EvolvRehab-MoveWell telerehabilitation for stroke survivors: study protocol for a feasibility with embedded initial proof-of-concept study.

INTRODUCTION: Stroke is a leading cause of disability throughout the world. Unilateral upper limb impairment is common in people who have had a stroke. As a result of impaired upper limb function, people who have had a stroke often employ abnormal 'compensatory' movements. In the short term, these compensatory movements allow the individual to complete tasks, though long-term movement in this manner can lead to limitations. Telerehabilitation offers the provision of rehabilitation services to patients at a remote location using information and communication technologies. 'EvolvRehab' is one such telerehabilitation system, which uses activities to assess and correct compensatory upper body movements, although the feasibility of its use is yet to be determined in National Health Service services. Using EvolvRehab, we aim to assess the feasibility of 6 weeks telerehabilitation in people after a stroke. METHODS AND ANALYSIS: A multisite feasibility study with embedded design phase. Normally distributed data will be analysed using paired samples t-tests; non-normally distributed data will be analysed using related samples Wilcoxon signed rank tests. Thematic content analysis of interview transcripts will be used to investigate the usability and perceived usefulness of the EvolvRehab kit. ETHICS AND DISSEMINATION: This study has received ethical approval from Solihull Research Ethics Committee (REC reference: 23/WM/0054). Dissemination will be carried out according to the dissemination plan co-written with stroke survivors, including academic publications and presentations; written reports; articles in publications of stakeholder organisations; presentations to and publications for potential customers. TRIAL REGISTRATION NUMBER: NCT05875792.

Plasmid-Borne Biosynthetic Gene Clusters within a Permanently Stratified Marine Water Column.

Plasmids are mobile genetic elements known to carry secondary metabolic genes that affect the fitness and survival of microbes in the environment. Well-studied cases of plasmid-encoded secondary metabolic genes in marine habitats include toxin/antitoxin and antibiotic biosynthesis/resistance genes. Here, we examine metagenome-assembled genomes (MAGs) from the permanently-stratified water column of the Cariaco Basin for integrated plasmids that encode biosynthetic gene clusters of secondary metabolites (smBGCs). We identify 16 plasmid-borne smBGCs in MAGs associated primarily with Planctomycetota and Pseudomonadota that encode terpene-synthesizing genes, and genes for production of ribosomal and non-ribosomal peptides. These identified genes encode for secondary metabolites that are mainly antimicrobial agents, and hence, their uptake via plasmids may increase the competitive advantage of those host taxa that acquire them. The ecological and evolutionary significance of smBGCs carried by prokaryotes in oxygen-depleted water columns is yet to be fully elucidated.

From the Caribbean to the Arctic, the most abundant microplastic particles in the ocean have escaped detection.

Comprehensive methodologies for monitoring microplastics (MPs) in the ocean are critical for accurately assessing abundances across a broad size spectrum, and to document distributions, sources, sinks, temporal trends, and exposure risks for organisms. Discrete 0.5-L water samples from the northeastern-coast of Venezuela (NECV), Pacific-Arctic Ocean (PAO), and Gulf Stream Current (GSC) were analyzed by Raman microspectroscopy to detect MPs not captured by net-tow surveys. Equivalent spherical diameters (ESD) of most MPs were <5 µm, accounting for 68, 83, 86 % of total inventories in NECV, GSC, PAO samples. We did not observe a single MP particle >53 µm ESD. Abundances of MPs in the 0.5-200 µm size fraction were 5-6 orders of magnitude higher than previous surveys that were almost exclusively based on net tow collections of MPs > 300 µm ESD. Abundances of MPs in NECV samples were ~10-fold higher than those from PAO and GSC. The most abundant polymers were polypropylene (PP), polystyrene (PS) and polyethylene terephthalate (PET), consistent with composition of plastic waste generated globally.

Lower urinary tract symptoms in men: the TRIUMPH cluster RCT.

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery. Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care. Design: This was a two-arm cluster randomised controlled trial. Setting: The trial was set in 30 NHS general practice sites in England. Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms. Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention. Main outcome measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms. Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014). Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.. Trial registration: This trial is registered as ISRCTN11669964. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Urinary problems among men become more common with age. Nearly one-third of all men aged > 65 years experience some urinary symptoms, which can have a substantial effect on their daily lives. Symptoms include needing to pass urine more often, urgently or during the night, and difficulties in passing urine. Men are usually diagnosed and treated by their general practitioner, and should be offered advice on controlling their symptoms themselves (e.g. lifestyle changes and exercises) before trying tablets or surgery. However, it is not known how helpful such advice is, and how general practices can effectively provide it. Thirty general practices in the West of England and Wessex took part in the study. Practices were split into two groups, with each practice providing either the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions care package or the practice's usual care to all of its patients in the trial. The TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package included a booklet of advice to help control urinary symptoms, with a nurse or healthcare assistant directing men to relevant sections according to their symptoms, and providing follow-up contacts. We mainly assessed the benefits of the TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package, compared with usual care, by using a questionnaire on urinary symptoms completed by participants. A total of 1077 men with urinary symptoms that bothered them joined the study. The main result was that men reported greater improvement in urinary symptoms with the TRIUMPH care package than with usual care, 12 months after joining the study. We also found that men receiving the TRIUMPH care package had a slight improvement in quality of life and outlook on their urinary symptoms. There was no difference between the two groups in the number of patients referred to hospital for treatment, the type, number and severity of side effects or cost to the NHS. Overall, the TRIUMPH care package was more effective in treating men with urinary symptoms than usual care by their general practice.

Preserved particulate organic carbon is likely derived from the subsurface sulfidic photic zone of the Proterozoic Ocean: evidence from a modern, oxygen-deficient lake.

Biological processes in the Proterozoic Ocean are often inferred from modern oxygen-deficient environments (MODEs) or from stable isotopes in preserved sediment. To date, few MODE studies have simultaneously quantified carbon fixation genes and attendant stable isotopic signatures. Consequently, how carbon isotope patterns reflect these pathways has not been thoroughly vetted. Addressing this, we profiled planktonic productivity and quantified carbon fixation pathway genes and associated organic carbon isotope values (δ13 CPOC ) of size-fractionated (0.2-2.7 and >2.7 µm) particulate matter from meromictic Fayetteville Green Lake, NY, USA. The high-O2 Calvin-Benson-Bassham (CBB) gene (cbbL) was most abundant in the <2.7 µm size fraction in shallow oxic and deep hypoxic waters, corresponding with cyanobacterial and eukaryote algal populations. The low-O2 CBB gene (cbbM) was most abundant near the lower oxycline boundary in the larger size fraction, coincident with purple sulfur bacteria populations. The reverse citric acid cycle gene (aclB) was equally abundant in both size fractions in the deepest photic zone, coinciding with green sulfur bacteria populations. Methane coenzyme reductase A (mcrA), of anaerobic methane cyclers, was most abundant at the lower oxycline boundary in both size fractions, coinciding with Methanoregula populations. δ13 CPOC values overlapped with the high-O2 CBB fixation range except for two negative excursions near the lower oxycline boundary, likely reflecting assimilation of isotopically-depleted groundwater-derived carbon by autotrophs and sulfate-reducers. Throughout aphotic waters, δ13 CPOC values of the large size fraction became 13 C-enriched, likely reflecting abundant purple sulfur bacterial aggregates. Eukaryote algae- or cyanobacteria-like isotopic signatures corresponded with increases in cbbL, cbbM, and aclB, and enrichment of exopolymer-rich prokaryotic photoautotrophs aggregates. Results suggest that δ13 CPOC values of preserved sediments from areas of the Proterozoic Ocean with sulfidic photic zones may reflect a mixture of alternate carbon-fixing populations exported from the deep photic zone, challenging the paradigm that sedimentary stable carbon isotope values predominantly reflect oxygenic photosynthesis from surface waters.

Cost-effectiveness of a primary healthcare intervention to treat male lower urinary tract symptoms: the TRIUMPH cluster randomised controlled trial.

