of complications partly due to barriers to accessing hospital care. This study compares pregnancy outcomes, maternal and neonatal morbidity and mortality of twin to singleton pregnancy in refugee and migrant clinics on the Thai Myanmar border.MethodsA retrospective review of medical records of all singleton and twin pregnancies delivered or followed at antenatal clinics of the Shoklo Malaria Research Unit from 1986 to 2020, with a known outcome and estimated gestational age. Logistic regression was done to compare the odds of maternal and neonatal outcomes between twin and singleton pregnancies.ResultsBetween 1986 and 2020 this unstable and migratory population had a recorded outcome of pregnancy of 28 weeks or more for 597 twin births and 59,005 singleton births. Twinning rate was low and stable (ConclusionIn this fragile setting where access to hospital care is difficult, three in four twins birthed vaginally. Twin pregnancies have a higher maternal morbidity and perinatal mortality, especially the second twin, compared to singleton pregnancies.

BackgroundChanges in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session.Methods/designEASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall.DiscussionThe EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition.

BackgroundAtrial fibrillation (AF) is associated with significant morbidity/mortality. AF-ablation is an increasingly used treatment. Currently, first-time AF-ablation success is 40-80% at 1-year, depending on individual factors. There is growing evidence for improved outcomes through management of AF risk-factors/comorbidities via patient education/exercise-rehabilitation. There are no studies assessing combined prehabilitation/rehabilitation in this cohort. The aim of this randomised controlled trial is to assess efficacy of comprehensive prehabilitation/rehabilitation and combining supervised exercise-training with AF risk-factor modification/education compared with standard care in people undergoing first-time AF ablation.MethodsThis single-centre pragmatic randomised controlled trial will recruit 106 adults with paroxysmal/persistent AF listed for first-time AF-ablation. Participants will be randomised 1:1 to cardiac prehabilitation/rehabilitation/education (CREED AF) intervention or standard care. Both groups will undergo AF-ablation at 8-weeks post-randomisation as per usual care. The CREED AF intervention will involve 6-weeks of prehabilitation (before AF-ablation) followed by 6-weeks rehabilitation (after AF-ablation) consisting of risk factor education/modification and supervised exercise training. Standard care will include a single 30-minute session of risk-factor education. Outcomes will be measured at baseline, 10-weeks and 12-months post AF-ablation, by researchers blinded to treatment allocation. The primary outcome is cardiorespiratory-fitness (peak oxygen uptake, VO2peak) assessed using cardiopulmonary exercise testing (CPET) at 10-weeks post-ablation. Secondary outcomes include health-related quality of life, AF recurrence/burden assessed by 7-day Holter-monitor, requirement for repeat AF-ablation, study defined major adverse cardiovascular events, and cost-effectiveness (incremental cost per quality-adjusted life year (QALY)).ConclusionsThis study will assess clinical-efficacy/cost-effectiveness of comprehensive prehabilitation/rehabilitation/patient-education for people undergoing first time AF-ablation. Results will inform clinical care and design of future multi-centre clinical trials.Trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT06042231.Date registered: September 18, 2023.

Bacteria produce a variety of polysaccharides with functional roles in cell surface coating, surface and host interactions, and biofilms. We have identified an 'Orphan' bacterial cellulose synthase catalytic subunit (BcsA)-like protein found in four model pseudomonads, P. aeruginosa PA01, P. fluorescens SBW25, P. putida KT2440 and P. syringae pv. tomato DC3000. Pairwise alignments indicated that the Orphan and BcsA proteins shared less than 41% sequence identity suggesting they may not have the same structural folds or function. We identified 112 Orphans among soil and plant-associated pseudomonads as well as in phytopathogenic and human opportunistic pathogenic strains. The wide distribution of these highly conserved proteins suggest they form a novel family of synthases producing a different polysaccharide. In silico analysis, including sequence comparisons, secondary structure and topology predictions, and protein structural modelling, revealed a two-domain transmembrane ovoid-like structure for the Orphan protein with a periplasmic glycosyl hydrolase family GH17 domain linked via a transmembrane region to a cytoplasmic glycosyltransferase family GT2 domain. We suggest the GT2 domain synthesises β-(1,3)-glucan that is transferred to the GH17 domain where it is cleaved and cyclised to produce cyclic-β-(1,3)-glucan (CβG). Our structural models are consistent with enzymatic characterisation and recent molecular simulations of the PaPA01 and PpKT2440 GH17 domains. It also provides a functional explanation linking PaPAK and PaPA14 Orphan (also known as NdvB) transposon mutants with CβG production and biofilm-associated antibiotic resistance. Importantly, cyclic glucans are also involved in osmoregulation, plant infection and induced systemic suppression, and our findings suggest this novel family of CβG synthases may provide similar range of adaptive responses for pseudomonads.

Background: Atrial fibrillation (AF) is associated with significant morbidity/mortality. AF-ablation is an increasingly used treatment. Currently, first-time AF-ablation success is 40–80% at 1-year, depending on individual factors. There is growing evidence for improved outcomes through management of AF risk-factors/comorbidities via patient education/exercise-rehabilitation. There are no studies assessing combined prehabilitation/rehabilitation in this cohort. The aim of this randomised controlled trial is to assess efficacy of comprehensive prehabilitation/rehabilitation and combining supervised exercise-training with AF risk-factor modification/education compared with standard care in people undergoing first-time AF ablation. Methods: This single-centre pragmatic randomised controlled trial will recruit 106 adults with paroxysmal/persistent AF listed for first-time AF-ablation. Participants will be randomised 1:1 to cardiac prehabilitation/rehabilitation/education (CREED AF) intervention or standard care. Both groups will undergo AF-ablation at 8-weeks post-randomisation as per usual care. The CREED AF intervention will involve 6-weeks of prehabilitation (before AF-ablation) followed by 6-weeks rehabilitation (after AF-ablation) consisting of risk factor education/modification and supervised exercise training. Standard care will include a single 30-minute session of risk-factor education. Outcomes will be measured at baseline, 10-weeks and 12-months post AF-ablation, by researchers blinded to treatment allocation. The primary outcome is cardiorespiratory-fitness (peak oxygen uptake, VO2peak) assessed using cardiopulmonary exercise testing (CPET) at 10-weeks post-ablation. Secondary outcomes include health-related quality of life, AF recurrence/burden assessed by 7-day Holter-monitor, requirement for repeat AF-ablation, study defined major adverse cardiovascular events, and cost-effectiveness (incremental cost per quality-adjusted life year (QALY)). Conclusions: This study will assess clinical-efficacy/cost-effectiveness of comprehensive prehabilitation/rehabilitation/patient-education for people undergoing first time AF-ablation. Results will inform clinical care and design of future multi-centre clinical trials. Trial registration: URL:https://www.clinicaltrials.gov; Unique identifier: NCT06042231.Date registered: September 18, 2023. [ABSTRACT FROM AUTHOR]

