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Abstract Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na+ conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.

In 2010, McKinsey conducted confidential interviews with over 2,000 executives, revealing that only 28 per cent believed that 'the quality of strategic decisions in their companies was generally good, 60 [...]

Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon’s decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing. Cite this article: Bone Jt Open 2024;5(6):464–478.

Abstract Background Dupuytren’s contractures (DC) are fibrous cords under the skin of the hand that cause one or more fingers to curl gradually and irreversibly towards the palm. These contractures are usually painless but can cause a loss of hand function. Two treatments for Dupuytren’s contractures are widely used within the National Health Service (NHS) in the UK: removal of the contractures via surgery (limited fasciectomy) and division of the contractures via a needle inserted through the skin (needle fasciotomy). This study aims to establish the clinical and cost-effectiveness of needle fasciotomy (NF) versus limited fasciectomy (LF) for the treatment of DC in the NHS, in terms of patient-reported hand function and resource utilisation. Methods/design Hand-2 is a national multi-centre, two-arm, parallel-group randomised, non-inferiority trial. Patients will be eligible to join the trial if they are aged 18 years or older, have at least one previously untreated finger with a well-defined Dupuytren’s contracture of 30° or greater that causes functional problems and is suitable for treatment with either LF or NF. Patients with a contracture of the distal interphalangeal joint only are ineligible. Eligible consenting patients will be randomised 1:1 to receive either NF or LF and will be followed up for 24 months post-treatment. A QuinteT Recruitment Intervention will be used to optimise recruitment. The primary outcome measure is the participant-reported assessment of hand function, assessed by the Hand Health Profile of the Patient Evaluation Measure (PEM) questionnaire at 12 months post-treatment. Secondary outcomes include other patient-reported measures, loss of finger movement, and cost-effectiveness, reported over the 24-month post-treatment. Embedded qualitative research will explore patient experiences and acceptability of treatment at 2 years post-surgery. Discussion This study will determine whether treatment with needle fasciotomy is non-inferior to limited fasciectomy in terms of patient-reported hand function at 12 months post-treatment. Trial registration International Standard Registered Clinical/soCial sTudy ISRCTN12525655. Registered on 18th September 2020.

Abstract Aim Families from socioeconomically deprived backgrounds appear to have been greatly impacted and face worsening inequalities as a result of the COVID-19 pandemic. With more than half of children in Newham, East London, living in poverty, this study aimed to investigate the impact of the COVID-19 lockdowns on families with a child under 5 years-old in Newham and identify their immediate needs to inform recovery efforts. Subjects and methods This was a qualitative study. Semi-structured interviews were conducted with 13 participants (2 fathers; 11 mothers) exploring the impact of the COVID-19 lockdowns on family life, neighbourhood and community and important relationships in the child’s world. Results All parents experienced significant impacts on family life and well-being because of the pandemic. Families were placed under increased stress and were concerned about the impacts on child development. Low-income families were most disadvantaged, experiencing lack of professional support, community engagement and inadequate housing. Conclusion Families were placed under increasing pressure during the pandemic and recovery efforts need to target those most affected, such as families from low-income households. Recovery efforts should target child social and language development, family mental health, professional service engagement and community involvement.

Summary: Background: Subthreshold depression is a risk factor for major depression and is associated with increased morbidity and mortality, especially in older adults. There is emerging evidence that digital interventions, including self-help interventions, may reduce depressive symptoms. We aimed to evaluate the effectiveness of a mobile messaging intervention at reducing subthreshold depressive symptoms among older adults in Brazil. Methods: PRODIGITAL was a single blind, two-arm, individually randomised controlled trial conducted in 46 primary care clinics in the city of Guarulhos, Brazil. Individuals aged 60+ years were contacted by phone following a randomly ordered list for a screening assessment. Those who presented with anhedonia and/or depressed mood (Patient Health Questionnaire (PHQ)-2≥1), and who subsequently scored between 5 and 9 on the PHQ-9 were invited to participate. The intervention arm received the ‘Viva Vida’ digital self-help intervention consisting of automated multi-media messages sent via WhatsApp. Forty-eight audio and visual messages based on psychoeducation and behavioural activation were automatically delivered over six weeks. The control arm received a single message containing information about depression. The primary outcome was the difference in mean PHQ-9 scores between treatment arms at the three-month follow-up. All primary analyses were performed according to allocated arm with imputed data. The trial is registered with ReBEC, RBR-6c7ghfd. Findings: Participants were recruited between 8 September 2021 and 19 August 2022. Of the 454 participants enrolled, 223 were randomised to the intervention arm, 231 to the control arm. Participants’ mean age was 65.3 years (SD 5.0) and 64.0% (n = 292) were female. A total of 385 (84.8%) completed the three-month follow-up assessment; no difference in mean PHQ-9 scores between the treatment arms was observed (adjusted difference: −0.61; 95% CI: −1.75, 0.53; p = 0.29). Interpretation: These results demonstrate that the Viva Vida digital self-help intervention did not help to improve subthreshold depressive symptoms amongst older adults. Further research is needed to understand why this self-help intervention was not effective in this population, and to explore how it might be adapted to achieve this goal. Funding: São Paulo Research Foundation and UK Joint Global Health Trials.