OBJECTIVES: To estimate the cost-effectiveness of a primary care intervention for male lower urinary tract symptoms (LUTS) compared with usual care. DESIGN: Economic evaluation alongside a cluster randomised controlled trial from a UK National Health Service (NHS) perspective with a 12-month time horizon. SETTING: Thirty NHS general practice sites in England. PARTICIPANTS: 1077 men aged 18 or older identified in primary care with bothersome LUTS. INTERVENTIONS: A standardised and manualised intervention for the treatment of bothersome LUTS was compared with usual care. The intervention group (n=524) received a standardised information booklet with guidance on conservative treatment for LUTS, urinary symptom assessment and follow-up contacts for 12 weeks. The usual care group (n=553) followed local guidelines between general practice sites. MEASURES: Resource use was obtained from electronic health records, trial staff and participants, and valued using UK reference costs. Quality-adjusted life-years (QALYs) were calculated from the EQ-5D-5L questionnaire. Adjusted mean differences in costs and QALYs and incremental net monetary benefit were estimated. RESULTS: 866 of 1077 (80.4%) participants had complete data and were included in the base-case analysis. Over the 12-month follow-up period, intervention and usual care arms had similar mean adjusted costs and QALYs. Mean differences were lower in the intervention arm for adjusted costs -£29.99 (95% CI -£109.84 to £22.63) while higher in the intervention arm for adjusted QALYs 0.001 (95% CI -0.011 to 0.014). The incremental net monetary benefit statistic was £48.01 (95% CI -£225.83 to £321.85) at the National Institute for Health and Care Excellence UK threshold of £20 000 per QALY. The cost-effectiveness acceptability curve showed a 63% probability of the intervention arm being cost-effective at this threshold. CONCLUSIONS: Costs and QALYs were similar between the two arms at 12 months follow-up. This indicates that the intervention can be implemented in general practice at neutral cost. TRIAL REGISTRATION NUMBER: ISRCTN11669964.

Microbes and microplastics: Community shifts along an urban coastal contaminant gradient.

Plastic substrates introduced to the environment during the Anthropocene have introduced new pathways for microbial selection and dispersal. Some plastic-colonising microorganisms have adapted phenotypes for plastic degradation (selection), while the spatial transport (dispersal) potential of plastic colonisers remains controlled by polymer-specific density, hydrography and currents. Plastic-degrading enzyme abundances have recently been correlated with concentrations of plastic debris in open ocean environments, making it critical to better understand colonisation of hydrocarbon degraders with plastic degradation potential in urbanised watersheds where plastic pollution often originates. We found that microbial colonisation by reputed hydrocarbon degraders on microplastics (MPs) correlated with a spatial contaminant gradient (New York City/Long Island waterways), polymer types, temporal scales, microbial domains and putative cell activity (DNA vs. RNA). Hydrocarbon-degrading taxa enriched on polyethylene and polyvinyl chloride substrates relative to other polymers and were more commonly recovered in samples proximal to New York City. These differences in MP colonisation could indicate phenotypic adaptation processes resulting from increased exposure to urban plastic runoff as well as differences in carbon bioavailability across polymer types. Shifts in MP community potential across urban coastal contaminant gradients and polymer types improve our understanding of environmental plastic discharge impacts toward biogeochemical cycling across the global ocean.

Treatment of lower urinary tract symptoms in men in primary care using a conservative intervention: cluster randomised controlled trial.

OBJECTIVE: To determine whether a standardised and manualised care intervention in men in primary care could achieve superior improvement of lower urinary tract symptoms (LUTS) compared with usual care. DESIGN: Cluster randomised controlled trial. SETTING: 30 National Health Service general practice sites in England. PARTICIPANTS: Sites were randomised 1:1 to the intervention and control arms. 1077 men (≥18 years) with bothersome LUTS recruited between June 2018 and August 2019: 524 were assigned to the intervention arm (n=17 sites) and 553 were assigned to the usual care arm (n=13 sites). INTERVENTION: Standardised information booklet developed with patient and expert input, providing guidance on conservative and lifestyle interventions for LUTS in men. After assessment of urinary symptoms (manualised element), general practice nurses and healthcare assistants or research nurses directed participants to relevant sections of the manual and provided contact over 12 weeks to assist with adherence. MAIN OUTCOME MEASURES: The primary outcome was patient reported International Prostate Symptom Score (IPSS) measured 12 months after participants had consented to take part in the study. The target reduction of 2.0 points on which the study was powered reflects the minimal clinically important difference where baseline IPSS is <20. Secondary outcomes were patient reported quality of life, urinary symptoms and perception of LUTS, hospital referrals, and adverse events. The primary intention-to-treat analysis included 887 participants (82% of those recruited) and used a mixed effects multilevel linear regression model adjusted for site level variables used in the randomisation and baseline scores. RESULTS: Participants in the intervention arm had a lower mean IPSS at 12 months (adjusted mean difference -1.81 points, 95% confidence interval -2.66 to -0.95) indicating less severe urinary symptoms than those in the usual care arm. LUTS specific quality of life, incontinence, and perception of LUTS also improved more in the intervention arm than usual care arm at 12 months. The proportion of urology referrals (intervention 7.3%, usual care 7.9%) and adverse events (intervention seven events, usual care eight events) were comparable between the arms. CONCLUSIONS: A standardised and manualised intervention in primary care showed a sustained reduction in LUTS in men at 12 months. The mean difference of -1.81 points (95% confidence interval -0.95 to -2.66) on the IPSS was less than the predefined target reduction of 2.0 points. TRIAL REGISTRATION: ISRCTN Registry ISRCTN11669964.