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within "non-visible" phenotypically defined cells has fundamental implications for our understanding of brain plasticity.

Background Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Methods Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. Results In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. Conclusions These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.

The primate fovea is specialized for high acuity chromatic vision, with the highest density of cone photoreceptors and a disproportionately large representation in visual cortex. The unique visual properties conferred by the fovea are conveyed to the brain by retinal ganglion cells, the somas of which lie at the margin of the foveal pit. Microelectrode recordings of these centermost retinal ganglion cells have been challenging due to the fragility of the fovea in the excised retina. Here we overcome this challenge by combining high resolution fluorescence adaptive optics ophthalmoscopy with calcium imaging to optically record functional responses of foveal retinal ganglion cells in the living eye. We use this approach to study the chromatic responses and spatial transfer functions of retinal ganglion cells using spatially uniform fields modulated in different directions in color space and monochromatic drifting gratings. We recorded from over 350 cells across three Macaca fascicularis primates over a time period of weeks to months. We find that the majority of the L vs. M cone opponent cells serving the most central foveolar cones have spatial transfer functions that peak at high spatial frequencies (20–40 c/deg), reflecting strong surround inhibition that sacrifices sensitivity at low spatial frequencies but preserves the transmission of fine detail in the retinal image. In addition, we fit to the drifting grating data a detailed model of how ganglion cell responses draw on the cone mosaic to derive receptive field properties of L vs. M cone opponent cells at the very center of the foveola. The fits are consistent with the hypothesis that foveal midget ganglion cells are specialized to preserve information at the resolution of the cone mosaic. By characterizing the functional properties of retinal ganglion cells in vivo through adaptive optics, we characterize the response characteristics of these cells in situ.

Background: Changes in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session. Methods/design: EASE will enroll 30 participants comprised of healthy younger adults (18–35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall. Discussion: The EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition. [ABSTRACT FROM AUTHOR]

IntroductionThis study aims to explore gender-related differences in persistent opioid use following an acute pain episode and evaluate potential explanatory variables.MethodsThis retrospective population-based study using administrative databases included all opioid-naïve patients in Ontario with renal colic between 2013 and 2017. The primary outcome was to assess any association between persistent opioid use at 3-6 months by gender. Key confounding covariates and explanatory variables examined included both care- and patient-related factors, specifically past evidence of mental health diagnoses.ResultsThe dataset of 64,240 males and 37,656 females demonstrated that 8.7% of males and 9.6% of females had evidence of persistent opioid use 3-6 months after presentation (OR 1.11, 95% CI 1.05, 1.17). Females had a higher incidence of mental health services utilization [44.5% vs 29.6% (pInterpretationAfter controlling for key covariates, females are at slightly higher risk of demonstrating long term opioid use following an episode of renal colic. Evidence of prior mental health service utilization and acute colic care did not appear to significantly explain these observations.

People with chronic low back pain (LBP) exhibit changes in postural control. Stereotypical muscle activations resulting from external perturbations include anticipatory (APAs) and compensatory (CPAs) postural adjustments. The aim and objective of this study was to determine differences in postural control strategies (peak amplitude, APAs and CPAs) between symptomatic and asymptomatic adults with and without Lumbar Disc Degeneration (LDD) using surface electromyography during forward postural perturbation. Ninety-seven subjects participated in the study (mean age 50 years (SD 12)). 3T MRI was used to acquire T2 weighted images (L1-S1). LDD was determined using Pfirrmann grading. A bespoke translational platform was designed to deliver horizontal perturbations in sagittal and frontal planes. Electromyographic activity was analysed bilaterally from 8 trunk and lower limb muscles during four established APA and CPA epochs. A Kruskal-Wallis H test with Bonferroni correction for multiple comparisons was conducted. Four groups were identified: no LDD no pain (n = 19), LDD no pain (n = 38), LDD pain (n = 35) and no LDD pain (n = 5). There were no significant differences in age or gender between groups. The most significant difference between groups was observed during forward perturbation. In the APA and CPA phases of predictable forward perturbation there were significant differences ankle strategy between groups (p = 0.007-0.008); lateral gastrocnemius and tibialis anterior activity was higher in the LDD pain than the LDD no pain group. There were no significant differences in the unpredictable condition (p>0.05). These findings were different from the remaining groups, where significant differences in hip strategy were observed during both perturbation conditions (p = 0.004-0.006). Symptomatic LDD patients exhibit different electromyographic strategies to asymptomatic LDD controls. Future LBP electromyographic research should benefit from considering assessment of both lower limbs in addition to the spine. This approach could prevent underestimation of postural control deficits and guide targeted rehabilitation.

