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According to the National Institute of Mental Health (NIMH), one in five adults living in the United States has a mental illness (2022). Despite the varying complexities and diagnoses associated with students who are navigating mental health issues, there are numerous approaches educators and professionals supporting adult learners can take to help students cope with mental health needs. The resources and accommodations presented in this article discuss best practices for students with mental health needs that are adapted using Hewitt's (2017) "Yes I Can: A Mental Health Guide for Adult Literacy Facilitators." The information in this article accounts for the most common student needs and ways for facilitators to incorporate best practices into their classrooms that can address various diverse learning requirements. [For part 2 of this Forum on supporting mental health, see EJ1389835. For part 3, see EJ1389833.]

Introduction: Health promotion MOOCs (hpMOOCs) can be designed to educate general audiences on global health issues and provide accessible evidence-based content. Thus, it is essential to assess the instructional design quality of hpMOOCs through more than one perspective to ensure course participants have an effective learning experience and their learning needs are met. Methods: Our study involved a comprehensive exploration of an hpMOOC about dementia risk reduction with sustained massive reach and established impact. To fully understand the quality of this course, instructional design elements were assessed from an instructional designer lens and a course participant lens. The designer lens involved a detailed review of the quality of the course against a recognized quality rubric. The participant lens involved topic modeling and thematic analysis of 1,531 responses to a feedback survey item in order to identify design elements preferred by participants. Results: While the course performs well and meets most quality standards, it falls short of fully meeting the criteria set by the rubric. However, the rubric could be further developed to better facilitate the quality assurance of hpMOOCs. The participant lens reveals the course meets participants' expectations and it offers two new avenues for enhancing the current presentation of course content. Conclusion: Assessing the quality of hpMOOCs through a dual lens provides triangulation that helps to gain a more comprehensive understanding of how to improve their instructional design quality.

Background Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting We analysed trials from all settings. Participants We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions We included all antidepressants. Main outcome measures Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people’s mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. What did we do? We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. What did we find? We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant’s effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group. Scientific summary Background Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients’ global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions. Objectives Our objective was to assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events and withdrawal. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions up until 4 January 2022. Selection criteria We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant or the same antidepressant at different doses, then the study was required to be double-blind. RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) were included but rated as at high risk of bias. We excluded RCTs where the follow-up was < 2 weeks and those with < 10 participants in each trial arm. We included any antidepressant at any dose, for any indication but used primarily for treatment of people with chronic pain and compared to placebo or active intervention. Participants We included adults (aged 18 years or older) reporting primary or secondary pain in any part of their body (except headache) as their primary complaint, that matched the International Association for the Study of Pain definition of chronic pain (i.e. at least 3 months’ duration). We included all trials regardless of the severity of participants’ chronic pain, although we extracted whether severity was part of the inclusion criteria of the individual studies. We excluded studies where the participants’ primary pain condition was headache or migraine. Data collection and analysis Two authors separately screened, extracted data and judged risk of bias. We synthesised the data using Bayesian network meta-analysis (NMA) and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve. We primarily used the Confidence in Network Meta-Analysis (CINeMA) framework and ‘Risk Of Bias due to Missing Evidence in Network meta-analysis’ (ROB-MEN) tool to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to assess the certainty of the evidence. Main results This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (n = 83) and parallel-armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks; seven studies provided no useable data and were omitted from the NMAs. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine trials, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes For pain relief, duloxetine standard dose showed a small to moderate effect for substantial pain relief [odds ratio 0.91, 95% confidence interval (CI) 0.56 to 0.84] and continuous pain intensity [standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24]. For pain intensity, milnacipran standard dose also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06) with moderate-certainty evidence. For mood, mirtazapine had a moderate effect (SMD −0.5, 95% CI −0.78 to −0.22), while duloxetine showed a small effect (−0.16, 95% CI −0.22 to −0.1); however, it is important to note that most trials excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the ‘normal’ or ‘subclinical’ ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were equally as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Authors’ conclusions Our review and NMAs show that despite studies investigating 25 different antidepressants, there is reliable evidence for only duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy and safety of any antidepressant. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