The Web-Based Pain-at-Work Toolkit With Telephone Support for Employees With Chronic or Persistent Pain: Protocol for a Cluster Randomized Feasibility Trial.

BACKGROUND: Chronic or persistent pain affects one's ability to work or be productive at work, generating high societal and economic burden. However, the provision of work-related advice and support for people with chronic pain is variable or lacking. The Pain-at-Work (PAW) Toolkit was cocreated with people who live with pain, health care professionals, and employers. It aims to increase knowledge about employee rights and how to access support for managing a painful chronic condition in the workplace and provides advice on lifestyle behaviors that facilitate the management of chronic pain. OBJECTIVE: We aimed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing access to the PAW Toolkit and telephone support calls from an occupational therapist (PAW) with treatment as usual (ie, standard support from their employer). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, and safety of this digital workplace health intervention. We will assess the candidate primary and secondary outcomes' feasibility and test research processes for a definitive trial. METHODS: This is an open-label, parallel 2-arm pragmatic feasibility cluster randomized controlled trial with exploratory health economics analysis and a nested qualitative interview study. We aim to recruit 120 participants from at least 8 workplace clusters (any type, >10 employees) in England. The recruitment of workplaces occurs via personal approach, and the recruitment of individual participants is web based. Eligible participants are vocationally active adults aged ≥18 years with internet access and self-reporting chronic pain interfering with their ability to undertake or enjoy productive work. A restricted 1:1 cluster-level randomization is used to allocate employment settings to PAW or treatment as usual; participants are unblinded to group allocation. Following site- and individual-level consent, participants complete a web-based baseline survey (time 0), including measures of work capacity, health and well-being, and health care resource use. Follow-up is performed at 3 months (time 1) and 6 months (time 2). Feasibility outcomes relate to recruitment; intervention fidelity (eg, delivery, reach, uptake, and engagement); retention; and follow-up. Qualitative evaluation (time 2) is mapped to the Capability, Opportunity, Motivation-Behavior model and will explore intervention acceptability to employees and employers, along with individual and contextual factors influencing the delivery and uptake of the intervention. RESULTS: Ethics approval was obtained in March 2023. Trial recruitment began in June 2023. CONCLUSIONS: The PAW Toolkit is the first evidence-based digital health intervention aimed at supporting the self-management of chronic or persistent pain at work. This study will inform the design of a definitive trial, including sample size estimation, approaches to cluster site identification, primary and secondary outcomes' selection, and the final health economic model. Findings will inform approaches for the future delivery of this digital health intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05838677; https://clinicaltrials.gov/study/NCT05838677. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51474.

Ultrasound Directed Reduction of Colles' type distal radial fractures in ED (UDiReCT): a feasibility randomised controlled trial.

BACKGROUND: There is a high rate of surgical fixation of displaced Colles' type distal radial wrist fractures despite fracture manipulation in the ED. Point-of-care ultrasound has been used to guide ED manipulations but its effect on the quality of fracture reduction or subsequent need for surgical fixation is unknown. This study aims to assess the feasibility of conducting a definitive randomised controlled trial to assess the use of ultrasound to guide these fracture manipulations. METHODS: We conducted a pragmatic randomised controlled feasibility trial in two EDs in England over a 6-month period (7 October 2019 to 6 April 2020). Adult patients with wrist fractures undergoing manipulation in the ED were randomised 1:1 to ultrasound-guided distal radial fracture manipulation or manipulation with sham ultrasound. The primary outcome for this study was trial recruitment rate. Other measures were recorded to assess potential future definitive trial outcomes and feasibility. RESULTS: Of 120 patients meeting inclusion criteria, 48 (40%) were recruited and randomised in the two centres, giving overall recruitment rates of 0.3 and 1.8 participants per week at each site, respectively, and 1 participant per week overall. The most common reason that patients were not included was research staff availability. After 6 weeks, six patients in each group (26% intervention, 24% control) had undergone surgical fixation, with 98% data completeness for this potential definitive trial primary outcome. Randomisation, blinding and data collection processes were effective but there were data limitations in the X-ray assessment of fracture positions. CONCLUSION: A definitive study of a similar design would be feasible within UK ED practice but organisational factors and research staff availability should be considered when estimating the predicted recruitment rate and required sites. 6-week surgical fixation rate was the most reliable outcome measure. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03868696).