The COVID-19 pandemic continues to impact human health and welfare on a global level. In March 2020, stringent national restrictions were enforced in the UK to protect public health and slow the spread of the SARS-CoV-2 virus. Restrictions were likely to have resulted in collateral consequences for the health and welfare of horses and ponies, especially those at risk of obesity and laminitis and this issue warranted more detailed exploration. The current study utilised qualitative methodology to investigate the implications of COVID-19 related policies upon equine management and welfare with a focus on horses and ponies at risk of laminitis and obesity. Twenty-four interviews with five sub-groups of key equestrian welfare stakeholders in the UK were conducted between May and July of 2020 to understand the challenges facing equine welfare in the context of laminitis and obesity susceptible animals. Thematic analysis revealed lockdown-associated factors with the potential to compromise welfare of horses and ponies at risk of obesity and laminitis. These included: disparate information and guidance, difficulties enacting public health measures in yard environments, and horses having reduced exercise during the pandemic. Positive examples of clear and consistent information sharing by farriers were reported to have improved horse owner understanding of routine hoof care during lockdown. Analysis suggested that the recommendations for supporting the management-based needs of horses under reduced supervision were not clearly defined, or were not sufficiently disseminated, across the equine industry. These findings support the development of guidelines specific to the care of horses and ponies at risk of obesity and laminitis through collaborative input from veterinary and welfare experts, to reduce the negative impacts of future lockdown events in the UK.

Background: In low- and middle-income countries twin births have a high risk of complications partly due to barriers to accessing hospital care. This study compares pregnancy outcomes, maternal and neonatal morbidity and mortality of twin to singleton pregnancy in refugee and migrant clinics on the Thai Myanmar border. Methods: A retrospective review of medical records of all singleton and twin pregnancies delivered or followed at antenatal clinics of the Shoklo Malaria Research Unit from 1986 to 2020, with a known outcome and estimated gestational age. Logistic regression was done to compare the odds of maternal and neonatal outcomes between twin and singleton pregnancies. Results: Between 1986 and 2020 this unstable and migratory population had a recorded outcome of pregnancy of 28 weeks or more for 597 twin births and 59,005 singleton births. Twinning rate was low and stable (<9 per 1,000) over 30 years. Three-quarters (446/597) of the twin pregnancies and 96% (56,626/59,005) of singletons birthed vaginally. During pregnancy, a significantly higher proportion of twin pregnancies compared to singleton had pre-eclampsia (7.0% versus 1.7%), gestational hypertension (9.9% versus 3.9%) and eclampsia (1.0% versus 0.2%). The stillbirth rate of twin 1 and twin 2 was higher compared to singletons: twin 1 25 per 1,000 (15/595), twin 2 64 per 1,000 (38/595) and singletons 12 per 1,000 (680/58,781). The estimated odds ratio (95% confidence interval (CI)) for stillbirth of twin 1 and twin 2 compared to singletons was 2.2 (95% CI 1.3–3.6) and 5.8 (95% CI 4.1–8.1); and maternal death 2.0 (0.95–11.4), respectively, As expected most perinatal deaths were 28 to <32 week gestation. Conclusion: In this fragile setting where access to hospital care is difficult, three in four twins birthed vaginally. Twin pregnancies have a higher maternal morbidity and perinatal mortality, especially the second twin, compared to singleton pregnancies. [ABSTRACT FROM AUTHOR]

Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92–0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic disrupted the world in 2020 by spreading at unprecedented rates and causing tens of thousands of fatalities within a few months. The number of deaths dramatically increased in regions where the number of patients in need of hospital care exceeded the availability of care. Many COVID-19 patients experience Acute Respiratory Distress Syndrome (ARDS), a condition that can be treated with mechanical ventilation. In response to the need for mechanical ventilators, designed and tested an emergency ventilator (EV) that can control a patient's peak inspiratory pressure (PIP) and breathing rate, while keeping a positive end expiratory pressure (PEEP). This article describes the rapid design, prototyping, and testing of the EV. The development process was enabled by rapid design iterations using additive manufacturing (AM). In the initial design phase, iterations between design, AM, and testing enabled a working prototype within one week. The designs of the 16 different components of the ventilator were locked by additively manufacturing and testing a total of 283 parts having parametrically varied dimensions. In the second stage, AM was used to produce 75 functional prototypes to support engineering evaluation and animal testing. The devices were tested over more than two million cycles. We also developed an electronic monitoring system and with automatic alarm to provide for safe operation, along with training materials and user guides. The final designs are available online under a free license. The designs have been transferred to more than 70 organizations in 15 countries. This project demonstrates the potential for ultra-fast product design, engineering, and testing of medical devices needed for COVID-19 emergency response.

There is increasing global commitment to establish early childhood interventions that promote the development of the millions of disadvantaged children in low- and middle-income countries not reaching their developmental potential. However, progress is hindered by the lack of valid developmental tests feasible for use at large scale. Consequently, there is an urgent need for such tests. Whilst screeners and single-domain tests ('short tests') are used as alternatives, their predictive validity in these circumstances is unknown. A longitudinal study in Bogota, Colombia began in 2011 when 1,311 children ages 6-42 months were given the Bayley Scales of Infant and Toddler Development (Bayley-III) by psychologists and randomized to receive one of two batteries of short tests under survey conditions. Concurrent validity of the short tests with the Bayley-III ('gold standard') was reported. In 2016, at 6-8 years, 940 of these children were given tests of IQ (Wechsler Intelligence Scale for Children, WISC-V) and school achievement (arithmetic, reading, and vocabulary) by psychologists. We compared the ability of the short tests, the Family Care Indicators (FCI), height-for-age, stunting (median height-for-age