BackgroundDigital health interventions show promise for weight management. However, few text-based behavior change interventions have been designed to support patients receiving intragastric balloons, and none have simultaneously evaluated weight loss, psychological well-being, and behavior change despite the crucial interplay of these factors in weight management. ObjectiveThis study aims to assess whether a health coach–led, asynchronous, text-based digital behavior change coaching intervention (DBCCI) delivered to participants receiving an intragastric balloon and its aftercare program was feasible and acceptable to participants and supported improved outcomes, including weight loss, psychological well-being, and lifestyle behavior change conducive to weight loss maintenance. MethodsThis 12-month, single-arm prospective study enrolled adults aged 21 to 65 years with BMI ≥27 kg/m2 receiving a procedureless intragastric balloon (PIGB) at 5 bariatric clinics in the United Kingdom and the Netherlands. Participants received the DBCCI and the clinic-led PIGB aftercare program (remotely delivered) for 6 months after PIGB placement and then no intervention for an additional 6 months. The DBCCI was an evidence-based, personalized intervention wherein health coaches supported participants via exchanged asynchronous in-app text-based messages. Over the 12-month study, we assessed percentage of total body weight loss and psychological well-being via self-administered validated questionnaires (Warwick-Edinburgh Mental Wellbeing Scale, Generalized Anxiety Disorder Scale, Impact of Weight on Quality of Life–Lite–Clinical Trials Version, Loss of Control Over Eating Scale–Brief, Weight Efficacy Lifestyle Questionnaire–Short Form, and Barriers to Being Active Quiz). Participant engagement with and acceptability of the intervention were assessed via self-reported surveys. ResultsOverall, 107 participants (n=96, 89.7% female; mean baseline BMI 35.4, SD 5.4 kg/m2) were included in the analysis. Mean total body weight loss was 13.5% (SEM 2.3%) at the end of the DBCCI and 11.22% (SEM 2.3%) at the 12-month follow-up (P

Background Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. Meeting A round-table discussion, held at St George’s University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation. Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. Conclusions With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.

It is unsurprising that equity has featured so prominently in the Pandemic Treaty negotiations – the Treaty is a direct response to the COVID-19 pandemic, which was characterised by gross inequality between high-income and LMICs. For all the talk at the start of the Treaty negotiation process of equity, of doing things differently in the future, it appears that very little will change. If it works, and there are very good reasons to believe that it will not work, it will at best make sure that a small proportion of vaccines end up where they need to be, and the rest will continue to go to the highest bidder, regardless of need, equity, or justice.

Abstract Background The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. Methods Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0–10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. Results Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and − 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. Conclusions The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years. Trial registration ISRCTN: 92,545,361.

Abstract During cell death, nucleosomes, the basic structural unit of chromatin, are released into the blood stream and elevated levels have been found in the plasma of patients with solid cancers. In this study, we demonstrate an increase in cell free circulating H3.1-nucleosomes levels in plasma samples from patients with hematological malignancy, non-Hodgkin lymphoma (NHL), relative to healthy donors. As histone post-translational modifications (PTMs) of circulating nucleosomes are described as potential biomarkers of various solid cancers, we investigated the epigenetic profile of nucleosomes from NHL patients following nucleosome enrichment (Nu.Q® capture) combined with mass spectrometry. Eight histones PTMs, including the acetylation of histone H3 at lysine 9, 14 and 18 as well as the methylation state of histone H3 at lysine 9, 27 and 36, were identified at a higher level in the plasma of NHL patients compared to healthy donors. These results were confirmed in a larger clinical cohort by immunoassay. Subsequently, the temporal profile of these histone PTMs in NHL patients undergoing treatment course highlighted the potential use of these new biomarkers to monitor treatment response and/or disease progression. Our results substantiate that levels of H3.1-nucleosomes are particularly elevated in NHL patients and may be a useful diagnostic tool. Moreover, our work emphasizes the crucial roles of the epigenetic marks present on circulating nucleosomes to detect and monitor tumor progression and/or treatment response of non-Hodgkin Lymphoma.

Abstract Background Unmanaged cardiometabolic health, low physical and cognitive activity, poor diet, obesity, smoking and excessive alcohol consumption are modifiable health risk factors for dementia and public health approaches to dementia prevention have been called for. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a dementia prevention public health study examining whether improving knowledge about modifiable dementia risk factors supports behaviour changes that reduce future dementia risk. Methods Residents of Tasmania, Australia, aged 50 + years who joined the 10-year ISLAND study were asked to complete annual online surveys about their knowledge, motivations and behaviours related to modifiable dementia risk. ISLAND included two knowledge-based interventions: a personalised Dementia Risk Profile (DRP) report based on survey responses, and the option to do a 4-week Preventing Dementia Massive Open Online Course (PDMOOC). Longitudinal regression models assessed changes in the number and type of risk factors, with effects moderated by exposures to the DRP report and engagement with the PDMOOC. Knowledge and motivational factors related to dementia risk were examined as mediators of risk behaviour change. Results Data collected between October 2019 and October 2022 (n = 3038, av. 63.7 years, 71.6% female) showed the mean number of modifiable dementia risk factors per participant (range 0 to 9) reduced from 2.17 (SD 1.24) to 1.66 (SD 1.11). This change was associated with the number of exposures to the DRP report (p = .042) and was stronger for PDMOOC participants (p = .001). The interaction between DRP and PDMOOC exposures yielded a significant improvement in risk scores (p = .004). The effect of PDMOOC engagement on behaviour change was partly mediated by increased knowledge (12%, p = .013). Self-efficacy enhanced the effect of knowledge on behaviour change, while perceived susceptibility to dementia mitigated this relationship. Conclusions The ISLAND framework and interventions, a personalised DRP report and the four-week PDMOOC, work independently and synergistically to increase dementia risk knowledge and stimulate health behaviour change for dementia risk reduction. ISLAND offers a feasible and scalable public health approach for redressing the rising prevalence of dementia.

