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Background: Children from low-income and racial/ethnic minority backgrounds are more prone to insufficient physical activity and heightened sedentary behaviors. This study aims to increase moderate to vigorous physical activity and decrease sedentary behaviors among high-risk children through an inclusive and transformative sport skill development physical education (PE) intervention. Methods: Elementary school-aged children were recruited from 3 public schools located in underserved communities in Houston, TX. Classrooms were randomly assigned to a sport-based PE class (intervention, 12 classrooms, n = 124) or a standard PE class (control, 13 classrooms, n = 133). The intervention was implemented at school by teachers over 10 weeks, whereas at home, the intervention group received equipment, virtual classes, and parent trainings. Activity behaviors were assessed using accelerometry (ActiGraph GT3X+) at baseline and post intervention. Multilevel linear mixed-effects models were conducted to examine changes in activity behaviors between the study conditions. Results: Participants were 9.33 (0.68) years old, and 46% were females, who identified as either Hispanic/Latino (48%) and/or Black (38%). The difference in minutes of weekend sedentary behavior change was 32 minutes between study conditions (P =.012). Specifically, intervention girls decreased weekend sedentary behavior by 37 minutes, whereas girls in the control condition increased by 8 minutes (P <.01). Despite the direction of change in overall, weekday, or weekend moderate to vigorous physical activity and overall or weekday sedentary behaviors in favor of the intervention, these effects did not reach the statistically significant level compared to the control condition. Conclusions: Sport-based PE intervention can be an important strategy to decrease child sedentary behaviors during out-of-school periods, particularly among girls. [ABSTRACT FROM AUTHOR]

Mercury (Hg) methylation genes (hgcAB) mediate the formation of the toxic methylmercury and have been identified from diverse environments, including freshwater and marine ecosystems, Arctic permafrost, forest and paddy soils, coal-ash amended sediments, chlor-alkali plants discharges and geothermal springs. Here we present the first attempt at a standardized protocol for the detection, identification and quantification of hgc genes from metagenomes. Our Hg-cycling microorganisms in aquatic and terrestrial ecosystems (Hg-MATE) database, a catalogue of hgc genes, provides the most accurate information to date on the taxonomic identity and functional/metabolic attributes of microorganisms responsible for Hg methylation in the environment. Furthermore, we introduce marky-coco, a ready-to-use bioinformatic pipeline based on de novo single-metagenome assembly, for easy and accurate characterization of hgc genes from environmental samples. We compared the recovery of hgc genes from environmental metagenomes using the marky-coco pipeline with an approach based on coassembly of multiple metagenomes. Our data show similar efficiency in both approaches for most environments except those with high diversity (i.e., paddy soils) for which a coassembly approach was preferred. Finally, we discuss the definition of true hgc genes and methods to normalize hgc gene counts from metagenomes.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

High-throughput RNA sequencing offers broad opportunities to explore the Earth RNA virome. Mining 5,150 diverse metatranscriptomes uncovered >2.5 million RNA virus contigs. Analysis of >330,000 RNA-dependent RNA polymerases (RdRPs) shows that this expansion corresponds to a 5-fold increase of the known RNA virus diversity. Gene content analysis revealed multiple protein domains previously not found in RNA viruses and implicated in virus-host interactions. Extended RdRP phylogeny supports the monophyly of the five established phyla and reveals two putative additional bacteriophage phyla and numerous putative additional classes and orders. The dramatically expanded phylum Lenarviricota, consisting of bacterial and related eukaryotic viruses, now accounts for a third of the RNA virome. Identification of CRISPR spacer matches and bacteriolytic proteins suggests that subsets of picobirnaviruses and partitiviruses, previously associated with eukaryotes, infect prokaryotic hosts.

Small genes (40,000 small-gene families in ∼2.3 million phage genome contigs. We find that small genes in phage genomes are approximately 3-fold more prevalent than in host prokaryotic genomes. Our approach enriches for small genes that are translated in microbiomes, suggesting the small genes identified are coding. More than 9,000 families encode potentially secreted or transmembrane proteins, more than 5,000 families encode predicted anti-CRISPR proteins, and more than 500 families encode predicted antimicrobial proteins. By combining homology and genomic-neighborhood analyses, we reveal substantial novelty and diversity within phage biology, including small phage genes found in multiple host phyla, small genes encoding proteins that play essential roles in host infection, and small genes that share genomic neighborhoods and whose encoded proteins may share related functions.

ObjectiveChronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH-driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.MethodsPotential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs.ResultsIn human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration.ConclusionOur novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.

Microbial sulfur metabolism contributes to biogeochemical cycling on global scales. Sulfur metabolizing microbes are infected by phages that can encode auxiliary metabolic genes (AMGs) to alter sulfur metabolism within host cells but remain poorly characterized. Here we identified 191 phages derived from twelve environments that encoded 227 AMGs for oxidation of sulfur and thiosulfate (dsrA, dsrC/tusE, soxC, soxD and soxYZ). Evidence for retention of AMGs during niche-differentiation of diverse phage populations provided evidence that auxiliary metabolism imparts measurable fitness benefits to phages with ramifications for ecosystem biogeochemistry. Gene abundance and expression profiles of AMGs suggested significant contributions by phages to sulfur and thiosulfate oxidation in freshwater lakes and oceans, and a sensitive response to changing sulfur concentrations in hydrothermal environments. Overall, our study provides fundamental insights on the distribution, diversity, and ecology of phage auxiliary metabolism associated with sulfur and reinforces the necessity of incorporating viral contributions into biogeochemical configurations.

Our current knowledge about nucleocytoplasmic large DNA viruses (NCLDVs) is largely derived from viral isolates that are co-cultivated with protists and algae. Here we reconstructed 2,074 NCLDV genomes from sampling sites across the globe by building on the rapidly increasing amount of publicly available metagenome data. This led to an 11-fold increase in phylogenetic diversity and a parallel 10-fold expansion in functional diversity. Analysis of 58,023 major capsid proteins from large and giant viruses using metagenomic data revealed the global distribution patterns and cosmopolitan nature of these viruses. The discovered viral genomes encoded a wide range of proteins with putative roles in photosynthesis and diverse substrate transport processes, indicating that host reprogramming is probably a common strategy in the NCLDVs. Furthermore, inferences of horizontal gene transfer connected viral lineages to diverse eukaryotic hosts. We anticipate that the global diversity of NCLDVs that we describe here will establish giant viruses-which are associated with most major eukaryotic lineages-as important players in ecosystems across Earth's biomes.

BACKGROUND:Virophages are small viruses with double-stranded DNA genomes that replicate along with giant viruses and co-infect eukaryotic cells. Due to the paucity of virophage reference genomes, a collective understanding of the global virophage diversity, distribution, and evolution is lacking. RESULTS:Here we screened a public collection of over 14,000 metagenomes using the virophage-specific major capsid protein (MCP) as "bait." We identified 44,221 assembled virophage sequences, of which 328 represent high-quality (complete or near-complete) genomes from diverse habitats including the human gut, plant rhizosphere, and terrestrial subsurface. Comparative genomic analysis confirmed the presence of four core genes in a conserved block. We used these genes to establish a revised virophage classification including 27 clades with consistent genome length, gene content, and habitat distribution. Moreover, for eight high-quality virophage genomes, we computationally predicted putative eukaryotic virus hosts. CONCLUSION:Overall, our approach has increased the number of known virophage genomes by 10-fold and revealed patterns of genome evolution and global virophage distribution. We anticipate that the expanded diversity presented here will provide the backbone for further virophage studies.