BACKGROUND:Warfarin is an anticoagulant medication proven effective in the initial treatment and secondary prevention of venous thromboembolism. Anti-Xa direct oral anticoagulants are alternatives to warfarin; however there is limited data assessing satisfaction after switching from warfarin to an anti-Xa direct oral anticoagulant in patients for treatment of venous thromboembolism. OBJECTIVES:To assess medication satisfaction in patients requiring anticoagulation for venous thromboembolism after conversion from warfarin to an anti-Xa direct oral anticoagulant. METHODS:A retrospective cohort study with prospective assessment of satisfaction and review of adverse events following anti-Xa direct oral anticoagulant replacement of warfarin for treatment of venous thromboembolism. Out of 165 patients who had switched from warfarin to rivaroxaban or apixaban from an outpatient haematology practice, 126 patients consented for a survey of patient's relative satisfaction of anti-Xa direct oral anticoagulant therapy compared with previous warfarin therapy using the Anti-Clot Burden and Benefits Treatment Scale and SWAN Score. RESULTS:The mean Anti-Clot Burden and Benefits and SWAN Score was 93% (56/60) and 83% (24.8/30) respectively reflecting high satisfaction with anti-Xa direct oral anticoagulants. 120 patients stated preference for anti-Xa direct oral anticoagulants over warfarin. Leading perceptions driving this was the reduction in frequency of medical contact and fewer bleeding side effects. Thirteen patients (10.3%) experienced an adverse event after the anti-Xa direct oral anticoagulant switch (majority were non-major bleeding) but most remained on anti-Xa direct oral anticoagulant treatment after management options were implemented with continued high satisfaction scores. CONCLUSIONS:Patient satisfaction with anti-Xa direct oral anticoagulant therapy for the treatment and prevention of venous thromboembolism after switching from warfarin in routine clinical practice appeared high. Improved patient convenience including reduced frequency of medical contact and fewer unpredictable side effects were perceived as significant advantages of anti-Xa direct oral anticoagulants compared to warfarin.

Observing animals directly in the field provides the most accurate understanding of animal behaviour and resource selection. However, making prolonged observation of undisturbed animals is difficult or impossible for many species. To overcome this problem for the Tasmanian devil (Sarcophilus harrisii), a cryptic and nocturnal carnivore, we developed animal-borne video collars to investigate activity patterns, foraging behaviour and social interactions. We collected 173 hours of footage from 13 individual devils between 2013 and 2017. Devils were active mostly at night, and resting was the most common behaviour in all diel periods. Devils spent more time scavenging than hunting and exhibited opportunistic and flexible foraging behaviours. Scavenging occurred mostly in natural vegetation but also in anthropogenic vegetation and linear features (roads and fence lines). Scavenging frequency was inversely incremental with size e.g. small carcasses were scavenged most frequently. Agonistic interactions with conspecifics occurred most often when devils were traveling but also occurred over carcasses or dens. Interactions generally involved vocalisations and brief chases without physical contact. Our results highlight the importance of devils as a scavenger in the Tasmanian ecosystem, not just of large carcasses for which devils are well known but in cleaning up small items of carrion in the bush. Our results also show the complex nature of intraspecific interactions, revealing greater detail on the context in which interactions occur. In addition, this study demonstrates the benefits of using animal-borne imaging in quantifying behaviour of elusive, nocturnal carnivores not previously seen using conventional field methods.

IntroductionCompositional data analysis is one appropriate method for co-dependent data, even when data are collected for a subdivision of the 24-hour period, such as the waking day. Objectives were to use compositional analyses to examine the combined and relative associations of sedentary time (ST), light-intensity physical activity (LPA), moderate-intensity physical activity (MPA), and vigorous-intensity physical activity (VPA) with cardiometabolic biomarkers in a representative sample of children and youth.MethodsThis cross-sectional study included 2544 participants aged 6-17 years from the 2003-2006 United States National Health and Nutrition Examination Survey. ST (ResultsThe composition of ST, LPA, MPA, and VPA was significantly associated with BMI z-score, log waist circumference, systolic and diastolic blood pressure, HDL-cholesterol, and log plasma glucose (variance explained: 1-29%). Relative to the other three behaviors, VPA was negatively associated with BMI z-score (γVPA = -0.206, p = 0.005) and waist circumference (γVPA = -0.03, p = 0.001). Conversely, ST was positively associated with waist circumference (γST = 0.029, p = 0.013). ST and VPA were also positively associated with diastolic blood pressure (γST = 2.700, p = 0.018; γVPA = 1.246, p = 0.038), relative to the other behaviors, whereas negative associations were observed for LPA (γLPA = -2.892, p = 0.026). Finally, VPA was positively associated with HDL-cholesterol, relative to other behaviors (γVPA = 0.058, pConclusionsThe ST and physical activity composition appears important for many aspects of cardiometabolic health in children and youth. Compositions with more time in higher-intensity activities may be better for some aspects of cardiometabolic health.

IntroductionWe conducted a detailed analysis of trends in new HIV diagnoses in Australia by country of birth, to understand any changes in epidemiology, relationship to migration patterns and implications for public health programs.MethodsPoisson regression analyses were performed, comparing the age-standardised HIV diagnosis rates per 100,000 estimated resident population between 2006-2010 and 2011-2015 by region of birth, with stratification by exposure (male-to-male sex, heterosexual sex-males and females). Correlation between the number of permanent and long-term arrivals was also explored using linear regression models.ResultsBetween 2006 and 2015, there were 6,741 new HIV diagnoses attributed to male-to-male sex and 2,093 attributed to heterosexual sex, with the proportion of diagnoses attributed to male-to-male sex who were Australian-born decreasing from 72.5% to 66.5%. Compared with 2006-2010, the average annual HIV diagnosis rate per 100,000 in 2011-15 attributed to male-to-male sex was significantly higher in men born in South-East Asia (summary rate ratio (SRR) = 1.37, p = 0.001), North-East Asia (SRR = 2.18, pConclusionThe epidemiology of HIV in Australia is changing, with an increase in HIV diagnosis rates attributed to male-to-male sex amongst men born in Asia and the Americas. Tailored strategies must be developed to increase access to, and uptake of, prevention, testing and treatment in this group.

