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Abstract Background Veterans have unique military risk factors and exposures during deployment that may augment their risk of post-acute sequelae of SARS-CoV-2 (PASC). The purpose of this study is to identify potential risk factors for PASC among Veterans in the national Airborne Hazards and Open Burn Pit Registry (AHOBPR). Methods This prospective observational study consisted of a semi-structured interview conducted via phone or videoconference from November 2021 to December 2022 among a stratified random sample of deployed Veterans nested within the national AHOBPR with laboratory-confirmed SARS-CoV-2 infection. PASC was defined as persistent new-onset symptoms lasting more than 2 months after initial SARS-CoV-2 infection. Deployment history, airborne hazards exposure and symptoms were obtained from the AHOBPR self-assessment questionnaire completed prior to SARS-CoV-2 infection (past). Post-infection symptoms and health behaviors obtained at study interview (present) were used to test the hypothesis that deployment experience and exposure increases the risk for PASC. Results From a sample of 212 Veterans, 149 (70%) met criteria for PASC with a mean age of 47 ± 8.7 years; 73 (49%) were women and 76 (51%) were men, and 129 (82.6%) continued to experience persistent symptoms of SARS-CoV-2 (596.8 ± 160.4 days since initial infection). Neither exposure to airborne hazards (OR 0.97, CI 0.92–1.03) or to burn pits (OR 1.00, CI 0.99-1.00) augmented risk for PASC. Conclusions PASC is highly common among Veterans enrolled in the AHOBPR, but we did not observe any unique military risk factors (e.g., airborne hazards exposure) that augmented the risk of PASC. Our findings may provide guidance to clinicians in the VHA network to administer appropriate care for Veterans experiencing PASC.

Abstract Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.5 million primary-care health records in over 740,000 individuals in the UK Biobank, Million Veteran Program USA, and Estonian Biobank, to discover and validate the genetic architecture of adiposity trajectories. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI by 14%. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (APOE missense variant). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology of quantitative traits in adulthood.

Non-stationary methods of flood frequency analysis are widespread in research but rarely implemented by practitioners. One reason may be that research papers on non-stationary statistical models tend to focus on model fitting rather than extracting the sort of results needed by designers and decision makers. It can be difficult to extract useful results from non-stationary models that include stochastic covariates for which the value in any future year is unknown. We explore the motivation for including such covariates, whether on their own or in addition to a covariate based on time. We set out a method for expressing the results of non-stationary models as an integrated flow estimate, which removes the dependence on the covariates. This can be defined either for a particular year or over a longer period of time. The methods are illustrated by application to a set of 375 river gauges across England and Wales. We find annual rainfall to be a useful covariate at many gauges, sometimes in conjunction with a time-based covariate. For estimating flood frequency in future conditions, we advocate exploring hybrid approaches that combine the best attributes of non-stationary statistical models and simulation models that can represent changes in climate and river catchments. HIGHLIGHTS We explore why and how to include physical variables as covariates in statistical models of flood frequency.; We develop and illustrate methods for extracting flow estimates from such models so that practitioners can obtain useful results.; Practitioners now have tools and guidance to apply non-stationary methods for flood management in England.;

Abstract The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.

Abstract Introduction Poor sleep health is associated with increased asthma morbidity and mortality. Accelerometers have been validated to assess sleep parameters though studies using this method in patients with asthma are sparse and none have compared mild to difficult-to-treat asthma populations. Methods We performed a retrospective analysis from two recent in-house trials comparing sleep metrics between patients with mild and difficult-to-treat asthma. Participants wore accelerometers for 24-hours/day for seven days. Results Of 124 participants (44 mild, 80 difficult-to-treat), no between-group differences were observed in sleep-window, sleep-time, sleep efficiency or wake time. Sleep-onset time was ~ 40 min later in the difficult-to-treat group (p = 0.019). Discussion Broadly, we observed no difference in accelerometer-derived sleep-metrics between mild and difficult-to-treat asthma. This is the largest analysis of accelerometer-derived sleep parameters in asthma and the first comparing groups by asthma severity. Sleep-onset initiation may be delayed in difficult-to-treat asthma but a dedicated study is needed to confirm.

[This corrects the article DOI: 10.1371/journal.pone.0287412.].

Co-delivery of anticancer drugs and biologics can provide synergetic effects and outperform single delivery therapies. Here, a nanoparticle (NP) system for co-delivery of methotrexate (MTX) and STAT3 siRNA has been developed and tested in vitro. Mesoporous silica nanoparticles (MSNs) were functionalized with chitosan (ch) by covalent grafting mediated by aminopropyl triethoxysilane (APTES) via glutaraldehyde as the linker. Co-delivery of MTX and STAT3 siRNA to MCF7 cells was demonstrated in cells by flow cytometric analysis and confocal laser scanning fluorescence microscopy for use in breast cancer treatment. MTX either competitively inhibits the dihydrofolate reductase (DHFR) receptor or suppresses the STAT3 metabolic pathway. STAT3 protein plays an essential role in cell division, proliferation and survival. Reduction of the protein by both MTX and STAT3 siRNA, achieved by chMSNs, significantly decreased the viability of breast cancer cells compared to single treatments alone. Cellular uptake of modified NPs was increased over time when additional free MTX was added implicating the DHFR receptor in uptake. In addition, protein corona compositions coated the NPs outer surface, were different between the NPs with and without drug potentially modulating cellular uptake. This study is the first report on co-delivery of MTX and STAT3 siRNA by chitosan modified MSNs.