Diverse secondary metabolites are expressed in particle-associated and free-living microorganisms of the permanently anoxic Cariaco Basin.

Secondary metabolites play essential roles in ecological interactions and nutrient acquisition, and are of interest for their potential uses in medicine and biotechnology. Genome mining for biosynthetic gene clusters (BGCs) can be used for the discovery of new compounds. Here, we use metagenomics and metatranscriptomics to analyze BGCs in free-living and particle-associated microbial communities through the stratified water column of the Cariaco Basin, Venezuela. We recovered 565 bacterial and archaeal metagenome-assembled genomes (MAGs) and identified 1154 diverse BGCs. We show that differences in water redox potential and microbial lifestyle (particle-associated vs. free-living) are associated with variations in the predicted composition and production of secondary metabolites. Our results indicate that microbes, including understudied clades such as Planctomycetota, potentially produce a wide range of secondary metabolites in these anoxic/euxinic waters.

Transport-limited reactions in microbial systems.

Predicting microbial metabolic rates and emergent biogeochemical fluxes remains challenging due to the many unknown population dynamical, physiological and reaction-kinetic parameters and uncertainties in species composition. Here, we show that the need for these parameters can be eliminated when population dynamics and reaction kinetics operate at much shorter time scales than physical mixing processes. Such scenarios are widespread in poorly mixed water columns and sediments. In this 'fast-reaction-transport' (FRT) limit, all that is required for predictions are chemical boundary conditions, the physical mixing processes and reaction stoichiometries, while no knowledge of species composition, physiology or population/reaction kinetic parameters is needed. Using time-series data spanning years 2001-2014 and depths 180-900 m across the permanently anoxic Cariaco Basin, we demonstrate that the FRT approach can accurately predict the dynamics of major electron donors and acceptors (Pearson r ≥ 0.9 in all cases). Hence, many microbial processes in this system are largely transport limited and thus predictable regardless of species composition, population dynamics and kinetics. Our approach enables predictions for many systems in which microbial community dynamics and kinetics are unknown. Our findings also reveal a mechanism for the frequently observed decoupling between function and taxonomy in microbial systems.

One Cell at a Time: Advances in Single-Cell Methods and Instrumentation for Discovery in Aquatic Microbiology.

Studying microbes from a single-cell perspective has become a major theme and interest within the field of aquatic microbiology. One emerging trend is the unfailing observation of heterogeneity in activity levels within microbial populations. Wherever researchers have looked, intra-population variability in biochemical composition, growth rates, and responses to varying environmental conditions has been evident and probably reflect coexisting genetically distinct strains of the same species. Such observations of heterogeneity require a shift away from bulk analytical approaches and development of new methods or adaptation of existing techniques, many of which were first pioneered in other, unrelated fields, e.g., material, physical, and biomedical sciences. Many co-opted approaches were initially optimized using model organisms. In a field with so few cultivable models, method development has been challenging but has also contributed tremendous insights, breakthroughs, and stimulated curiosity. In this perspective, we present a subset of methods that have been effectively applied to study aquatic microbes at the single-cell level. Opportunities and challenges for innovation are also discussed. We suggest future directions for aquatic microbiological research that will benefit from open access to sophisticated instruments and highly interdisciplinary collaborations.

Cost-effectiveness of a physical activity and behaviour maintenance programme on functional mobility decline in older adults: an economic evaluation of the REACT (Retirement in Action) trial.