PurposeVideo corroboration of player incurred impacts (PII) using trunk-worn wearable sensors (WS) among national ice-hockey team members.Methods23 members of the U.S. National (NTDP) U18 team consented to procedures approved by EMU Human Subjects Committee. Bioharness-3 (Zephyr, MD) WS recorded occurrences of PII during games and impacts were generated using Impact Processor (Zephyr, MD). Eight players with the top activity levels each game determined by WS, were observed using video and synchronized with game video collected by NTDP staff. Impacts identified by WS of 6-7.9 g (Z3), 8-9.9 g (Z4) and 10+ g (Z5) were used to corroborate PII. Magnitude and duration of each identified impact were compared by category using MANOVA with Tukey post hoc (α = 0.05; SPSS 22.0, IBM, NY).ResultsOf 419 on-ice impacts, 358 were confirmed true PII (85.5%), 60 as other non-PII (14.3%) and 1 false positive (0.2%). For 358 PII, 17 (4.1%) were 1) Board contact/no check, 74 (17.7%), 2) Board contact/check, 202 (48.2%), 3) Open ice check, 65 (15.5%), 4) Player fall. Of 60 Non-PII, 19 (4.5%) as 5) other form of player to player event, 16 (3.8%) as 6) Hard Stop, 19 (4.5%) as 7) Slapshots and 6 (1.4%) as 8) other identifiable player events. 160 of the 200 Z3 events were PII (80%), 103 of 110 Z4 events (93.6%) and 95 of 109 Z5 events were PII (87.2%). The magnitude of impacts was not different by category, but the duration of category 6 (Hard stop; .058 s) was lower than categories 2, 4 and 7 (.112, .112, .133 s, respectively, p < .05).ConclusionThese data show that using some limited criteria (e.g. impact magnitude and duration), PII can be identified with relatively high accuracy in ice hockey using trunk-worn wearable sensors.

Cultivated watermelon (Citrullus lanatus) is one of the most important food crops in the Cucurbitaceae family. Diversification after domestication has led cultivated watermelons to exhibit diverse fruit flesh colors, including red, yellow, and orange. Recently, there has been increased interest in red-fleshed watermelons because they contain the antioxidant cis-isomeric lycopene. We performed whole genome resequencing (WGRS) of 24 watermelons with different flesh colors to identify single-nucleotide polymorphisms (SNPs) related to high lycopene content. The resequencing data revealed 203,894-279,412 SNPs from read mapping between inbred lines and the 97103 reference genome. In total, 295,065 filtered SNPs were identified, which had an average polymorphism information content of 0.297. Most of these SNPs were intergenic (90.1%) and possessed a transversion (Tv) rate of 31.64%. Overall, 2,369 SNPs were chosen at 0.5 Mb physical intervals to analyze genetic diversity across the 24 inbred lines. A neighbor-joining dendrogram and principal coordinate analysis (PCA) based on the 2,369 SNPs revealed that the 24 inbred lines could be grouped into high and low lycopene-type watermelons. In addition, we analyzed SNPs that could discriminate high lycopene content, red-fleshed watermelon from low lycopene, yellow or orange watermelon inbred lines. For validation, 19 SNPs (designated as WMHL1-19) were chosen randomly, and cleavage amplified polymorphic sequence (CAPS) markers were designed. Genotyping of the above 24 lines and 12 additional commercial cultivars using WMHL1-19 CAPS markers resulted in match rates of over 0.92 for most validated markers in correlation with the flesh color phenotypes. Our results provide valuable genomic information regarding the high lycopene content phenotype of red-fleshed cultivated watermelons, and the identified SNPs will be useful for the development of molecular markers in the marker-assisted breeding of watermelons with high lycopene content.

[This corrects the article DOI: 10.1371/journal.pone.0194809.].

Increasing vessel traffic in the marine environment due to commercial and recreational activities has amplified the number of conflicts with marine animals. However, there are limited multi-year observations of the healing rate of marine animals following vessel strike. Here we document the healing rate of a reef manta ray Mobula alfredi, following lacerations caused by a propeller along the pectoral fin. We demonstrate a high healing capacity, with wound length following a negative exponential curve over time. Lacerations healed to 5% of the initial wound length (i.e. 95% closure) within 295 days. The wounds appeared to stabilise at this point as observed more than three years following the incident and resulted in a distinctive scarring pattern. Examination of an extensive photo-identification catalogue of manta rays from the Ningaloo Coast World Heritage Area showed that the scarring pattern occurs more frequently than previously recognised, as the wounds had been previously attributed to failed predation attempts. This study provides baseline information for wound healing from vessel strike in reef manta rays and indirect evidence for increased vessel strikes on manta rays within the Ningaloo Coast World Heritage Area. We discuss the implication for spatial and behavioural management of vessels around manta rays.

Epizootic hemorrhagic disease (EHD) is a viral arthropod-borne disease affecting wild and domestic ruminants, caused by infection with epizootic hemorrhagic disease virus (EHDV). EHDV is transmitted to vertebrate animal hosts by biting midges in the genus Culicoides Latreille (Diptera: Ceratopogonidae). Culicoides sonorensis Wirth and Jones is the only confirmed vector of EHDV in the United States but is considered rare in Florida and not sufficiently abundant to support EHDV transmission. This study used ecological niche modeling to map the potential geographical distributions and associated ecological variable space of four Culicoides species suspected of transmitting EHDV in Florida, including Culicoides insignis Lutz, Culicoides stellifer (Coquillett), Culicoides debilipalpis Hoffman and Culicoides venustus Lutz. Models were developed with the Genetic Algorithm for Rule Set Production in DesktopGARP v1.1.3 using species occurrence data from field sampling along with environmental variables from WorldClim and Trypanosomiasis and Land use in Africa. For three Culicoides species (C. insignis, C. stellifer and C. debilipalpis) 96-98% of the presence points were predicted across the Florida landscape (63.8% - 72.5%). For C. venustus, models predicted 98.00% of presence points across 27.4% of Florida. Geographic variations were detected between species. Culicoides insignis was predicted to be restricted to peninsular Florida, and in contrast, C. venustus was predicted to be primarily in north Florida and the panhandle region. Culicoides stellifer and C. debilipalpis were predicted nearly statewide. Environmental conditions also differed by species, with some species' ranges predicted by more narrow ranges of variables than others. The Normalized Difference Vegetation Index (NDVI) was a major predictor of C. venustus and C. insignis presence. For C. stellifer, Land Surface Temperature, Middle Infrared were the most limiting predictors of presence. The limiting variables for C. debilipalpis were NDVI Bi-Annual Amplitude and NDVI Annual Amplitude at 22.5% and 28.1%, respectively. The model outputs, including maps and environmental variable range predictions generated from these experiments provide an important first pass at predicting species of veterinary importance in Florida. Because EHDV cannot exist in the environment without the vector, model outputs can be used to estimate the potential risk of disease for animal hosts across Florida. Results also provide distribution and habitat information useful for integrated pest management practices.