Abstract Introduction People experiencing homelessness (PEH) have poorer health than housed people but face barriers accessing care and being involved in research. As an often‐ignored group, their contribution to help shape research that is for and about them is essential, as it can strengthen the research proposal, in turn facilitating research and outcomes that are relevant to this vulnerable group. Methods Six people with experience of homelessness attended a PPI consultation aided by Pathway, a UK homeless peer advocacy charity, which coordinates an ‘Experts by Experience’ group. We present reflections on conducting PPI with PEH that informed the development of a physiotherapy research proposal. Kolb's Experiential Learning Cycle guided reflections across four stages: (1) describing the PPI experience; (2) reviewing and reflecting on the PPI experience; (3) learning from the PPI experience; and (4) planning and trying out learning. Results Reflections highlighted the importance of: working closely with an advocacy organisation and leader to reach under‐served people; the diversity of experiences; using familiar venues, contingency and budget planning; flexibility and ‘allowing time; talking less; listening more’; planning for early and ongoing PPI, and the potential of mobile ‘one‐off’ PPI outreach models to reach vulnerable groups. Conclusion Kolb's Experiential Learning Cycle aided team reflection on feedback from PEH, which helped refine and strengthen a physiotherapy research proposal. The project was unfunded. However, a reflective model helped maximize learning and impact including for future PPI and research. The novel application of Kolb's Experiential Learning Cycle provided structure, facilitated reflection and enhanced individual and collective learning and may benefit capturing learning from PPI with other vulnerable populations. Patient or Public Contribution We highlight how a PPI consultation with people with experience of homelessness helped shape a funding proposal. Additionally, the reflections of the experts by experience team leader are included.

Abstract Background Difficult-to-control asthma associated with elevated body mass index (BMI) is challenging with limited treatment options. The effects of pulmonary rehabilitation (PR) in this population are uncertain. Methods This is a randomised controlled trial of an eight-week asthma-tailored PR programme versus usual care (UC) in participants with difficult-to-control asthma and BMI ≥ 25 kg/m2. PR comprised two hours of education and supervised exercise per week, with encouragement for two individual exercise sessions. Primary outcome was difference in change in Asthma Quality of Life Questionnaire (AQLQ) in PR versus UC groups between visits. Secondary outcomes included difference in change in Asthma Control Questionnaire-6 (ACQ6), and a responder analysis comparing proportion reaching minimum clinically important difference for AQLQ and ACQ6. Results 95 participants were randomised 1:1 to PR or UC. Median age was 54 years, 60% were female and median BMI was 33.8 kg/m2. Mean (SD) AQLQ was 3.9 (+/-1.2) and median (IQR) ACQ6 2.8(1.8–3.6). 77 participants attended a second visit and had results analysed. Median (IQR) change in AQLQ was not significantly different: 0.3 (− 0.2 to 0.6) in PR and − 0.1 (− 0.5 to 0.4) in UC, p = 0.139. Mean change in ACQ6 was significantly different: − 0.4 (95% CI − 0.6 to − 0.2) in PR and 0 (− 0.3 to + 0.3) in UC, p = 0.015, but below minimum clinically important difference. In ACQ6 responder analysis, minimum clinically important difference was reached by 18 PR participants (54.5%) versus 10 UC (22.7%), p = 0.009. Dropout rate was 31% between visits in PR group, and time to completion was significantly prolonged in PR group at 94 (70–107) days versus 63 (56–73) in UC, p

Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic-differing in immune strategy, transcriptional program, and pathway use depending on infection history.

Serial intravital 2-photon microscopy of the kidney and other abdominal organs is a powerful technique to assess tissue function and structure simultaneously and over time. Thus, serial intravital microscopy can capture dynamic tissue changes during health and disease and holds great potential to characterize (patho-) physiological processes with subcellular resolution. However, successful image acquisition and analysis require significant expertise and impose multiple potential challenges. Abdominal organs are rhythmically displaced by breathing movements which hamper high-resolution imaging. Traditionally, kidney intravital imaging is performed on inverted microscopes where breathing movements are partly compensated by the weight of the animal pressing down. Here, we present a custom and easy-to-implement setup for intravital imaging of the kidney and other abdominal organs on upright microscopes. Furthermore, we provide image processing protocols and a new plugin for the free image analysis software FIJI to process multichannel fluorescence microscopy data. The proposed image processing pipelines cover multiple image denoising algorithms, sample drift correction using 2D registration, and alignment of serial imaging data collected over several weeks using landmark-based 3D registration. The provided tools aim to lower the barrier of entry to intravital microscopy of the kidney and are readily applicable by biomedical practitioners.

Abstract Background Acute low back pain is a common condition, has high burden, and there are evidence-to-practice gaps in the chiropractic and physiotherapy setting for imaging and giving advice to stay active. The aim of this cluster randomised trial was to estimate the effects of a theory- and evidence-based implementation intervention to increase chiropractors’ and physiotherapists’ adherence to a guideline for acute low back pain compared with the comparator (passive dissemination of the guideline). In particular, the primary aim of the intervention was to reduce inappropriate imaging referral and improve patient low back pain outcomes, and to determine whether this intervention was cost-effective. Methods Physiotherapy and chiropractic practices in the state of Victoria, Australia, comprising at least one practising clinician who provided care to patients with acute low back pain, were invited to participate. Patients attending these practices were included if they had acute non-specific low back pain (duration less than 3 months), were 18 years of age or older, and were able to understand and read English. Practices were randomly assigned either to a tailored, multi-faceted intervention based on the guideline (interactive educational symposium plus academic detailing) or passive dissemination of the guideline (comparator). A statistician independent of the study team undertook stratified randomisation using computer-generated random numbers; four strata were defined by professional group and the rural or metropolitan location of the practice. Investigators not involved in intervention delivery were blinded to allocation. Primary outcomes were X-ray referral self-reported by clinicians using a checklist and patient low back pain-specific disability (at 3 months). Results A total of 104 practices (43 chiropractors, 85 physiotherapists; 755 patients) were assigned to the intervention and 106 practices (45 chiropractors, 97 physiotherapists; 603 patients) to the comparator; 449 patients were available for the patient-level primary outcome. There was no important difference in the odds of patients being referred for X-ray (adjusted (Adj) OR: 1.40; 95% CI 0.51, 3.87; Adj risk difference (RD): 0.01; 95% CI − 0.02, 0.04) or patient low back pain-specific disability (Adj mean difference: 0.37; 95% CI − 0.48, 1.21, scale 0–24). The intervention did lead to improvement for some key secondary outcomes, including giving advice to stay active (Adj OR: 1.96; 95% CI 1.20, 3.22; Adj RD: 0.10; 95% CI 0.01, 0.19) and intending to adhere to the guideline recommendations (e.g. intention to refer for X-ray: Adj OR: 0.27; 95% CI 0.17, 0.44; intention to give advice to stay active: Adj OR: 2.37; 95% CI 1.51, 3.74). Conclusions Intervention group clinicians were more likely to give advice to stay active and to intend to adhere to the guideline recommendations about X-ray referral. The intervention did not change the primary study outcomes, with no important differences in X-ray referral and patient disability between groups, implying that hypothesised reductions in health service utilisation and/or productivity gains are unlikely to offset the direct costs of the intervention. We report these results with the caveat that we enrolled less patients into the trial than our determined sample size. We cannot recommend this intervention as a cost-effective use of resources. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12609001022257 . Retrospectively registered on 25 November 2009