Design Parallel-group randomised controlled trial. Methods Participants Adolescents aged 11–17 years, diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome and with no local specialist treatment centre, were referred to a specialist service in South West England. Interventions Fatigue In Teenagers on the interNET in the National Health Service is a web-based myalgic encephalomyelitis/chronic fatigue syndrome-focused cognitive–behavioural therapy programme for adolescents, supported by individualised written, asynchronous electronic consultations with a clinical psychologist/cognitive–behavioural therapy practitioner. The comparator was videocall-delivered activity management with a myalgic encephalomyelitis/chronic fatigue syndrome clinician. Both treatments were intended to last 6 months. Objectives Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for paediatric myalgic encephalomyelitis/chronic fatigue syndrome. Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for those with mild/moderate comorbid mood disorders. From a National Health Service perspective, estimate the cost-effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management over a 12-month horizon. Primary Outcome 36-item Short Form Health Survey Physical Function subscale at 6 months post randomisation. Randomisation Web-based, using minimisation with a random component to balance allocated groups by age and gender. Blinding While the investigators were blinded to group assignment, this was not possible for participants, parents/carers and therapists. Results The treatment of 314 adolescents was randomly allocated, 155 to Fatigue In Teenagers on the interNET in the National Health Service. Mean age was 14 years old and 63% were female. Primary outcome At 6 months, participants allocated to Fatigue In Teenagers on the interNET in the National Health Service were more likely to have improved physical function (mean 60.5, standard deviation 29.5, n = 127) compared to Activity Management (mean 50.3, standard deviation 26.5, n = 138). The mean difference was 8.2 (95% confidence interval 2.7 to 13.6, p = 0.003). The result was similar for participants meeting the National Institute for Health and Care Excellence 2021 diagnostic criteria. Secondary outcomes Fatigue In Teenagers on the interNET in the National Health Service participants attended, on average, half a day more school per week at 6 months than those allocated Activity Management, and this difference was maintained at 12 months. There was no strong evidence that comorbid mood disorder impacted upon the relative effectiveness of the two interventions. Similar improvement was seen in the two groups for pain and the Clinical Global Impression scale, with a mixed picture for fatigue. Both groups continued to improve, and no clear difference in physical function remained at 12 months [difference in means 4.4 (95% confidence interval −1.7 to 10.5)]. One or more of the pre-defined measures of a worsening condition in participants during treatment, combining therapist and patient reports, were met by 39 (25%) participants in the Fatigue In Teenagers on the interNET in the National Health Service group and 42 (26%) participants in the Activity Management group. A small gain was observed for the Fatigue In Teenagers on the interNET in the National Health Service group compared to Activity Management in quality-adjusted life-years (0.002, 95% confidence interval −0.041 to 0.045). From an National Health Service perspective, the costs were £1047.51 greater in the Fatigue In Teenagers on the interNET in the National Health Service group (95% confidence interval £624.61 to £1470.41). At a base cost-effectiveness threshold of £20,000 per quality-adjusted life-year, the incremental cost-effectiveness ratio was £457,721 with incremental net benefit of −£1001 (95% confidence interval −£2041 to £38). Conclusion At 6 months post randomisation, compared with Activity Management, Fatigue In Teenagers on the interNET in the National Health Service improved physical function and school attendance. The additional cost of Fatigue In Teenagers on the interNET in the National Health Service and limited sustained impact mean it is unlikely to be cost-effective. Trial registration This trial is registered as ISRCTN18020851. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/109) and is published in full in Health Technology Assessment; Vol. 28, No. 70. See the NIHR Funding and Awards website for further award information. Plain language summary Why did we do the study? The best evidence for the treatment of adolescents with myalgic encephalomyelitis/chronic fatigue syndrome is cognitive–behavioural therapy for fatigue delivered in person. In the United Kingdom, most adolescents with myalgic encephalomyelitis/chronic fatigue syndrome cannot get this specialist treatment where they live. Fatigue In Teenagers on the interNET in the National Health Service is an online treatment using cognitive–behavioural therapy designed for myalgic encephalomyelitis/chronic fatigue syndrome, which has been shown to work in