Roux-en-Y gastric bypass surgery (RYGB) is the most common and effective weight loss procedure for severe obesity. However, a significant increase in addictive behaviors and new-onset substance use disorder (SUD) are sometimes observed post-surgery. The endogenous opioid system is known to play a major role in motivated behavior and reward, as well as the abuse of substances, including alcohol, tobacco, opioids and highly palatable foods. Here, we examined the effects of RYGB on mu-opioid receptor levels in the brain. Male Sprague-Dawley rats were assigned to one of four groups: standard diet with sham surgery (control), ad libitum high-energy high-fat (HF) diet with sham surgery, calorie restricted HF diet with sham surgery (Sham-FR), or HF diet with RYGB surgery. Control and HF groups were fed their respective diets for 8 weeks, with surgery performed on the eighth week. After 9 weeks on their respective diets post-surgery, animals were sacrificed for mu-opioid receptor autoradiography using the [3H] [D-Ala2,N-Me-Phe4-Gly5-ol]- enkephalin (DAMGO) ligand. Rats with RYGB showed reduced DAMGO binding in the central amygdala compared to sham-operated HF diet controls, and in the hypothalamus compared to high-fat fed Sham-FR. Diet alone did not change [3H] DAMGO binding in any region. These findings show that RYGB surgery, independent of diet or caloric restriction, decreases mu opioid signaling in specific regions important for stress and energy regulation. Thus, RYGB surgery may lead to greater stress sensitivity via downregulated mu opioid signaling in the central amygdala, which may contribute to the observed increased risk in some subjects for addictive behavior.

BACKGROUND:The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors. METHODS:PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling. RESULTS:Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model. CONCLUSION:Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

Contentious issues in calf rearing include milk feeding practices and single versus group housing. The current study was performed on a high producing 170 Holstein cow dairy farm, to investigate the impact of nutrition and housing on growth and reproduction. Heifer calves (n = 100) were allocated in birth order to one of two commonly used management strategies. All calves received 3-4 litres of dam specific colostrum within 6 hours of birth. Group A calves were group housed from birth and fed milk replacer (MR) ad libitum via a computerised machine utilising a single teat, with weaning commencing at 63 days of age. Group R calves were initially housed in individual pens and received 2.5 litres of MR twice daily via a bucket until 21 days of age when they were group housed and fed 3 litres of MR twice daily via a group trough with weaning commencing at 56 days. From 12 weeks of age onwards, calves in both dietary groups were subject to common nutritional and husbandry protocols. All breeding of heifers was via artificial insemination with no hormonal intervention. Calves were weighed, body condition scored and morphometric measures recorded weekly up till 12 weeks of age then monthly until conception. Pre-weaning growth rates (kg/day) were significantly higher in Group A calves compared to Group R (0.89, 95% CI 0.86-0.93 vs 0.57, 95% CI 0.54-0.6 kg/day P < 0.001) with the most marked differences observed during the first three weeks of life (0.72, 95% CI 0.61-0.82 vs 0.17, 95% CI 0.08-0.26 P < 0.001). Whilst Group A calves gained body condition score (BCS) throughout the pre-weaning phase, Group R calves lost BCS during the first 4 weeks of life. Data suggested that Group R calves supported skeletal growth during this period by catabolising body tissue. Group A calves had a greater risk of disease than group R calves during the pre-weaning phase (diarrhoea: odds ratio 3.86, 95% CI 1.67-8.9; pneumonia: odds ratio 5.80, 95% CI 2.33-14.44) although no calves died during this period. Whilst pneumonia had a significant impact on growth during the study duration (P = 0.008), this was not the case for diarrhoea. Whilst univariate analysis failed to show any statistically significant group differences (P > 0.050) in any of the mean values of measured reproductive parameters, multivariable Cox regression suggested that there was a weak trend (P = 0.072) for Group A animals to achieve first service earlier than their Group R counterparts (62.6 weeks versus 65.3 weeks). Irrespective of dietary group, the hazard for achievement of all measured reproductive parameters, apart from time to puberty, was 20-40% less for heifers borne from multiparous dams compared to heifers from primiparous dams.

Recent in vitro and in vivo studies have highlighted the importance of the cell nucleus in governing migration through confined environments. Microfluidic devices that mimic the narrow interstitial spaces of tissues have emerged as important tools to study cellular dynamics during confined migration, including the consequences of nuclear deformation and nuclear envelope rupture. However, while image acquisition can be automated on motorized microscopes, the analysis of the corresponding time-lapse sequences for nuclear transit through the pores and events such as nuclear envelope rupture currently requires manual analysis. In addition to being highly time-consuming, such manual analysis is susceptible to person-to-person variability. Studies that compare large numbers of cell types and conditions therefore require automated image analysis to achieve sufficiently high throughput. Here, we present an automated image analysis program to register microfluidic constrictions and perform image segmentation to detect individual cell nuclei. The MATLAB program tracks nuclear migration over time and records constriction-transit events, transit times, transit success rates, and nuclear envelope rupture. Such automation reduces the time required to analyze migration experiments from weeks to hours, and removes the variability that arises from different human analysts. Comparison with manual analysis confirmed that both constriction transit and nuclear envelope rupture were detected correctly and reliably, and the automated analysis results closely matched a manual analysis gold standard. Applying the program to specific biological examples, we demonstrate its ability to detect differences in nuclear transit time between cells with different levels of the nuclear envelope proteins lamin A/C, which govern nuclear deformability, and to detect an increase in nuclear envelope rupture duration in cells in which CHMP7, a protein involved in nuclear envelope repair, had been depleted. The program thus presents a versatile tool for the study of confined migration and its effect on the cell nucleus.