BackgroundExertional dyspnea and exercise intolerance are frequently endorsed in Veterans of post 9/11 conflicts in Southwest Asia (SWA). Studying the dynamic behavior of ventilation during exercise may provide mechanistic insight into these symptoms. Using maximal cardiopulmonary exercise testing (CPET) to experimentally induce exertional symptoms, we aimed to identify potential physiological differences between deployed Veterans and non-deployed controls.Materials and methodsDeployed (n = 31) and non-deployed (n = 17) participants performed a maximal effort CPET via the Bruce treadmill protocol. Indirect calorimetry and perceptual rating scales were used to measure rate of oxygen consumption ([Formula: see text]), rate of carbon dioxide production ([Formula: see text]), respiratory frequency (f R), tidal volume (VT), minute ventilation ([Formula: see text]), heart rate (HR), perceived exertion (RPE; 6-20 scale), and dyspnea (Borg Breathlessness Scale; 0-10 scale). A repeated measures analysis of variance (RM-ANOVA) model (2 groups: deployed vs non-deployed X 6 timepoints: 0%, 20%, 40%, 60%, 80%, and 100% [Formula: see text]) was conducted for participants meeting valid effort criteria (deployed = 25; non-deployed = 11).ResultsSignificant group (η2partial = 0.26) and interaction (η2partial = 0.10) effects were observed such that deployed Veterans exhibited reduced f R and a greater change over time relative to non-deployed controls. There was also a significant group effect for dyspnea ratings (η2partial = 0.18) showing higher values in deployed participants. Exploratory correlational analyses revealed significant associations between dyspnea ratings and fR at 80% (R2 = 0.34) and 100% (R2 = 0.17) of [Formula: see text], but only in deployed Veterans.ConclusionRelative to non-deployed controls, Veterans deployed to SWA exhibited reduced fR and greater dyspnea during maximal exercise. Further, associations between these parameters occurred only in deployed Veterans. These findings support an association between SWA deployment and affected respiratory health, and also highlight the utility of CPET in the clinical evaluation of deployment-related dyspnea in Veterans.

A variety of nanostructures capable of generating strong local electromagnetic fields (hot spots) in interaction with radiation have been under intensive investigation towards plasmonic applications in surface-enhanced Raman scattering (SERS), biosensing, broadband absorbers, thermophotovoltaics, photocatalysis, etc. In many cases, these nanostructures are formed on a surface or embedded into a near-surface layer of the dielectric substrate, making some part of the field dissipate into the bulk and not contribute to the desired plasmonic functionality. To reduce such losses, the interface between the metallic nanostructures and the dielectric environment should be engineered. In the current work, Au nanodiscs are fabricated on Si posts of very small diameter (pin-shaped structures), enabling them to decouple the strong optical near fields localized at the nanodiscs from the bulk Si substrate. The Si post diameter is optimized by adjusting the gas flow rates in reactive-ion etching, resulting in a minimum post diameter of 20 nm at the nanodisc interface. The effect of this diameter on the localized surface plasmon resonance of the nanodisc is investigated with linear optical spectroscopic measurements, where a significant spectral blue shift of the resonance band is noticed compared to similar discs formed on bulk Si surface. The experimental results are compared with modelling where a 3-fold increase in the electric field enhancement is demonstrated. The fabricated pin-shaped nanostructures are tested in SERS measurements showing a significant increase in the enhancement factor in the order of 106. Thus, this work suggests a way of engineering 3D morphology to tune the substrate influence on the plasmonic properties of nanostructures and to develop efficient nanofabrication technologies.

Summary: Autism spectrum disorder (ASD) is diagnosed three to four times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common inherited genetic risk for ASD are less studied, particularly within families. Leveraging the Danish iPSYCH resource, we found siblings of female ASD cases (n = 1,707) had higher rates of ASD than siblings of male ASD cases (n = 6,270; p

Abstract Background Renal lymphoma in dogs is rare and has a poor prognosis. Granular lymphocyte morphology is rarely reported in canine renal lymphoma. Mild to moderate polycythemia is reported in a number of canine renal lymphoma cases. Case presentation A 10-year-old Labrador retriever presented to a university veterinary teaching hospital after a 1-month history of polyuria, polydipsia, and pollakiuria and a 2-week history of abdominal distention, lethargy, and increased respiratory effort. Abdominal ultrasound showed a wedge-shaped to rounded, heterogeneously hypoechoic mass lesion in the left kidney. Cytologic analysis of a percutaneous aspirate of the mass was consistent with lymphoma of granular lymphocytes. Severe polycythemia (hematocrit 0.871) was noted on a complete blood cell count. Clonality analysis identified a clonally rearranged T-cell receptor (TCR) gene and immunohistochemical staining was CD3+, CD79a- and CD11d+, supporting cytotoxic T-cell lymphoma. Conclusions To our knowledge, this is the first report of renal cytotoxic T-cell lymphoma with severe polycythemia in a dog. Severe polycythemia and renal cytotoxic T-cell lymphoma are both rare in dogs; this report adds to the body of knowledge on these conditions.

Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.

Abstract Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.

BackgroundJust-in-time adaptive interventions (JITAIs) provide real time in-the-moment behavior change support to people when they need it most. JITAIs could be a viable way to provide personalized physical activity (PA) support to older adults in the community. However, it is unclear how feasible it is to remotely deliver a PA intervention through a smartphone to older adults or how acceptable they would find a JITAI targeting PA in everyday life. ObjectiveThe aims of this study are to describe the development of JitaBug, a personalized smartphone-delivered JITAI designed to support older adults to increase or maintain their PA level, assess the feasibility of conducting an effectiveness trial of the JitaBug intervention, and explore the acceptability of JitaBug among older adults in a free-living setting. MethodsThe intervention was developed using the Behavior Change Wheel and consisted of a wearable activity tracker (Fitbit) and a companion smartphone app (JitaBug) that delivered goal-setting, planning, reminders, and JITAI messages to encourage achievement of personalized PA goals. Message delivery was tailored based on time of day, real time PA tracker data, and weather conditions. We tested the feasibility of remotely delivering the intervention with older adults in a 6-week trial. Data collection involved assessment of PA through accelerometery and activity tracker, self-reported mood and mental well-being through ecological momentary assessment, and contextual information on PA through voice memos. Feasibility outcomes included recruitment capability and adherence to the intervention, intervention delivery in the wild, appropriateness of data collection methodology, adverse events, and participant satisfaction. ResultsOf the 46 recruited older adults (aged 56-72 years), 31 (67%) completed the intervention. The intervention was successfully delivered as intended; 87% (27/31) of the participants completed the intervention independently; 94% (2247/2390) of the PA messages were successfully delivered; 99% (2239/2261) of the Fitbit and 100% (2261/2261) of the weather data calls were successful. Valid and usable wrist-worn accelerometer data were obtained from 90% (28/31) of the participants at baseline and follow-up. On average, the participants recorded 50% (7.9/16, SD 7.3) of the voice memos, 38% (3.3/8, SD 4.2) of the mood assessments, and 50% (2.1/4, SD 1.6) of the well-being assessments through the app. Overall acceptability of the intervention was very good (23/30, 77% expressed satisfaction). Participant feedback suggested that more diverse and tailored PA messages, app use reminders, technical refinements, and an improved user interface could improve the intervention and make it more appealing. ConclusionsThis study suggests that a smartphone-delivered JITAI is an acceptable way to support PA in older adults in the community. Overall, the intervention is feasible; however, based on user feedback, the JitaBug app requires further technical refinements that may enhance use, engagement, and user satisfaction before moving to effectiveness trials.

Understanding the biological identity of nanoparticles has mainly focused on the hard protein corona with the soft corona largely overlooked. Here, using click-chemistry, the authors report on a capture system for the identification of the soft corona proteins and investigate the effects on cell interactions.

The demand for telemedicine has been increasing over the past several years with the growth of technology and digital connectivity in our daily lives. With the impact of the global coronavirus disease 2019 pandemic, telemedicine implementation has become a necessity for many specialties because social distancing measures have greatly affected access to routine medical care. This article presents a detailed and systematic approach to conducting a hand physical examination during a video telemedicine encounter. Although the telemedicine physical examination has limitations, most components of the normal physical examination can be completed remotely with a systematic approach. We enumerate modifications to maximize examination remotely and present considerations for improved delivery of telemedicine care. These methods may be beneficial to providers incorporating telemedicine into their practice.

Background: This study examined the volume and patterns of physical activity (PA) and sedentary time (ST) across different segments of the week among boys and girls. Methods: A total of 188 children aged 7–12 years wore a wrist-mounted ActiGraph GT3X+ accelerometer for 7 days. Time spent in PA and ST was calculated using ActiLife software. The mean number of minutes of light PA, moderate PA, vigorous PA, moderate-to-vigorous PA (MVPA), and ST were calculated per weekday (before school, during school, and after school) and per weekend day (morning and afternoon–evening). Results: After school represented the greatest accumulation of ST compared with before school and during school segments. Boys engaged in 225.4 min/day of ST (95% confidence interval (CI): 216–235), and girls engaged in 222.2 min/day of ST (95%CI: 213–231). During school, boys engaged in significantly more MVPA than girls (46.1 min/day (95%CI: 44–48) vs. 40.7 min/day (95%CI: 39–43)). Across the whole weekday, boys participated in significantly more MVPA than girls (103.9 min/day (95%CI: 99–109) vs. 95.7 min/day (95%CI: 90–101)). The weekend afternoon–evening segment represented the larger accumulation of ST, where boys were significantly more sedentary than girls (367.5 min/day (95%CI: 353–382) vs. 339.8 min/day (95%CI: 325–355), respectively). Conclusion: Our findings suggest that children are highly sedentary and spend little of their time in school in MVPA, especially girls. Routine breaks in school elicit increases in light PA and MVPA. Future work should consider the use of more active breaks within school time to encourage PA and reduce ST. Keywords: Accelerometry, School, Segments, Weekday, Youth