Abstract Long‐term health conditions, whether mental or physical, often co‐occur in adolescents. For instance, adolescents with chronic pain may experience co‐occurring primary psychological disorders. In this scoping review, we determine the influence of co‐occurring chronic pain and primary psychological disorders on adolescents' functioning. A systematic search of six databases was conducted to identify articles if they were: (1) peer‐reviewed; (2) reported original findings; (3) included participants aged 11–19 years, who experienced chronic pain (i.e., pain lasting 3 months or more) and had a co‐occurring diagnosis of a primary psychological disorder; and (4) assessed functioning. Searches returned 9864 articles after the removal of duplicates. A two‐phase abstract and full‐text screening process identified two eligible articles which compared emotional functioning (n = 1) and social functioning (n = 2) between groups of adolescents with co‐occurring chronic pain and primary psychological disorders with adolescents only reporting chronic pain. Overall findings revealed no differences in social functioning, but adolescents with co‐occurring chronic pain and a primary psychological disorder (depression and anxiety) reported worse emotional functioning compared with adolescents with chronic pain alone. This review confirms the limited research on the co‐occurrence of primary psychological disorders and chronic pain in adolescents by only identifying two eligible articles exploring the co‐occurrence of chronic pain with depression, anxiety, and/or attentional disorders.

BackgroundVaccination during pregnancy is an important healthcare intervention for safeguarding the health of the mother and their infants. Ethnic disparities in recruitment to vaccine research studies during pregnancy potentially contribute to health inequalities. The aim of the current study was to explore the barriers and enablers influencing the willingness of pregnant women from ethnic minority backgrounds to participate in vaccine research studies.Methods and findingsSemi-structured qualitative online interviews were conducted with 23 pregnant women from diverse ethnic backgrounds in the UK. Interviews were transcribed verbatim, and thematically analysed. Our findings suggest that participants perceived vaccines and vaccine research, in principle, to be beneficial to the individual and to society, and understood the value of vaccination in mitigating severity of disease and protecting the health of mothers and their infants. Apprehension over the safety of vaccination in pregnancy was common and reduced willingness to participate. For those that decided to participate in vaccine trials in pregnancy, this was seen as an act of solidarity, a way to contribute to a collective responsibility for the public health of the community. Personal and community connections and representation-seeing people from their own communities represented in in the recruitment process shapped decisions about vaccine trial participating. Trust and mistrust in health systems, shaped by past experiences of interacting with healthcare professionals were likely to inform whether they would consider participating. Practical considerations such as excessive time commitments related to study procedures, travel and organising childcare were barrier to participation. The level of invasiveness of trial procedures were also a concern, although increased monitoring during the trial was seen as a potential benefit, mitigating some safety concerns.ConclusionsOur study reinforcing previously identified barriers to vaccine participation among pregnant women from diverse ethnic communities. This study underlines the need to develop tailored interventions that focus on fostering trust with the aid of community engagement to understand cultural contexts, establishing authentic representation, and address practical considerations, to contribute to enhancing vaccine trial participation in pregnancy in those from diverse ethnic communities.