Background The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain. Objectives To improve outcomes for people with chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services. Design The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies. Setting NHS, secondary care, primary care. Participants People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain. Interventions A care pathway for the management of people with pain at 3 months after knee replacement. Main outcome measures Patient-reported outcomes and cost-effectiveness over 12 months. Data sources Literature databases, the National Joint Registry, Hospital Episode Statistics, patient-reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events. Review methods Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis. Results In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre-operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m2 and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri-operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13; p = 0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08; p = 0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation. Limitations Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome. Conclusions The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals. Future work Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors. Study registration All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information. Plain language summary People with severe knee osteoarthritis may have knee replacement surgery to reduce pain and disability. Although highly successful for many people, some people report long-term pain. Our research looked at why some people are more likely to have long-term pain, its personal and economic consequences, and how to prevent and treat it. We reviewed previous research; analysed UK health-care databases; interviewed and met with patients, surgeons and health-care professionals; and developed and evaluated a new care pathway for patients with pain after knee replacement. We found that about one in seven people experience significant pain 6 months after knee replacement. For many, pain fluctuates over time. Some people with long-term pain feel that nothing more can be done to help and that further treatments may even cause harm. Changes to aspects of patient health and care merit further research as they may prevent the development of long-term pain. The Support and Treatment After joint Replacement pathway comprises a detailed assessment by a trained health-care professional; referral to appropriate services, such as an orthopaedic surgeon, physiotherapist, general practitioner for treatment of depression or anxiety, or pain specialist; and telephone follow-up. A total of 363 people with pain at 3 months after their knee replacement were randomly allocated to receive either the Support and Treatment After joint Replacement pathway or their hospital’s usual care. Participants were followed for 1 year to assess their long-term pain. We also looked at health-care costs and the acceptability of the Support and Treatment After joint Replacement pathway to patients and health-care professionals. This research was supported by a dedicated patient advisory group. For people with pain after knee replacement, the Support and Treatment After joint Replacement pathway leads to reduced long-term pain severity and reduced interference with everyday life, and is acceptable to patients and health-care professionals. NHS, personal social services and patient costs were lower in the group receiving the Support and Treatment After joint Replacement pathway. Scientific summary Background Chronic pain after total knee replacement places considerable burden on individuals, society and the NHS. With nearly 100,000 patients receiving knee replacements in the NHS annually, around 20,000 patients will have chronic post-surgical pain. Pre-operative prediction of who will have chronic pain after knee replacement is of limited value, referral for assessment and care is inconsistent and varies widely, and people do not necessarily receive or seek care. This programme aimed to address these issues and provide evidence on improvements to patient care and service delivery. Objectives The programme aimed to improve outcomes for patients with chronic pain ≥ 3 months after total knee replacement. Specific programme objectives were as follows: 1.synthesise evidence on the effectiveness of interventions for preventing chronic pain after knee replacement and the treatment of chronic pain after diverse surgeries, and identify post-surgical predictors of chronic pain after knee replacement 2.characterise the long-term trajectory of chronic pain, including pain characteristics and resource use up to 5 years after total knee replacement 3.finalise an assessment process and a care pathway for patients with chronic pain after total knee replacement 4.evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for patients with chronic pain after total knee replacement 5.identify reasons for non-use of services 6.make evidence-based suggestions about the best-practice care for patients with chronic pain after total knee replacement and evaluate the implementation of these. Methods To meet the objectives, we conducted six work packages. Work package 1: systematic reviews and analysis of national databases Systematic reviews of the following were carried out: post-surgical predictors of chronic pain after total knee replacement; the effectiveness of pre-, peri- and post-operative interventions for chronic pain after total knee replacement; and the effectiveness of interventions for chronic pain after diverse surgeries. In addition, we undertook an analysis of data from the National Joint Registry (NJR) linked to Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs) databases to identify post-operative predictors of chronic pain. Work package 2: long-term follow-up and analysis of databases Using the annual follow-up of the Clinical Outcomes in Arthroplasty Study (COASt) cohort of patients with total knee replacement, we were able to collect pain and resource use data for 5 years after surgery. We also analysed the Clinical Practice Research Datalink (CPRD), linked to the Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs) database, to characterise the natural history of chronic pain after total knee replacement, including resource use. Work package 3: finalisation of an assessment protocol and care pathway Consensus questionnaires completed by and meetings with health-care professionals were used to refine our previously developed intervention. We also tested intervention delivery and acceptability with 10 patients and evaluated the views of 10 health-care professional stakeholders on future implementation using a questionnaire based on the Normalisation Measure Development (NoMAD) instrument. Work package 4: randomised controlled trial The multicentre Support and Treatment After joint Replacement (STAR) randomised controlled trial was carried out with 363 participants to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for patients with chronic pain after total knee replacement. The primary follow-up time point was 12 months post randomisation and the coprimary outcomes were the Brief Pain Inventory (BPI) severity and interference scales (scored 0–10), with the minimal clinically important difference pre-specified as 1 point on either scale. Two embedded qualitative studies with 56 patients explored trial processes and acceptability of the intervention. Work package 5: qualitative study We undertook a qualitative interview study with 34 people with chronic pain after total knee replacement who made little or no use of formal health-care services and explored reasons for non-use of services. Work package 6: implementation and dissemination Interviews, based on the NoMAD instrument, were carried out with 14 health-care professionals who implemented the intervention within the trial. An online meeting, short animated film and survey were all used to communicate findings to key stakeholders and engage health-care professionals in maximising the embedding of the intervention in practice. A range of dissemination activities to engage health-care professionals, researchers, policy-makers, patients and the public were undertaken. Patient and public involvement Patient and public involvement was integral to the programme’s design and remained at its core during the programme. We worked with an existing patient forum and developed a complementary group focusing exclusively on chronic pain after total knee replacement. Contributions of this group included the design of study materials and processes, research management and dissemination strategies. Results Work package 1: systematic reviews Our systematic review of post-operative risk factors for chronic pain after total knee replacement included 14 studies published up to October 2016, with data from 1168 people. Studies focused on acute pain, function and psychological factors. Risk factor measures and outcomes were heterogeneous. In a narrative synthesis we were unable to draw firm conclusions on potential interventions. The need for further prospective studies in representative populations was clear. Research published up to December 2018 into pre-operative interventions mainly focused on exercise and education. In the eight trials, with a total of 960 people randomised, there was no association with these interventions and long-term pain outcomes. In the peri-operative setting, we identified 44 trials published up to February 2018, with a range of 10 to 280 people randomised. Unifactorial interventions including some forms of analgesia, early rehabilitation, electrical muscle stimulation and anabolic steroids were associated with improved long-term pain outcomes. However, studies were small and merit further evaluation. There was reassurance that some common peri-operative treatments are not associated with chronic pain. Post-operative interventions evaluated in 17 trials published up to November 2016, with a total of 2485 people randomised, mainly focused on physiotherapy. There was no strong evidence favouring one format of therapy over another. There has been little research into treatments for chronic pain after total knee replacement. Considering interventions for general chronic post-surgical pain, we identified 66 randomised trials with a total of 3149 participants in our systematic review with searches up to March 2016. A more focused updated search including treatments for chronic pain after arthroplasty of the large joints was conducted in October 2020. Many unifactorial interventions have been evaluated, and specific nerve-focused treatments deserve further research. Work packages 1 and 2: analysis of national databases We undertook two analyses of linked databases to identify pre-, peri- and post-operative risk factors for chronic pain outcome. In the first analysis with NJR and HES data, the pre- and 6-month-post-operative Oxford Knee Scores (OKS) was available for 258,386 patients, 43,702 (16.9%) of whom were identified as having chronic pain at 6 months post surgery. Post-surgical predictors of chronic pain were mechanical complication of prosthesis, surgical site infection, readmission, reoperation, revision and an extended hospital stay. However, these post-surgical predictors explained only a limited amount of variability in chronic pain outcome. In the second analysis, we analysed primary care data from CPRD and secondary care data from the HES–PROMs database and included 4570 patients. At 