the Netherlands. To find out if Fatigue In Teenagers on the interNET in the National Health Service would be beneficial in the United Kingdom, we compared Fatigue In Teenagers on the interNET in the National Health Service to Activity Management. Activity Management is the treatment most often offered to children and young people with myalgic encephalomyelitis/chronic fatigue syndrome in the United Kingdom, and aims to avoid peaks in activity (sometimes called ‘pacing’). What was the question? Does Fatigue In Teenagers on the interNET in the National Health Service lead to greater improvements in children and young people with myalgic encephalomyelitis/chronic fatigue syndrome when compared to Activity Management, when both interventions are delivered remotely? What did we do? We compared Fatigue In Teenagers on the interNET in the National Health Service and Activity Management in two comparable groups of children, and measured physical function at 6 months as the main indication of improvement. We measured how much the treatments cost and we asked children and young people, their parents and treatment providers what they thought about the two interventions. What did we find? At 6 months, adolescents saw greater improvements in physical function, and attended half a day more school per week, with Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management. Both interventions were associated with improvements over 12 months, with there being no clear difference between them after that time. However, the Fatigue In Teenagers on the interNET in the National Health Service treatment was more expensive. What does this mean? We have shown that cognitive–behavioural therapy for fatigue can be provided online to children as Fatigue In Teenagers on the interNET in the National Health Service, leading to faster improvement in physical function and greater school attendance compared to Activity Management. However, Fatigue In Teenagers on the interNET in the National Health Service is expensive and is unlikely to be good value for money. Scientific summary Objectives Primary objective To investigate whether cognitive–behavioural therapy (CBT) specifically designed for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and delivered over the internet [Fatigue In Teenagers on the interNET in the National Health Service (FITNET-NHS)] is effective and cost-effective compared to Activity Management for children with ME/CFS who do not have access to a local specialist ME/CFS service. Secondary objectives (1) Estimate the effectiveness of FITNET-NHS compared to Activity Management for those with mild/moderate comorbid mood disorders (anxiety/depression). (2) Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management. (3) Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management for those with mild/moderate comorbid mood disorders (anxiety/depression). Methods Trial design Randomised controlled trial (RCT) comparing FITNET-NHS with Activity Management. Participants were allocated in a 1 : 1 ratio, minimised by age and gender. We conducted an internal pilot (first 12 months) and integrated qualitative methods to optimise recruitment and retention. Participants Adolescents aged 11–17 years with a diagnosis of ME/CFS [defined using National Institute for Health and Care Excellence (NICE) 2007 Criteria], who did not have a local specialist ME/CFS service. To have a confirmed diagnosis, potential participants were required to have been assessed by a paediatrician (or equivalent specialist doctor), and to have had screening bloods taken. We excluded adolescents if: they were not disabled by fatigue; their fatigue was due to another cause (including primary anxiety/depression); they had access to a local specialist service; they were unable to complete video calls or FITNET-NHS treatment modules; they were pregnant. Setting We identified potentially eligible adolescents at referral to the specialist paediatric ME/CFS service at the Royal United Hospital, Bath. Patients were referred to the service by their general practitioner (GP) or paediatrician (or equivalent specialist). Between September 2018 and March 2020, we offered GP surgeries the opportunity to become patient identification centres. In these sites, database searches were conducted to identify potentially eligible adolescents, who were then offered referral to the Bath Royal United Hospital for eligibility assessment. Recruitment Potentially eligible adolescents were contacted by the clinical team by telephone to discuss the opportunity to take part in the FITNET-NHS trial. Interested adolescents were sent study information, including a link to the Revised Children’s Anxiety and Depression Scale (RCADS) questionnaire. Eligibility assessment Adolescents who were interested were invited to an eligibility assessment conducted by a specialist nurse. The nurse checked if: (1) they had debilitating persistent or relapsing fatigue for at least 3 months, but not life-long; (2) fatigue was not the result of ongoing exertion and not substantially alleviated by rest; (3) they