Abstract Background Captive koala breeding programmes are essential for long-term species management. However, breeding efficacy is frequently impacted by high neonatal mortality rates in otherwise healthy females. Loss of pouch young typically occurs during early lactation without prior complications during parturition and is often attributed to bacterial infection. While these infections are thought to originate from the maternal pouch, little is known about the microbial composition of koala pouches. As such, we characterised the koala pouch microbiome across the reproductive cycle and identified bacteria associated with mortality in a cohort of 39 captive animals housed at two facilities. Results Using 16S rRNA gene amplicon sequencing, we observed significant changes in pouch bacterial composition and diversity between reproductive time points, with the lowest diversity observed following parturition (Shannon entropy — 2.46). Of the 39 koalas initially sampled, 17 were successfully bred, after which seven animals lost pouch young (overall mortality rate — 41.18%). Compared to successful breeder pouches, which were largely dominated by Muribaculaceae (phylum — Bacteroidetes), unsuccessful breeder pouches exhibited persistent Enterobacteriaceae (phylum — Proteobacteria) dominance from early lactation until mortality occurred. We identified two species, Pluralibacter gergoviae and Klebsiella pneumoniae, which were associated with poor reproductive outcomes. In vitro antibiotic susceptibility testing identified resistance in both isolates to several antibiotics commonly used in koalas, with the former being multidrug resistant. Conclusions This study represents the first cultivation-independent characterisation of the koala pouch microbiota, and the first such investigation in marsupials associated with reproductive outcomes. Overall, our findings provide evidence that overgrowth of pathogenic organisms in the pouch during early development is associated with neonatal mortality in captive koalas. Our identification of previously unreported, multidrug resistant P. gergoviae strains linked to mortality also underscores the need for improved screening and monitoring procedures aimed at minimising neonatal mortality in future. Video Abstract

Pathogen evolution of drug resistance often occurs in a stepwise manner via the accumulation of multiple mutations that in combination have a non-additive impact on fitness, a phenomenon known as epistasis. The evolution of resistance via the accumulation of point mutations in the DHFR genes of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) has been studied extensively and multiple studies have shown epistatic interactions between these mutations determine the accessible evolutionary trajectories to highly resistant multiple mutations. Here, we simulated these evolutionary trajectories using a model of molecular evolution, parameterised using Rosetta Flex ddG predictions, where selection acts to reduce the target-drug binding affinity. We observe strong agreement with pathways determined using experimentally measured IC50 values of pyrimethamine binding, which suggests binding affinity is strongly predictive of resistance and epistasis in binding affinity strongly influences the order of fixation of resistance mutations. We also infer pathways directly from the frequency of mutations found in isolate data, and observe remarkable agreement with the most likely pathways predicted by our mechanistic model, as well as those determined experimentally. This suggests mutation frequency data can be used to intuitively infer evolutionary pathways, provided sufficient sampling of the population.

Abstract Background The 25-item Dementia Knowledge Assessment Scale (DKAS2) is a widely used tool for measuring knowledge of dementia. To increase the applicability of the Chinese-language version of the tool (DKAS-TC) for the general public, this study aimed to develop a shortened version using the item response theory (IRT) approach. Methods A total of 401 participants voluntarily completed a Chinese-language version of the DKAS2 questionnaire (DKAS-TC) at the start of dementia awareness training courses in 2020 and 2021. The four Rasch family models were used to analyze the dimensionality of the shortened scale (the DKAS-s) and to confirm its accuracy in measuring dementia knowledge. Results The results justified supported the use of a dichotomous response scale for responding to the DKAS-s and demonstrated good fit of the data to a Rasch model with the four dimensions of “Causes and Characteristics”, “Communication and Engagement”, “Care Needs”, and “Risks and Health Promotion”. Moreover, we shortened the DKAS-TC by selecting items that had both above-average discriminative ability and above-average information. The DKAS-s retained 64.13% of the information contained in the DKAS-TC, resulting in a 16-item scale which retained four items in each of the original four dimensions. The DKAS-s also correlated highly (≥0.95) with the DKAS-TC and exhibited a sizeable range of difficulty of dementia knowledge. Conclusions The DKAS-s is expected to be more efficient in field settings while retaining an acceptable level of psychometric properties when used as a survey instrument to measure the general public’s knowledge of dementia.

Objectives To explore the effect of changes in national clinical recommendations in 2019 that extended provision of survival focused care to babies born at 22 weeks’ gestation in England and Wales.Design Population based cohort study.Setting England and Wales, comprising routine data for births and hospital records.Participants Babies alive at the onset of care in labour at 22 weeks+0 days to 22 weeks+6 days and at 23 weeks+0 days to 24 weeks+6 days for comparison purposes between 1 January 2018 and 31 December 2021.Main outcome measures Percentage of babies given survival focused care (active respiratory support after birth), admitted to neonatal care, and surviving to discharge in 2018-19 and 2020-21.Results For the 1001 babies alive at the onset of labour at 22 weeks' gestation, a threefold increase was noted in: survival focused care provision from 11.3% to 38.4% (risk ratio 3.41 (95% confidence interval 2.61 to 4.45)); admissions to neonatal units from 7.4% to 28.1% (3.77 (2.70 to 5.27)), and survival to discharge from neonatal care from 2.5% to 8.2% (3.29 (1.78 to 6.09)). More babies of lower birth weight and early gestational age received survival focused care in 2020-21 than 2018-19 (46% to 64% at