BACKGROUND: Mobility limitations in older populations have a substantial impact on health outcomes, quality of life, and social care costs. The Retirement in Action (REACT) randomised controlled trial assessed a 12-month community-based group physical activity and behaviour maintenance intervention to help prevent decline in physical functioning in older adults at increased risk of mobility limitation. We aimed to do an economic evaluation of the REACT trial to investigate whether the intervention is cost-effective. METHODS: In this health economic evaluation, we did cost-effectiveness and cost-utility analyses of the REACT programme versus standard care on the basis of resource use, primary outcome, and health-related quality-of-life data measured in the REACT trial. We also developed a decision analytic Markov model that forecasts the mobility of recipients beyond the 24-month follow-up of the trial and translated this into future costs and potential benefit to health-related quality of life using the National Health Service and Personal Social Services perspective. Participants completed questionnaire booklets at baseline, and at 6, 12, and 24 months after randomisation, which included a resource use questionnaire and the EQ-5D-5L and 36-item short-form survey (SF-36) health-related quality-of-life instruments. The cost of delivering the intervention was estimated by identifying key resources, such as REACT session leader time, time of an individual to coordinate the programme, and venue hire. EQ-5D-5L and SF-36 responses were converted to preference-based utility values, which were used to estimate quality-adjusted life-years (QALYs) over the 24-month trial follow-up using the area-under-the-curve method. We used generalised linear models to examine the effect of the REACT programme on costs and QALYs and adjust for baseline covariates. Costs and QALYs beyond 12 months were discounted at 3·5% per year. This is a pre-planned analysis of the REACT trial; the trial itself is registered with ISRCTN (ISRCTN45627165). FINDINGS: The 12-month REACT programme was estimated to cost £622 per recipient to deliver. The most substantial cost components are the REACT session leader time (£309 per participant), venue hire (£109), and the REACT coordinator time (£80). The base-case analysis of the trial-based economic evaluation showed that reductions in health and social care usage due to the REACT programme could offset the REACT delivery costs (£3943 in the intervention group vs £4043 in the control group; difference: -£103 [95% CI -£695 to £489]) with a health benefit of 0·04 QALYs (0·009-0·071; 1·354 QALYs in the intervention group vs 1·314 QALYs in the control group) within the 24-month timeframe of the trial. INTERPRETATION: The REACT programme could be considered a cost-effective approach for improving the health-related quality of life of older adults at risk of mobility limitations. FUNDING: National Institute for Health Research Public Health Research Programme.

Effect of a physical activity and behaviour maintenance programme on functional mobility decline in older adults: the REACT (Retirement in Action) randomised controlled trial.

BACKGROUND: Mobility limitations in old age can greatly reduce quality of life, generate substantial health and social care costs, and increase mortality. Through the Retirement in Action (REACT) trial, we aimed to establish whether a community-based active ageing intervention could prevent decline in lower limb physical functioning in older adults already at increased risk of mobility limitation. METHODS: In this pragmatic, multicentre, two-arm, single-blind, parallel-group, randomised, controlled trial, we recruited older adults (aged 65 years or older and who are not in full-time employment) with reduced lower limb physical functioning (Short Physical Performance Battery [SPPB] score 4-9) from 35 primary care practices across three sites (Bristol and Bath; Birmingham; and Devon) in England. Participants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal physical activity (64 1-h exercise sessions) and behavioural maintenance (21 45-min sessions) programme delivered by charity and community or leisure centre staff in local communities. Randomisation was stratified by site and adopted a minimisation approach to balance groups by age, sex, and SPPB score, using a centralised, online, randomisation algorithm. Researchers involved in data collection and analysis were masked but participants were not because of the nature of the intervention. The primary outcome was change in SPPB score at 24 months, analysed by intention to treat. This trial is registered with ISRCTN, ISRCTN45627165. FINDINGS: Between June 20, 2016, and Oct 30, 2017, 777 participants (mean age 77·6 [SD 6·8] years; 66% female; mean SPPB score 7·37 [1·56]) were randomly assigned to the intervention (n=410) and control (n=367) groups. Primary outcome data at 24 months were provided by 628 (81%) participants (294 in the control group and 334 in the intervention group). At the 24-month follow-up, the SPPB score (adjusted for baseline SPPB score, age, sex, study site, and exercise group) was significantly greater in the intervention group (mean 8·08 [SD 2·87]) than in the control group (mean 7·59 [2·61]), with an adjusted mean difference of 0·49 (95% CI 0·06-0·92; p=0·014), which is just below our predefined clinically meaningful difference of 0·50. One adverse event was related to the intervention; the most common unrelated adverse events were heart conditions, strokes, and falls. INTERPRETATION: For older adults at risk of mobility limitations, the REACT intervention showed that a 12-month physical activity and behavioural maintenance programme could help prevent decline in physical function over a 24-month period. FUNDING: National Institute for Health Research Public Health Research Programme (13/164/51).

Qualitative Assessment of the Conservative Management of Nocturia with Standardised Written Materials for Lower Urinary Tract Symptoms in Men Treated in Primary Care.