had post-exertional malaise (and increase in fatigue and other symptoms after exertion); and (4) their fatigue was severe enough to cause substantial reduction in previous levels of occupational, educational, social or personal activities. The recruiting nurse checked that the screening blood tests had been done within the previous 12 months and were normal. The nurse then assessed whether the adolescent had comorbid mental health problems or a primary mental health problem. Patients were asked to complete the RCADS. Those scoring within the borderline or above the age-/gender-validated threshold answered further questions to determine if they were at risk of harm and whether their anxiety/depression was sufficiently severe to explain the fatigue. This enabled us to ensure that those recruited had a diagnosis of ME/CFS from a specialist but also had 3 months of disabling fatigue plus one further symptom and did not have an exclusionary diagnosis and therefore had ME/CFS according to the contemporary United Kingdom (UK) guideline. Consent If adolescents were eligible and interested in taking part in the FITNET-NHS trial, consent and assent (patients aged 11–15 years) were obtained using an online form. Randomisation We used an automated web randomisation service operated by Bristol Trials Centre. Participants were allocated in a 1 : 1 ratio. Allocation used minimisation to balance by age and gender with a random component to preserve allocation concealment. Blinding It was not possible to blind the participant, family or the clinical service. The investigators (including the senior statistician who wrote the statistical analysis plan) were blinded to treatment allocation. The study statistician was unblinded as they reported to the Data Safety and Monitoring Committee. Interventions Fatigue In Teenagers on the interNET in the National Health Service (FITNET-NHS) This is a web-based modular specialist CBT programme designed to be used by adolescents with ME/CFS and their parents. We adapted the Dutch FITNET platform for UK adolescents. FITNET-NHS is delivered using asynchronous individualised e-consultations within the web-based platform. Contact is weekly initially and then becomes less frequent. The therapist works with patients and parents separately. FITNET-NHS has psycho-educational and CBT chapters for patients and a parallel programme for parents. There are 19 chapters. Chapters 1–3 introduce ME/CFS, CBT and the role of therapists; Chapter 4 discusses treatment goals; Chapters 5–19 are about cognitive and behavioural strategies. There are diaries for patients that are visible to the therapist. FITNET-NHS is individualised for patients. Chapters 5–19 are unlocked (made available) by the therapist according to clinical presentation, needs and formulation. Fidelity was assessed in clinical supervisions. Activity Management Participants and their families received information on ME/CFS, Activity Management, sleep and symptoms management. Participants could use an online app to record their activity. Activity Management was delivered via videocall. In the initial assessment, participants had a detailed assessment of physical and cognitive activity. The participant and therapist agreed a ‘baseline’ of activity, which is the average level of activity. Participants were asked to record activity, and then, when activity was stable, to increase activity gradually in a flexible and individual way. The initial assessment was 90 minutes (but this could be split into two shorter sessions). Follow-up video calls (60 minutes each) were organised 2–6 weeks apart. In November 2017, the number of follow-up sessions was increased from 3 to 6 in response to participant feedback. Fidelity was assessed using a checklist of mandatory, flexible and prohibited elements. Data sources Adolescent- and parent-completed measures, collected online using research electronic data capture. Therapist reports. Routinely collected data from local systems and from NHS Digital. Qualitative interviews with adolescents, parents and therapists. Measures Primary outcome Disability measured using the 36-item Short Form Health Survey Physical Function subscale (SF-36-PFS) measured 6 months after randomisation. We included outcome data returned in a 5-to-9-month window post randomisation. Secondary outcomes (Measured at 3, 6 and 12 months unless specified): Physical function (3 and 12 months); fatigue [Chalder fatigue scale and checklist individual strength (CIS) fatigue scale]; school attendance (self-reported days per week attending school, or whether receiving home tuition); mental health {RCADS; pain [visual analogue scale (VAS)]; Clinical Global Impression Scale; quality of life [EuroQol-5 Dimensions Youth (EQ-5D-Y)]; parent-completed resource use questionnaire; parent-completed work productivity and activity impairment questionnaire general health (WPAI:GH)}. Demographic data were collected at recruitment and included: age, sex, postcode, ethnicity, symptoms, months since illness onset, presence of comorbid illnesses. Harms/adverse events We prospectively