Mouse models of breast cancer with specific molecular subtypes (e.g., ER or HER2 positive) in an immunocompetent or an immunocompromised environment significantly contribute to our understanding of cancer biology, despite some limitations, and they give insight into targeted therapies. However, an ideal triple-negative breast cancer (TNBC) mouse model is lacking. What has been missing in the TNBC mouse model is a sequential progression of the disease in an essential native microenvironment. This notion inspired us to develop a TNBC-model in syngeneic mice using a mammary intraductal (MIND) method. To achieve this goal, Mvt-1and 4T1 TNBC mouse cell lines were injected into the mammary ducts via nipples of FVB/N mice and BALB/c wild-type immunocompetent mice, respectively. We established that the TNBC-MIND model in syngeneic mice could epitomize all breast cancer progression stages and metastasis into the lungs via lymphatic or hematogenous dissemination within four weeks. Collectively, the syngeneic mouse-TNBC-MIND model may serve as a unique platform for further investigation of the underlying mechanisms of TNBC growth and therapies.

The primate foveola, with its high cone density and magnified cortical representation, is exquisitely specialized for high-resolution spatial vision. However, uncovering the wiring of retinal circuitry responsible for this performance has been challenging due to the difficulty in recording receptive fields of foveal retinal ganglion cells (RGCs) in vivo. In this study, we use adaptive optics scanning laser ophthalmoscopy (AOSLO) to image the calcium responses of RGCs in the living primate, with a stable, high precision visual stimulus that allowed us to localize the receptive fields of hundreds of foveal ganglion cells. This approach revealed a precisely radial organization of foveal RGCs, despite the many distortions possible during the extended developmental migration of foveal cells. By back projecting the line connecting RGC somas to their receptive fields, we have been able to define the 'physiological center' of the foveola, locating the vertical meridian separating left and right hemifields in vivo.

There is growing recognition that with sympathetic management, plantation forests may contain more biodiversity than previously thought. However, the extent to which they may support bat populations is contentious. Many studies have demonstrated active avoidance of coniferous plantations and attributed this to the lack of available roost sites and low invertebrate density. In contrast, other work, carried out in plantation dominated landscapes have shown that certain bat species are able to exploit these areas. However, the extent to which bats use plantations for roosting and foraging, or simply move through the plantation matrix to access more favourable sites is unclear. We radio tracked female Pipistrellus pygmaeus over two summers to establish the extent to which individual bats use Sitka Spruce plantations in southern Scotland for foraging and roosting and assess the implications for felling operations on bats. Maternity roosts identified (n = 17) were in all in buildings and most were large (> 500 individuals). We found no evidence of bats roosting in mature Sitka Spruce crop trees, although several bats used roosts in old or dead beech and oak trees as an alternative to their main maternity roost. Home ranges were much larger (mean 9.6 ± 3.12 km2) than those reported from other studies (0.6-1.6 km2), and it is likely that roost availability rather than food abundance constrains P. pygmaeus use of Sitka Spruce plantations. At the landscape scale, most individuals selected coniferous habitats over other habitat types, covering large distances to access plantation areas, whilst at a local scale bats used forest tracks to access water, felled stands or patches of broadleaf cover within the plantation. Sitka Spruce plantations support a high abundance of Culicoides impuctatus, the Highland midge which may act as a reliable and plentiful food source for females during lactation, an energetically expensive period. The use of felled stands for foraging by bats has implications for forest management as wind turbines, following small-scale felling operations, are increasingly being installed in plantations; wind turbines have been associated with high bat mortality in some countries. Decisions about siting wind turbines in upland plantations should consider the likelihood of increased bat activity post felling.

BACKGROUND AND OBJECTIVES:Exercise capacity is reduced in chronic kidney failure (CKF). Intra-dialytic cycling is beneficial, but comorbidity and fatigue can prevent this type of training. Low-frequency electrical muscle stimulation (LF-EMS) of the quadriceps and hamstrings elicits a cardiovascular training stimulus and may be a suitable alternative. The main objectives of this trial were to assess the feasibility and efficacy of intra-dialytic LF-EMS vs. cycling. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS:Assessor blind, parallel group, randomized controlled pilot study with sixty-four stable patients on maintenance hemodialysis. Participants were randomized to 10 weeks of 1) intra-dialytic cycling, 2) intra-dialytic LF-EMS, or 3) non-exercise control. Exercise was performed for up to one hour three times per week. Cycling workload was set at 40-60% oxygen uptake (VO2) reserve, and LF-EMS at maximum tolerable intensity. The control group did not complete any intra-dialytic exercise. Feasibility of intra-dialytic LF-EMS and cycling was the primary outcome, assessed by monitoring recruitment, retention and tolerability. At baseline and 10 weeks, secondary outcomes including cardio-respiratory reserve, muscle strength, and cardio-arterial structure and function were assessed. RESULTS:Fifty-one (of 64 randomized) participants completed the study (LF-EMS = 17 [77%], cycling = 16 [80%], control = 18 [82%]). Intra-dialytic LF-EMS and cycling were feasible and well tolerated (9% and 5% intolerance respectively, P = 0.9). At 10-weeks, cardio-respiratory reserve (VO2 peak) (Difference vs. control: LF-EMS +2.0 [95% CI, 0.3 to 3.7] ml.kg-1.min-1, P = 0.02, and cycling +3.0 [95% CI, 1.2 to 4.7] ml.kg-1.min-1, P = 0.001) and leg strength (Difference vs. control: LF-EMS, +94 [95% CI, 35.6 to 152.3] N, P = 0.002 and cycling, +65.1 [95% CI, 6.4 to 123.8] N, P = 0.002) were improved. Arterial structure and function were unaffected. CONCLUSIONS:Ten weeks of intra-dialytic LF-EMS or cycling improved cardio-respiratory reserve and muscular strength. For patients who are unable or unwilling to cycle during dialysis, LF-EMS is a feasible alternative.

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within "non-visible" phenotypically defined cells has fundamental implications for our understanding of brain plasticity.

[This corrects the article DOI: 10.1371/journal.pone.0183926.].