Abstract Background Interventions to encourage active modes of travel (walking, cycling) may improve physical activity levels, but longitudinal evidence is limited and major change in the built environment / travel infrastructure may be needed. East Village (the former London 2012 Olympic Games Athletes Village) has been repurposed on active design principles with improved walkability, open space and public transport and restrictions on residential car parking. We examined the effect of moving to East Village on adult travel patterns. Methods One thousand two hundred seventy-eight adults (16+ years) seeking to move into social, intermediate, and market-rent East Village accommodation were recruited in 2013–2015, and followed up after 2 years. Individual objective measures of physical activity using accelerometry (ActiGraph GT3X+) and geographic location using GPS travel recorders (QStarz) were time-matched and a validated algorithm assigned four travel modes (walking, cycling, motorised vehicle, train). We examined change in time spent in different travel modes, using multilevel linear regresssion models adjusting for sex, age group, ethnicity, housing group (fixed effects) and household (random effect), comparing those who had moved to East Village at follow-up with those who did not. Results Of 877 adults (69%) followed-up, 578 (66%) provided valid accelerometry and GPS data for at least 1 day (≥540 min) at both time points; half had moved to East Village. Despite no overall effects on physical activity levels, sizeable improvements in walkability and access to public transport in East Village resulted in decreased daily vehicle travel (8.3 mins, 95%CI 2.5,14.0), particularly in the intermediate housing group (9.6 mins, 95%CI 2.2,16.9), and increased underground travel (3.9 mins, 95%CI 1.2,6.5), more so in the market-rent group (11.5 mins, 95%CI 4.4,18.6). However, there were no effects on time spent walking or cycling. Conclusion Designing walkable neighbourhoods near high quality public transport and restrictions on car usage, may offer a community-wide strategy shift to sustainable transport modes by increasing public transport use, and reducing motor vehicle travel.

In modern life, several factors such as genetics, exposure to toxins, and aging have resulted in significant levels of male infertility, estimated to be approximately 18% worldwide. In response, substantial progress has been made to improve in vitro fertilization treatments (e.g. microsurgical testicular sperm extraction (m-TESE), intra-cytoplasmic sperm injection (ICSI), and round spermatid injection (ROSI)). Mimicking the structure of testicular natural extracellular matrices (ECM) outside of the body is one clear route toward complete in vitro spermatogenesis and male fertility preservation. Here, a new wave of technological innovations is underway applying regenerative medicine strategies to cell-tissue culture on natural or synthetic scaffolds supplemented with bioactive factors. The emergence of advanced bioengineered systems suggests new hope for male fertility preservation through development of functional male germ cells. To date, few studies aimed at in vitro spermatogenesis have resulted in relevant numbers of mature gametes. However, a substantial body of knowledge on conditions that are required to maintain and mature male germ cells in vitro is now in place. This review focuses on advanced bioengineering methods such as microfluidic systems, bio-fabricated scaffolds, and 3D organ culture applied to the germline for fertility preservation through in vitro spermatogenesis.

Background Identifying predictors of success in postgraduate examinations can help guide the career choices of medical students and may aid early identification of trainees requiring extra support to progress in specialty training. We assessed whether performance on the educational performance measurement (EPM) and situational judgement test (SJT) used for selection into foundation training predicted success at the Membership of the Royal College of Surgeons (MRCS) examination.Methods This was a longitudinal, cohort study using data from the UK Medical Education Database (https://www.ukmed.ac.uk). UK medical graduates who had attempted Part A (n=2585) and Part B (n=755) of the MRCS between 2014 and 2017 were included. χ2 and independent t-tests were used to examine the relationship between medical school performance and sociodemographic factors with first-attempt success at MRCS Part A and B. Multivariate logistic regression was employed to identify independent predictors of MRCS performance.Results The odds of passing MRCS increased by 55% for Part A (OR 1.55 (95% CI 1.48 to 1.61)) and 23% for Part B (1.23 (1.14 to 1.32)) for every additional EPM decile point gained. For every point awarded for additional degrees in the EPM, candidates were 20% more likely to pass MRCS Part A (1.20 (1.13 to 1.29)) and 17% more likely to pass Part B (1.17 (1.04 to 1.33)). For every point awarded for publications in the EPM, candidates were 14% more likely to pass MRCS Part A (1.14 (1.01 to 1.28)). SJT score was not a statistically significant independent predictor of MRCS success.Conclusion This study has demonstrated the EPM’s independent predictive power and found that medical school performance deciles are the most significant measure of predicting later success in the MRCS. These findings can be used by medical schools, training boards and workforce planners to inform evidence-based and contemporary selection and assessment strategies.

Various host factors may impact within-host pathogen evolution. Here, the authors develop a Bayesian approach for identifying host-pathogen interactions using large data sets of pathogen diversity, and apply it to investigate HLA-induced selection in the HIV-1 genome.

The study of physical activity in older adults is becoming more and more relevant. For evaluation of physical activity recommendations, intensity-specific accelerometer cut-points are utilized. However, research on accelerometer cut-points for older adults is still scarce. The aim of the study was to generate placement-specific cut-points of ActiGraph GT3X+ activity counts and raw measures of acceleration to determine physical activity intensity in older adults. A further aim was to compare the validity of the generated cut-points for a range of different physical activities. The study was a single experimental trial using a convenience sample. Study participants were 20 adults aged 59 to 73 years. Accelerometers were worn at six different placements (one on each wrist, one on each ankle, and two at the hip) and breath-by-breath indirect calorimetry was used as the reference for energy. The experiment comprised of two parts; a) The first required participants to walk on a treadmill at incremental speeds (3.0-5.0 km·h-1), and b) Five different everyday activities (reading, cleaning, shopping, cycling, aerobics) were staged in the laboratory setting. Accelerometer cut-points (activity counts, raw data) were derived for each of the investigated placements by linear regression using the treadmill part. Performance of the cut-points was assessed by applying the cut-points to the everyday activities. We provide cut-points for six placements and two accelerometer metrics in the specific age group. However, the derived cut-points did not outperform published ones. More research and innovative approaches are needed for improving internal and external validity of research results across populations and age groups.