BACKGROUND: Many men prefer conservative treatment of lower urinary tract symptoms (LUTS) but education and self-help guidance are limited in primary care. OBJECTIVE: To report qualitative interview findings for men reporting nocturia in a primary care setting for LUTS. DESIGN, SETTING, AND PARTICIPANTS: TRIUMPH (Treating Urinary Symptoms in Men in Primary Healthcare) is a multicentre cluster randomised trial of standardised manualised care (a booklet delivered by a health care professional) versus usual care for LUTS. The participants (524 in the intervention arm and 553 in the usual care arm) were men presenting for primary care for LUTS at 30 general practice (GP) sites in the UK. INTERVENTION: Delivery of a LUTS self-management booklet by health care staff in comparison to usual care for men with LUTS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The qualitative component included 58 early-stage (0-3 mo after study enrolment) and 33 late-stage (3-9 mo later) interviews with participants to assess their experience of LUTS and conservative treatment in primary care. Purposive sampling was used to select participants for interview. RESULTS AND LIMITATIONS: Nocturia is a common driver for seeking health care and is perceived by men as relatively acceptable to discuss. Information and self-help guidance were largely absent from descriptions of GP consultations, other than reducing evening caffeine and fluid intake. The TRIUMPH LUTS intervention booklet offers explanations and self-management guidance. Men with long-term disruptive symptoms, a perception that the booklet content was novel or worthwhile, and a belief that self-management might help, were more receptive to the intervention. In follow-up, improvements in nocturia were related to successful implementation of several aspects of the guidance. Most men were willing to complete a bladder diary, but some found it inconvenient, especially men in employment. The characteristics of the trial population mean that the findings may not apply to all men. CONCLUSIONS: Reassuring men that nocturia is part of ageing without offering them information and support risks reinforcing the tendency to discount problematic LUTS. The trial booklet and the training of health care professionals support guidance on nocturia self-management, which is most effective for men receptive to this approach. However, the nature of the trial population means that the findings may not apply to all men. PATIENT SUMMARY: Men are more comfortable in discussing waking at night to urinate than talking about other urinary symptoms with their GP. This problem should lead to a detailed discussion of all urinary symptoms rather than being thought of as a sign of ageing. An information booklet and nurse consultation helped many men to improve this symptom.

The impact of universal cardiopulmonary exercise testing on perioperative pathways and short-term patient outcomes following elective pancreatic surgery: A retrospective cohort study.

Background: The utility of Cardiopulmonary Exercise Testing (CPET) to identify higher risk surgical patients remains controversial. There is limited research investigating the value of preoperative CPET to plan perioperative pathways for patients undergoing major pancreatic surgery. Methods: Retrospective cohort study, comprising two groups before and after a change in referral policy for High Risk preoperative anaesthetic clinic with CPET. Period 1 discretionary referral and Period 2: universal referral. The primary aim was to investigate the impact of this policy change on critical care use (planned vs unplanned) on the day of surgery and on delayed critical care admission. Secondary end points included a comparison of the total number of critical care bed days, days in hospital, complication rates and mortality data between the two cohorts. Results: 177 patients were included; 114 in Period 1 and 63 in Period 2. There was a reduction in unplanned day of surgery postoperative admissions to critical care (28.1% vs. 11.1%, p = 0.008). Seven (6.1%) of patients in Period 1 and 1 (1.6%) patient in Period 2 had delayed admission, though no p value was calculated due to the small numbers involved. Complication rates were similar in each group. The median critical care bed days was 1 (range 0-21) days in Period 1 and 1 (0-13) days in Period 2. Conclusions: A universal referral policy for preoperative CPET demonstrated a decrease in unplanned day of surgery critical care admissions and a trend towards reducing delayed (>24 h postop) critical care admission which could be investigated in a larger study. No measurable impact was seen on clinical outcomes.

Raman Microspectroscopy Goes Viral: Infection Dynamics in the Cosmopolitan Microalga, Emiliania huxleyi.

Emiliania huxleyi is a cosmopolitan member of the marine phytoplankton. This species' capacities for carbon sequestration and sulfur mobilization make it a key player in oceanic biogeochemical cycles that influence climate on a planetary scale. Seasonal E. huxleyi blooms are abruptly terminated by viral epidemics caused by a clade of large DNA viruses collectively known as coccolithoviruses (EhVs). EhVs thereby mediate a significant part of material and energy fluxes associated with E. huxleyi population dynamics. In this study, we use spontaneous Raman microspectroscopy to perform label-free and non-invasive measurements of the macromolecular composition of individual virions and E. huxleyi host cells. Our novel autofluorescence suppression protocol enabled spectroscopic visualization of evolving macromolecular redistributions in individual E. huxleyi cells at different stages of EhV infection. Material transfer from E. huxleyi hosts to single EhV-163 virions was confirmed by combining stable isotope probing (SIP) experiments with Raman microspectroscopy. Inheritance of the host cells' 13C-enriched isotopic signature was quantified based on red shifts of Raman peaks characteristic of phenylalanine's phenyl ring. Two-dimensional Raman mapping of EhV-infected E. huxleyi cells revealed that the compact region producing an intense Raman DNA signal (i.e., the nucleus) in healthy E. huxleyi cells becomes diffuse during the first hours of infection. Raman DNA emissions integrated throughout individual cells decreased during the infection cycle. Our observations are consistent with EhV-163 degrading the host's nuclear DNA, scavenging released nucleotides for its own genome replication, and shedding newly-produced virions prior to host lysis via budding.