This study employed an intersectional approach (operationalized as the combination of more than one social identity) to examine the relationship between aspects of social identity (i.e., race, gender, age, SES), self-reported level of mistreatment, and attributions for discrimination. Self-reported discrimination has been researched extensively and there is substantial evidence of its association with adverse physical and psychological health outcomes. Few studies, however, have examined the relationship of multiple demographic variables (including social identities) to overall levels self-reported mistreatment as well the selection of attributions for discrimination. A diverse community sample (N = 292; 42.12% Black; 47.26% male) reported on experiences of discrimination using the Everyday Discrimination Scale. General linear models were used to test the effect of sociodemographic characteristics (i.e., race, gender, age, SES) on total discrimination score and on attributions for discrimination. To test for intersectional relationships, we tested the effect of two-way interactions of sociodemographic characteristics on total discrimination score and attributions for discrimination. We found preliminary support for intersectional effects, as indicated by a significant race by age interaction on the selection of the race attribution for discrimination; gender by SES on the age attribution; age by gender on the education attribution; and race by SES on the economic situation attribution. Our study extends prior work by highlighting the importance of testing more than one factor as contributing to discrimination, particularly when examining to what sources individuals attribute discrimination.

Abstract The incidence of chronic and recurrent pain increases in adolescence. Prevalence of adolescent chronic pain is estimated to be 11%‐44%, with approximately 5% adolescents experiencing moderate‐to‐severe chronic pain. Adolescents with chronic pain also report unwanted changes in emotional, social, and developmental functioning. Very little is known about how adolescents with chronic pain make sense of their development, the role of pain in that development, and how such developmental trajectories progress over time. A multi‐methods qualitative study was designed to explore how adolescents make sense of their experience of chronic pain in the context of development. Nine adolescents (8 girls) aged 12‐22 years old (Mean = 15.7, SD = 2.8) were recruited from a UK national pain service. Adolescents completed an interview on entering the service, and a follow‐up interview 12 months later. They also completed monthly diaries in this 12‐month period. Data comprised 18 interviews and 60 diary entries, which were analyzed using inductive reflexive thematic analysis. Analyses generated one overarching theme entitled “tug of war: push and pull,” demonstrating developmental tension related to pain, and the cumulative impact these had over time. This overarching theme comprised two subthemes which capture these tensions across the developmental domains of peer relationships and autonomy. The first subtheme, “the shifting sands of peer relationships,” explores the ever‐changing closeness between self and peers. The second subtheme referred to “restricted choices” and how pain limited the participants' autonomy but that this, over time could push development forward. These results extend previous cross‐sectional research on the developmental consequences of chronic pain, showing the dynamic fluctuations and alterations to developmental trajectories over time.

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.

Abstract Background Approximately 20% of people experience chronic postsurgical pain after total knee replacement. The STAR randomised controlled trial (ISCRTN92545361) evaluated the clinical- and cost-effectiveness of a new multifaceted and personalised care pathway, compared with usual care, for people with pain at three months after total knee replacement. We report trial participants’ experiences of postoperative pain and the acceptability of the STAR care pathway, which consisted of an assessment clinic at three months, and up to six follow-up telephone calls over 12 months. Methods Semi-structured interviews were conducted with 27 people (10 men, 17 women) between February 2018 and January 2020. Participants were sampled purposively from the care pathway intervention group and interviewed after completion of the final postoperative trial questionnaire at approximately 15 months after knee replacement. Interviews were audio-recorded, transcribed, anonymised and analysed using inductive thematic analysis. Findings Many participants were unprepared for the severity and impact of postoperative pain, which they described as extreme and constant and that tested their physical and mental endurance. Participants identified ‘low points’ during their recovery, triggered by stiffening, pain or swelling that caused feelings of anxiety, depression, and pain catastrophising. Participants described the STAR assessment clinic as something that seemed “perfectly normal” suggesting it was seamlessly integrated into NHS care. Even in the context of some ongoing pain, the STAR care pathway had provided a source of support and an opportunity to discuss concerns about their ongoing recovery. Conclusions People who have knee replacement may be unprepared for the severity and impact of postoperative pain, and the hard work of recovery afterwards. This highlights the challenges of preparing patients for total knee replacement and suggests that clinical attention is needed if exercise and mobilising is painful beyond the three month postoperative period. The STAR care pathway is acceptable to people with pain after total knee replacement.