Retinal axon projections form a map of the visual environment in the tectum. A zebrafish larva typically detects a prey object in its peripheral visual field. As it turns and swims towards the prey, the stimulus enters the central, binocular area, and seemingly expands in size. By volumetric calcium imaging, we show that posterior tectal neurons, which serve to detect prey at a distance, tend to respond to small objects and intrinsically compute their direction of movement. Neurons in anterior tectum, where the prey image is represented shortly before the capture strike, are tuned to larger object sizes and are frequently not direction-selective, indicating that mainly interocular comparisons serve to compute an object’s movement at close range. The tectal feature map originates from a linear combination of diverse, functionally specialized, lamina-specific, and topographically ordered retinal ganglion cell synaptic inputs. We conclude that local cell-type composition and connectivity across the tectum are adapted to the processing of location-dependent, behaviorally relevant object features.

Case summary A case of nasal adenocarcinoma as a suspected secondary malignant neoplasm following definitive radiation therapy and multiagent chemotherapy for nasal lymphoma is described. An 11-year-old spayed female domestic shorthair cat was presented for a 3-week history of progressive facial swelling located over the nasal planum and extending to the medial canthus of the right eye. The cat was previously diagnosed with nasal lymphoma and treated with chemotherapy and definitive radiation 2.5 years prior. Although a definitive diagnosis could not be obtained via cytology, recurrent lymphoma was suspected based on the cat’s history and recurrent clinical signs. A lymphoma-directed chemotherapy protocol was attempted, but no clinical response was achieved. The cat was euthanased owing to progressive clinical signs and a diagnosis of nasal adenocarcinoma was made on necropsy examination. Both the original diagnosis of nasal lymphoma and the secondary diagnosis of nasal adenocarcinoma were confirmed with immunohistochemistry. Relevance and novel information Secondary malignant neoplasm following radiation therapy is infrequently reported in the veterinary literature. In the few reports that exist, most have described sarcoma development in the dog following radiation therapy. In the present report, we describe a cat with a suspected radiation-induced nasal adenocarcinoma that developed 2.5 years after definitive radiation treatment for nasal lymphoma.

This paper examines the use of risk models to predict the timing and location of wildfires caused by electricity infrastructure. Our data include historical ignition and wire-down points triggered by grid infrastructure collected between 2015–2019 in Pacific Gas & Electricity territory along with various weather, vegetation, and very high resolution data on grid infrastructure including location, age, and materials. With these data we explore a range of machine learning methods and strategies to manage training data imbalance. The best area under the receiver operating characteristic we obtain is 0.776 for distribution feeder ignitions and 0.824 for transmission line wire-down events, both using the histogram-based gradient boosting tree algorithm with under-sampling. We then use these models to identify which information provides the most predictive value. After line length, we find that weather and vegetation features dominate the list of top important features for ignition or wire-down risk. Distribution ignition models show more dependence on slow-varying vegetation variables such as burn index, energy release content, and tree height, whereas transmission wire-down models rely more on primary weather variables such as wind speed and precipitation. These results point to the importance of improved vegetation modeling for feeder ignition risk models, and improved weather forecasting for transmission wire-down models. We observe that infrastructure features make small but meaningful improvements to risk model predictive power.

Current influenza vaccine approaches largely focus on highly variable epitopes with high immunogenicity or epitopes of low variability that often have low immunogenicity. Here, Thompson et al. identify a highly immunogenic epitope of limited variability in the head domain of the H1 haemagglutinin and show protection from diverse H1N1 strains in mice.

Abstract Background Increases in physical activity through active travel have the potential to have large beneficial effects on populations, through both better health outcomes and reduced motorized traffic. However accurately identifying travel mode in large datasets is problematic. Here we provide an open source tool to quantify time spent stationary and in four travel modes(walking, cycling, train, motorised vehicle) from accelerometer measured physical activity data, combined with GPS and GIS data. Methods The Examining Neighbourhood Activities in Built Living Environments in London study evaluates the effect of the built environment on health behaviours, including physical activity. Participants wore accelerometers and GPS receivers on the hip for 7 days. We time-matched accelerometer and GPS, and then extracted data from the commutes of 326 adult participants, using stated commute times and modes, which were manually checked to confirm stated travel mode. This yielded examples of five travel modes: walking, cycling, motorised vehicle, train and stationary. We used this example data to train a gradient boosted tree, a form of supervised machine learning algorithm, on each data point (131,537 points), rather than on journeys. Accuracy during training was assessed using five-fold cross-validation. We also manually identified the travel behaviour of both 21 participants from ENABLE London (402,749 points), and 10 participants from a separate study (STAMP-2, 210,936 points), who were not included in the training data. We compared our predictions against this manual identification to further test accuracy and test generalisability. Results Applying the algorithm, we correctly identified travel mode 97.3% of the time in cross-validation (mean sensitivity 96.3%, mean active travel sensitivity 94.6%). We showed 96.0% agreement between manual identification and prediction of 21 individuals’ travel modes (mean sensitivity 92.3%, mean active travel sensitivity 84.9%) and 96.5% agreement between the STAMP-2 study and predictions (mean sensitivity 85.5%, mean active travel sensitivity 78.9%). Conclusion We present a generalizable tool that identifies time spent stationary and time spent walking with very high precision, time spent in trains or vehicles with good precision, and time spent cycling with moderate precisionIn studies where both accelerometer and GPS data are available this tool complements analyses of physical activity, showing whether differences in PA may be explained by differences in travel mode. All code necessary to replicate, fit and predict to other datasets is provided to facilitate use by other researchers.