6 months after surgery, 10.4% of patients were classified as non-responders to surgery regarding their knee pain. Expressing the effects as absolute risk differences allowed us to quantify the relative importance of individual risk factors in terms of the absolute proportions of patients achieving poor pain outcomes. Pre-operative risk factors were having only mild knee pain symptoms, currently smoking, living in the most deprived areas, having a body mass index between 35 and 40 kg/m2 and having had previous knee arthroscopy surgery. Post-operative risk factors were revision surgery and manipulation under anaesthetic within 3 months after the operation, and use of opioids and antidepressants within 3 months after surgery. Work package 2: long-term follow-up of COASt cohort and analysis of national databases We characterised the long-term trajectory of chronic pain, including pain characteristics and resource use, through the 5-year follow-up of the COASt cohort of 1581 patients with total knee replacement, and analysis of the linked CPRD and HES databases. We applied cluster analysis to data on 128,145 patients with primary total knee replacement included in the English PROMs programme to derive a cut-off point on the pain subscale of the OKS. A high-pain group was identified, defined as those with a score of ≤ 14 points on the OKS pain subscale 6 months after total knee replacement. About one in eight people experienced chronic pain 1 year after total knee replacement. Of these patients with chronic pain after surgery, after imputing significant missing data assumed to be missing at random, 65% experienced no-chronic-pain by year 5, 31% fluctuated and 4% remained in chronic pain. People with chronic pain in year 1 had worse quality of life to start with; this improved, but less rapidly than for those not in chronic pain. People with chronic pain reported slightly higher primary care consultation costs than those not in chronic pain but their prescriptions for analgesia were much more frequent, more costly to the health-care system and continued to grow even after surgery, especially prescriptions for opioids. Work package 3: finalisation of an assessment protocol and care pathway We refined and finalised the novel STAR care pathway and associated training materials. The STAR care pathway involves a clinic appointment for patients who have troublesome pain at 3 months after surgery. A specially trained extended scope practitioner (ESP) conducts a clinic assessment with the patient, comprising history, examination, radiography and questionnaire completion. Based on this assessment, which focuses on understanding the reasons for and impact of the pain, the patient is referred to the appropriate existing services for treatment, such as a surgeon, general practitioner (GP) or specialist, or receives ongoing monitoring. The ESP follows up with patients by telephone for up to 12 months. Work package 4: randomised controlled trial In a multicentre pragmatic, open randomised controlled trial, we evaluated the STAR care pathway. We screened 5036 people, randomised 363 patients with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales and collected 12-month outcomes from 313 (85%) randomised participants. The sample had a mean age of 67 years, was 60% female and 94% white. Our analysis of clinical effectiveness indicated that at 12 months the intervention arm had lower mean pain severity and lower mean pain interference than the usual care arm. For pain interference at 12 months, the adjusted difference in means was –0.68 points on the Brief Pain Inventory pain interference scale [95% CI –1.29, –0.08; p = 0.026]. For pain severity at 12 months, the adjusted difference in means was –0.65 points on the Brief Pain Inventory pain severity scale [95% CI –1.17, –0.13; p = 0.014]. Our analysis of cost-effectiveness indicated that people receiving the STAR pathway from an NHS and personal social services perspective had lower costs (–£724, 95% CI -£1500 to £51) and more quality-adjusted life-years (QALYs) (0.03, 95% CI –0.008 to 0.06) than those receiving usual care. The STAR pathway was the cost-effective option: the incremental net monetary benefit at the £20,000-per-QALY threshold was £1256 (95% CI £164 to £2348). This was also the case from a patient perspective. Embedded qualitative research found that patients thought that the STAR pathway was acceptable, and patients described how it provided an opportunity for them to discuss their concerns and to receive more information about their condition while ensuring they received further treatment and ongoing support. Work package 5: qualitative study In semistructured interviews with 34 people, we found that people with chronic pain after total knee replacement who made little or no use of services did so because they became stuck in a cycle of appraisal of the validity of their need for help and concern that treatment may not be of benefit. Some were concerned that further treatment may even worsen their pain or cause further harm. When describing chronic post-surgical pain, some participants described sensations of discomfort including heaviness, numbness, pressure and tightness associated with the prosthesis, and some also reported a lack of felt connection with their knee as their movement was no longer natural and required deliberate attention, and that they had a lack of confidence in it. Work package 6: implementation and dissemination We found that health-care professionals involved in the delivery and implementation of the STAR care pathway valued its focus on the identification of neuropathic pain and psychosocial issues, enhanced patient care, formalisation and validation of referral practices and an increased knowledge of pain management. Stakeholders supported formal implementation