Beating Adolescent Self-Harm (BASH): a randomised controlled trial comparing usual care versus usual care plus a smartphone self-harm prevention app (BlueIce) in young adolescents aged 12-17 who self-harm: study protocol.

INTRODUCTION: A mobile app, BlueIce, was codesigned with young people with a history of self-harm to provide them with more accessible and available evidence-based support at times of distress. A preliminary evaluation found that BlueIce was acceptable, safe and used by young people and helped to reduce self-harm. The present study is designed to assess the effectiveness and cost-effectiveness of adding BlueIce to usual Child and Adolescent Mental Health Service (CAMHS). METHODS AND ANALYSIS: This study is a single-blind, randomised controlled trial comparing usual CAMHS care with usual care plus BlueIce. A total of 138 adolescents aged 12-17 with current or a history of self-harm will be recruited through the Oxford Health National Health Service (NHS) Foundation Trust via their CAMHS clinician. The primary outcome is self-harm at 12 weeks assessed using the Risk Taking and Self-Harm Inventory for Adolescents. Secondary outcomes include mood, anxiety, hopelessness, general behaviour, sleep and impact on everyday life at 12 weeks and 6 months. Health-related quality of life and healthcare resource utilisation data will be collected at baseline, 12 weeks and 6 months. Postuse interviews at 12 weeks will determine the acceptability, safety and usability of BlueIce. ETHICS AND DISSEMINATION: The study was approved by the NHS South Central-Oxford B NHS Research Ethics Committee (19/SC/0212) and by the Health Research Authority (HRA) and Health and Care Research Wales. Findings will be disseminated in peer review open-access journals and at academic conferences. TRIAL REGISTRATION NUMBER: ISRCTN10541045.

Using Stable Isotope Probing and Raman Microspectroscopy To Measure Growth Rates of Heterotrophic Bacteria.

The suitability of stable isotope probing (SIP) and Raman microspectroscopy to measure growth rates of heterotrophic bacteria at the single-cell level was evaluated. Label assimilation into Escherichia coli biomass during growth on a complex 13C-labeled carbon source was monitored in time course experiments. 13C incorporation into various biomolecules was measured by spectral "red shifts" of Raman-scattered emissions. The 13C- and 12C-isotopologues of the amino acid phenylalanine (Phe) proved to be quantitatively accurate reporter molecules of cellular isotopic fractional abundances (fcell). Values of fcell determined by Raman microspectroscopy and independently by isotope ratio mass spectrometry (IRMS) over a range of isotopic enrichments were statistically indistinguishable. Progressive labeling of Phe in E. coli cells among a range of 13C/12C organic substrate admixtures occurred predictably through time. The relative isotopologue abundances of Phe determined by Raman spectral analysis enabled the accurate calculation of bacterial growth rates as confirmed independently by optical density (OD) measurements. The results demonstrate that combining SIP and Raman microspectroscopy can be a powerful tool for studying bacterial growth at the single-cell level on defined or complex organic 13C carbon sources, even in mixed microbial assemblages. IMPORTANCE Population growth dynamics and individual cell growth rates are the ultimate expressions of a microorganism's fitness under its environmental conditions, whether natural or engineered. Natural habitats and many industrial settings harbor complex microbial assemblages. Their heterogeneity in growth responses to existing and changing conditions is often difficult to grasp by standard methodologies. In this proof-of-concept study, we tested whether Raman microspectroscopy can reliably quantify the assimilation of isotopically labeled nutrients into E. coli cells and enable the determination of individual growth rates among heterotrophic bacteria. Raman-derived growth rate estimates were statistically indistinguishable from those derived by standard optical density measurements of the same cultures. Raman microspectroscopy can also be combined with methods for phylogenetic identification. We report the development of Raman-based techniques that enable researchers to directly link genetic identity to functional traits and rate measurements of single cells within mixed microbial assemblages, currently a major technical challenge in microbiological research.