Neal Cooper,1 Mazen Roshdy,1 Jason D Sciarretta,1 Christoph Kaufmann,1 Scott Duncan,1 John Davis,1 Francisco Igor Macedo2 1Department of Surgery, Grand Strand Health, Myrtle Beach, SC, USA; 2Dewitt-Daughtry Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA Abstract: Popliteal artery injuries (PAIs) remain a challenging entity and carry the greatest risk of limb loss among traumatic lower extremity vascular injuries. Operative management of traumatic popliteal vascular injuries continues to evolve. Improved diagnostic imaging and the introduction of endovascular techniques offered alternative modalities to traditional surgical management. Despite major efforts in establishing protocols and guidelines in the management of vascular trauma, optimal strategies of traumatic PAIs are still under investigation. Herein, we discussed the role of multidisciplinary team, involving trauma and endovascular surgeons, emergency department personnel, and interventional radiologists in the management of complex PAIs. Keywords: multidisciplinary, popliteal artery injury, trauma

Kynurenine-3-monooxygenase (KMO) is an emerging clinical target for treatment of neurodegenerative diseases and acute pancreatitis. Here, the authors report potent inhibitors that bind KMO in an unexpected conformation, offering structural and mechanistic insights for future drug discovery ventures.

Background: Limited studies have examined the diagnostic performance of body mass index (BMI), waist circumference (WC) or waist-to-height ratio (WHtR) for identifying cardiometabolic risk (increased clustered glucose, triglycerides, mean arterial pressure and inv-HDL-cholesterol) in pre-adolescent youth. Aim: To compare the utility of BMI, WC and WHtR as predictors of cardiometabolic risk (CMR) in Scottish pre-adolescent children. Subjects and methods: A cross-sectional analysis of 223 Scottish children (55.2% boys, mean age =8.4 years) was undertaken. BMI, WC and WHtR were used as exposure variables within multivariate logistic regression analysis and ROC analysis to examine the utility of these anthropometrical indices in identifying those at cardiometabolic risk. Results: Individuals with an elevated WHtR, WC and BMI were 3.51 (95% CI = 1.71–7.23; p

Plain English summary Researchers who conduct studies in health and social care are encouraged to involve the public as early as possible in the process of designing their studies. Before their studies are allowed to start researchers must seek approval from a Research Ethics Committee, which will assess whether the study is going to be safe and ethical for patients or healthy volunteers to take part in. The process of ethical review does not consider how researchers work with patients and the public early on to design their studies. Furthermore, there is no requirement for researchers to seek ethical approval for public involvement. However, in our work advising researchers about public involvement we have found that the ways in which researchers involve the public in the design of their studies are sometimes unintentionally unethical, and this is the focus of our paper. We have observed ten areas where ethical issues may arise because of the actions researchers may or may not take and which might consequently have a negative impact. Therefore, we have used these observations to develop a “framework” to help researchers and the public work together at the early design stage in ways that are ethical. Our intention for the framework is to help researchers be mindful of these ten areas and how easily ethical issues can arise. The framework suggests some ways to overcome the potential issues in each of the ten areas. The ten areas are: 1) Allocating sufficient time for public involvement; 2) Avoiding tokenism; 3) Registering research design stage public involvement work with NHS Research & Development Trust Office at earliest opportunity; 4) Communicating clearly from the outset; 5) Entitling public contributors to stop their involvement for any unstated reasons; 6) Operating fairness of opportunity; 7) Differentiating qualitative research methods and public involvement activities; 8) Working sensitively; 9) Being conscious of confidentiality and 10) Valuing, acknowledging and rewarding public involvement. We looked to see whether any other similar approaches to helping researchers address potential ethical issues when working with the public on designing studies have been published and to our knowledge none exist. Our framework is presented as a draft and believe that it would now benefit from input from researchers and the public to gauge how useful it is and whether there are any other possible situations that it might need to cover. Abstract The current paper highlights real life examples of how ethical issues can arise during public involvement activities at the research design stage. We refer to “the research design stage” as the time between the generation of the research ideas and when formal permissions to start the work including ethical approval are granted. We argue that although most researchers work ethically at this early stage, some may still benefit from being informed about ethically conscious approaches to involving the public. The paper highlights 10 ethical issues that we have observed with involving the public at the research design stage. We provide examples of these observed scenarios to illustrate the issues and make suggestions for how they can be avoided to help researchers become more ethically conscious when involving the public at the research design stage. Currently the draft framework comprises: 1) Allocating sufficient time for public involvement; 2) Avoiding tokenism; 3) Registering research design stage public involvement work with NHS Research & Development Trust Office at earliest opportunity; 4) Communicating clearly from the outset; 5) Entitling public contributors to stop their involvement for any unstated reasons; 6) Operating fairness of opportunity; 7) Differentiating qualitative research methods and public involvement activities; 8) Working sensitively; 9) Being conscious of confidentiality and 10) Valuing, acknowledging and rewarding public involvement. The draft framework will help researchers to recognise the ethical issues when involving the public and is intended to be used voluntarily in a self-regulatory way. We believe that the draft framework requires further consultation and input from the wider research community and the public before endorsement by national UK bodies such as INVOLVE and the Health Research Authority (HRA).

Background: Recommendations on resistance training (RT) set-volume protocols in preparation for spaceflight muscular strength conditioning remains equivocal. A meta-analysis was performed on the effects of single-set (S), or three-set (M3) RT on muscular strength per exercise for different body segments and joint types (multi-joint and single-joint).Methods: Computerized searches were performed on PubMed, MEDLINE and SPORTDiscus™. Twelve studies were considered appropriate according to pre-set eligibility criteria. Outcomes analyzed were pre-to-post-muscular strength change on; multi-joint and single-joint combined; upper body only; lower body only; multi-joint exercises only; single-joint exercises only.Results: Upper body exercise analysis on combined subjects and untrained subjects only reported greater but not significant strength gains with M3 (ES 0.37; 95% CI 0.09–0.82; P = 0.11 and ES 0.35; 95% CI−0.49 to 1.19; P = 0.42). Trained only subjects reported superior strength gains with M3 (ES 0.63; 95% CI 0.34–0.92; P =