BACKGROUND:Patients with advanced chronic kidney disease (CKD) experience complex functional and structural changes of the cardiopulmonary and musculoskeletal system. This results in reduced exercise tolerance, quality of life and ultimately premature death. We investigated the relationship between subjective measures of health related quality of life and objective, standardised functional measures for cardiovascular and pulmonary health. METHODS:Between April 2010 and January 2013, 143 CKD stage-5 or CKD5d patients (age 46.0±1.1y, 62.2% male), were recruited prospectively. A control group of 83 healthy individuals treated for essential hypertension (HTN; age 53.2±0.9y, 48.22% male) were recruited at random. All patients completed the SF-36 health survey questionnaire, echocardiography, vascular tonometry and cardiopulmonary exercise testing. RESULTS:Patients with CKD had significantly lower SF-36 scores than the HTN group; for physical component score (PCS; 45.0 vs 53.9, p

The domestic cat (Felis catus) is an invasive exotic in many locations around the world and is thought to be a key factor driving recent mammal declines across northern Australia. Many mammal species native to this region now persist only in areas with high topographic complexity, provided by features such as gorges or escarpments. Do mammals persist in these habitats because cats occupy them less, or despite high cat occupancy? We show that occupancy of feral cats was lower in mammal-rich habitats of high topographic complexity. These results support the idea that predation pressure by feral cats is a factor contributing to the collapse of mammal communities across northern Australia. Managing impacts of feral cats is a global conservation challenge. Conservation actions such as choosing sites for small mammal reintroductions may be more successful if variation in cat occupancy with landscape features is taken into account.

In low- and middle-income countries (LIMCs), measuring early childhood development (ECD) with standard tests in large scale surveys and evaluations of interventions is difficult and expensive. Multi-dimensional screeners and single-domain tests ('short tests') are frequently used as alternatives. However, their validity in these circumstances is unknown. We examined the feasibility, reliability, and concurrent validity of three multi-dimensional screeners (Ages and Stages Questionnaires (ASQ-3), Denver Developmental Screening Test (Denver-II), Battelle Developmental Inventory screener (BDI-2)) and two single-domain tests (MacArthur-Bates Short-Forms (SFI and SFII), WHO Motor Milestones (WHO-Motor)) in 1,311 children 6-42 months in Bogota, Colombia. The scores were compared with those on the Bayley Scales of Infant and Toddler Development (Bayley-III), taken as the 'gold standard'. The Bayley-III was given at a center by psychologists; whereas the short tests were administered in the home by interviewers, as in a survey setting. Findings indicated good internal validity of all short tests except the ASQ-3. The BDI-2 took long to administer and was expensive, while the single-domain tests were quickest and cheapest and the Denver-II and ASQ-3 were intermediate. Concurrent validity of the multi-dimensional tests' cognitive, language, and fine motor scales with the corresponding Bayley-III scale was low below 19 months. However, it increased with age, becoming moderate-to-high over 30 months. In contrast, gross motor scales' concurrence was high under 19 months and then decreased. Of the single-domain tests, the WHO-Motor had high validity with gross motor under 16 months, and the SFI and SFII expressive scales showed moderate correlations with language under 30 months. Overall, the Denver-II was the most feasible and valid multi-dimensional test and the ASQ-3 performed poorly under 31 months. By domain, gross motor development had the highest concurrence below 19 months, and language above. Predictive validity investigation is needed to further guide the choice of instruments for large scale studies.

Clubroot, caused by Plasmodiophora brassicae, is an important disease on Brassica species worldwide. A clubroot resistance gene, Rcr1, with efficacy against pathotype 3 of P. brassicae, was previously mapped to chromosome A03 of B. rapa in pak choy cultivar "Flower Nabana". In the current study, resistance to pathotypes 2, 5 and 6 was shown to be associated with Rcr1 region on chromosome A03. Bulked segregant RNA sequencing was performed and short read sequences were assembled into 10 chromosomes of the B. rapa reference genome v1.5. For the resistant (R) bulks, a total of 351.8 million (M) sequences, 30,836.5 million bases (Mb) in length, produced 120-fold coverage of the reference genome. For the susceptible (S) bulks, 322.9 M sequences, 28,216.6 Mb in length, produced 109-fold coverage. In total, 776.2 K single nucleotide polymorphisms (SNPs) and 122.2 K insertion / deletion (InDels) in R bulks and 762.8 K SNPs and 118.7 K InDels in S bulks were identified; each chromosome had about 87% SNPs and 13% InDels, with 78% monomorphic and 22% polymorphic variants between the R and S bulks. Polymorphic variants on each chromosome were usually below 23%, but made up 34% of the variants on chromosome A03. There were 35 genes annotated in the Rcr1 target region and variants were identified in 21 genes. The numbers of poly variants differed significantly among the genes. Four out of them encode Toll-Interleukin-1 receptor / nucleotide-binding site / leucine-rich-repeat proteins; Bra019409 and Bra019410 harbored the higher numbers of polymorphic variants, which indicates that they are more likely candidates of Rcr1. Fourteen SNP markers in the target region were genotyped using the Kompetitive Allele Specific PCR method and were confirmed to associate with Rcr1. Selected SNP markers were analyzed with 26 recombinants obtained from a segregating population consisting of 1587 plants, indicating that they were completely linked to Rcr1. Nine SNP markers were used for marker-assisted introgression of Rcr1 into B. napus canola from B. rapa, with 100% accuracy in this study.

One of the key gaps in understanding the impacts of predation by small mammalian predators on prey is how habitat structure affects the hunting success of small predators, such as feral cats. These effects are poorly understood due to the difficulty of observing actual hunting behaviours. We attached collar-mounted video cameras to feral cats living in a tropical savanna environment in northern Australia, and measured variation in hunting success among different microhabitats (open areas, dense grass and complex rocks). From 89 hours of footage, we recorded 101 hunting events, of which 32 were successful. Of these kills, 28% were not eaten. Hunting success was highly dependent on microhabitat structure surrounding prey, increasing from 17% in habitats with dense grass or complex rocks to 70% in open areas. This research shows that habitat structure has a profound influence on the impacts of small predators on their prey. This has broad implications for management of vegetation and disturbance processes (like fire and grazing) in areas where feral cats threaten native fauna. Maintaining complex vegetation cover can reduce predation rates of small prey species from feral cat predation.