of the STAR pathway. Whether or not this would be supported by hospital management was felt to be dependent on whether or not it was shown to be cost-effective. Conclusions: implications for health care After knee replacement, screening for pain with the OKS pain subscale beginning at 2 months after surgery can facilitate the delivery of targeted care from 3 months. Our findings indicate that the STAR care pathway can provide improved care and outcomes for people who have pain after knee replacement. To our knowledge, the STAR care pathway is the first multifactorial intervention for the treatment of post-surgical pain to have been evaluated in a randomised controlled trial. In database analyses and systematic reviews, we identified risk factors for and univariable interventions to prevent or treat chronic pain. After further research these may provide additional components to the care pathway. Our work also indicates that people with pain could be empowered to seek health care and that health-care professionals can be encouraged provide support. This could include information for people living with chronic pain to inform them that health care may provide benefit and that seeking care is not futile. Informing patients of the likely outcomes after surgery may be a key part of pre- and post-surgical care. Recommendations for research We recommend that further research addresses the following points, numbered in descending order of priority: 1.How to implement the STAR care pathway into the NHS. 2.How to improve communication between patients and professionals before surgery. 3.Whether or not patient education and supportive care can enable earlier recognition of chronic pain. 4.The STAR care pathway showed benefit to patients for both pain and interference at 6 and 12 months. Further follow-up would describe the longer-term outcomes of this intervention and the health-care resources utilised by participants. 5.How to reshape the STAR pathway for other surgeries. 6.The STAR programme focused on care after surgery. Future research could make use of the recently developing evidence base about the time before surgery as an opportunity for intervention. Specifically, we now have a greater understanding of risk factors for poor outcome and using this understanding to design and evaluate pre-surgical intervention may prove of long-term benefit to patients and health-care systems. 7.How to better manage patient’s feelings of disconnectedness from the new knee and sensations of otherness to improve incorporation of the prosthesis. 8.Promising interventions, identified in systematic reviews and suggested by our risk factor studies, should be evaluated in appropriately powered high-quality randomised controlled trials. 9.New interventions with evidence of effectiveness in the treatment of chronic pain after knee replacement should be considered as new components of multifaceted personalised care as delivered in the STAR intervention. Study registration All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The STAR randomised trial was registered as ISRCTN92545361. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.

Hugely concerning changes to health outcomes have been observed in the UK since the early 2010s, including reductions in life expectancy and widening of inequalities. These have been attributed to UK Government 'austerity' policies which have profoundly affected poorer populations. Studies in mainland Europe have shown associations between austerity and increases in adverse birth outcomes such as low birthweight (LBW). The aim here was to establish whether the period of UK austerity was also associated with higher risks of such outcomes. We analysed all live births in Scotland between 1981 and 2019 (n  = 2.3 million), examining outcomes of LBW, preterm birth (PB) and small-for-gestational-age (SGA). Descriptive trend analyses, segmented regression (to identify changes in trends) and logistic regression modelling (to compare risk of outcomes between time periods) were undertaken, stratified by infant sex and quintiles of socioeconomic deprivation. There were marked increases in LBW and PB rates in the austerity period, particularly in the most deprived areas. However, rates of SGA decreased, suggesting prematurity as the main driver of LBW rather than intrauterine growth restriction. The regression analyses confirmed these results: trends in LBW and PB changed within 1–3 years of the period in which austerity was first implemented, and that period was associated with higher risk of such outcomes in adjusted models. The results add to the European evidence base of worsening birth outcomes associated with austerity-related economic adversity. The newly elected UK government needs to understand the causes of these changes, and the future implications for child and adult health. [ABSTRACT FROM AUTHOR]

Background Neuropathic-like pain, fatigue, cognitive difficulty, catastrophizing, anxiety, sleep disturbance, depression and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterize this across painful musculoskeletal conditions. Methods CAP was derived from the 8-item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had OA, back pain or FM. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee OA. Results Data were from 3579 participants (58% female, median age 71 years), including subgroups with OA (n  = 1158), back pain (n  = 1292) or FM (n  = 177). Across the three subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high [ICC = 0.89 (95% CI 0.84–0.92)] and CAP scores fit to one- and two-factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50–0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. Conclusions Central aspects of pain are reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state. [ABSTRACT FROM AUTHOR]