Previous school-based interventions have produced positive effects upon measures of children's health and wellbeing but such interventions are often delivered by external experts which result in short-term effects. Thus, upskilling and expanding the resources available to classroom teachers could provide longer-term solutions. This paper presents a feasibility study of an online health resource (Healthy Schools Resource: HSR) developed to assist primary school teachers in the delivery of health-related education. Four schools (n = 2 intervention) participated in this study. Study feasibility was assessed by recruitment, retention and completion rates of several outcomes including height, weight, waist circumference, blood pressure and several metabolic markers including HDL-cholesterol, triglycerides, glucose and dietary knowledge following a 10-12-week intervention period. The process evaluation involved fidelity checks of teachers' use of the HSR and post-intervention teacher interviews. A total of 614 consent forms were issued and 267 were returned (43%), of which, 201 confirmed consent for blood sampling (75%). Retention of children participating in the study was also high (96%). Of the 13 teachers who delivered the intervention to the children, four teachers were excluded from further analyses as they did not participate in the fidelity checks. Overall, teachers found the online resource facilitative of teaching health and wellbeing and several recommendations regarding the resource were provided to inform further evaluations. Recruitment and retention rates suggest that the teacher led intervention is feasible and acceptable to both teachers, parents and children. Initial findings provide promising evidence that given a greater sample size, a longer intervention exposure period and changes made to the resource, teachers' use of HSR could enhance measures of health and wellbeing in children.

INTRODUCTION:The components of minute ventilation, respiratory frequency and tidal volume, appear differentially regulated and thereby afford unique insight into the ventilatory response to exercise. However, respiratory frequency and tidal volume are infrequently reported, and have not previously been considered among military veterans with Gulf War Illness. Our purpose was to evaluate respiratory frequency and tidal volume in response to a maximal cardiopulmonary exercise test in individuals with and without Gulf War Illness. MATERIALS AND METHODS:20 cases with Gulf War Illness and 14 controls participated in this study and performed maximal cardiopulmonary exercise test on a cycle ergometer. Ventilatory variables (minute ventilation, respiratory frequency and tidal volume) were obtained and normalized to peak exercise capacity. Using mixed-design analysis of variance models, with group and time as factors, we analyzed exercise ventilatory patterns for the entire sample and for 11 subjects from each group matched for race, age, sex, and height. RESULTS:Despite similar minute ventilation (p = 0.57, η2p = 0.01), tidal volume was greater (p = 0.02, η2p = 0.16) and respiratory frequency was lower (p = 0.004, η2p = 0.24) in Veterans with Gulf War Illness than controls. The findings for respiratory frequency remained significant in the matched subgroup (p = 0.004, η2p = 0.35). CONCLUSION:In our sample, veterans with Gulf War Illness adopt a unique exercise ventilatory pattern characterized by reduced respiratory frequency, despite similar ventilation relative to controls. Although the mechanism(s) by which this pattern is achieved remains unresolved, our findings suggest that the components of ventilation should be considered when evaluating clinical conditions with unexplained exertional symptoms.

The biomolecule layer adsorbed at the nanoparticle surface and defined as protein corona affects the nanoparticle biophysical properties and functions. Here, the authors suggest that rapidly-exchanging proteins on the outermost layer of the corona modulate sulphidation of silver nanoparticles in vitro.

A simple approach to enhance the refractive index sensitivity of gold nanodisks immobilized on electrically conducting indium tin oxide (ITO) substrates has been demonstrated. A two-fold increase in sensitivity to bulk refractive index change was achieved by substrate under-etching of gold nanodisks on ITO in 50 mM sulfuric acid. The influence of an intermediate titanium adhesion layer was investigated and was found to markedly influence the etching pattern and time. Etching with an adhesion layer resulted in enhanced refractive index sensitivity on disk-on-pin like structures after long etching times, whereas etching of disks deposited directly on ITO resulted in a disk-on-pincushion like configuration and similarly enhanced sensitivity already at shorter times. The gold disks remained electrically connected to the ITO substrate throughout etching and allowed site-specific electrodeposition of poly(3-aminophenol) at the nanodisks, showing enhanced thin-film refractive index sensitivity. This work demonstrates a simple method for enhancing refractive index sensitivity of nanostructures on ITO substrates for combined electrochemical and optical platforms, and subsequently a method to modify the surface of the electrically connected nanostructures, which has potential application in biosensing.

Background: Given the current global child obesity epidemic, testing the effectiveness of interventions in reducing obesity and its influencers is paramount. The purpose of this study was to determine immediate and long-term changes in body mass index and psychosocial variables following a 10-week lifestyle intervention.Methods: Seven hundred and seventy participants (8.75 ± 0.98 years of age, 379 boys and 391 girls) took part in the study. Participants had height, weight, and psychosocial questionnaires assessed at pre- and post-control, pre- and post-intervention, and 6-months post-intervention. Participants completed a weekly 10-week intervention consisting of healthy eating and physical activity education, physical activity, parental involvement, and behavior change techniques. Regression models were fit with correlated errors where the correlation occurred only between time points, not between subjects, and the nesting effects of school and area deprivation were controlled.Results: Regression models revealed a significant decrease in body mass index from pre- to post-intervention of 0.8512 kg/m2 (P = 0.0182). No Changes in body mass index occurred from post-intervention to 6-month follow-up (P = 0.5446). The psychosocial variables did not significantly change.Conclusions: This lifestyle intervention may be an effective means for improving body mass index in primary school children in the short-term if the duration of the intervention is increased, but these changes may not be sustained without on-going support.

The plasmonic coupling between gold caps and holes in thin films was investigated experimentally and through finite-difference time-domain (FDTD) calculations. Sparse colloidal lithography combined with a novel thermal treatment was used to control the vertical spacing between caps and hole arrays and compared to separated arrays of holes or caps. Optical spectroscopy and FDTD simulations reveal strong coupling between the gold caps and both Bloch Wave-surface plasmon polariton (BW-SPP) modes and localized surface plasmon resonance (LSPR)-type resonances in hole arrays when they are in close proximity. The interesting and complex coupling between caps and hole arrays reveals the details of the field distribution for these simple to fabricate structures.