collected the following data: (1) clinician-reported serious deterioration in health, (2) a decrease of ≥ 20 in SF-36-PFS between baseline and 3, 6 or 12 months or scores of ‘much’ or ‘very much’ worse on the Clinical Global Impression scale or (3) withdrawal from treatment because of feeling worse. Safety outcomes were reported to the Data Safety Monitoring Committee. Resource use data In addition to study documentation and patient/parent questionnaires, we used patient-level data recorded on the Royal United Hospitals Bath NHS Trusts electronic patient record system (Millennium). We obtained secondary care data on outpatient visits, inpatient visits and emergency department attendances from NHS Digital. Costs were valued using 2019/20 prices. Analysis Sample size Our sample size of 314 participants (assuming 15% attrition) gives 90% power at 5% significance to detect a 10-point (0.4 standard deviation) difference for the SF-36-PFS for our primary outcome. The original sample size was powered to detect a difference in the subgroup with mental health problems, but this was revised during the study. Statistical methods We used an intention-to-treat analysis in study participants who completed the primary outcome. We used multivariable linear regression analysis adjusting for baseline values of the outcome, age and gender. The treatment effect was estimated as an adjusted difference between sample means. We conducted the following pre-planned sensitivity analyses: we adjusted for variation across participants in the time between randomisation and the 6-month outcome; the primary analysis was repeated with an additional binary covariate distinguishing participants recruited before or after 1 September 2019 (distinguishing those with a 6-month assessment before or during the COVID-19 pandemic); we repeated the analysis in those who completed one or more modules/sessions of their allocated intervention. We conducted a sensitivity analysis for participants with ME/CFS according to the NICE (2021) criteria. We adapted the regression model used for the primary analysis to the secondary outcome variables. We estimated the effectiveness of FITNET-NHS compared with Activity Management in participant subgroups defined by the presence or absence of anxiety or depression (defined by the RCADS). Health economic analysis We used an intention-to-treat approach and multiple imputation by chained equation to minimise bias due to missing data. We combined cost and quality-adjusted life-year (QALY) data to calculate an incremental cost-effectiveness ratioand an incremental net monetary benefit (iNMB) statistic. We performed a subgroup analysis to explore the interaction between comorbid anxiety/depression and cost-effectiveness. Prespecified sensitivity analyses include conducting a complete-case analysis and repeating the primary analysis using the tariff paid by Clinical Commissioning Groups instead of reference costs. Qualitative methods We integrated qualitative methods into the pilot and main phase of the trial to explore trial conduct, recruitment and intervention acceptability. We analysed recruitment to trial consultations and conducted in-depth interviews with recruiters, trial therapists and participants. Results were used to improve recruitment and make small changes to the interventions. Qualitative analysis was ongoing and iterative, commencing soon after data collection. Audio recordings were transcribed, checked and imported into NVivo (QSR International, Warrington, UK). The data were systematically assigned codes and analysed thematically using techniques of constant comparison. Results Of 892 referrals between 1 November 2016 and 31 October 2020, 550 were eligible, of which 155 were allocated to FITNET-NHS and 159 to Activity Management. 265 adolescents were included in the primary analysis (127 for FITNET-NHS and 138 for Activity Management). The baseline characteristics were similar between the treatment arms. 147 participants had either comorbid depression or anxiety (145 depression, 34 anxiety and 32 both). The number completing 80% or more of expected modules/sessions was lower for FITNET-NHS participants (58, 38%) compared to Activity Management participants (124, 78%). Participants in the FITNET-NHS group had a greater improvement in physical function compared to the Activity Management group at 6 months [mean difference 8.2, 95% confidence interval (CI) 2.7 to 13.6]. The sensitivity analyses confirmed the primary analysis. This was true for participants with ME/CFS defined using the NICE (2021) criteria. At 6 months, those allocated to FITNET-NHS were, on average, attending half a day more of school per week compared to Activity Management, and this difference was maintained at 12 months. They experienced less fatigue (with the CIS fatigue measure) at both 6 and 12 months. There was no strong evidence that either treatment was more effective in those with comorbid depression/anxiety, and similar levels of improvement were noted for pain, the Clinical Global Improvement Score, and fatigue measured using the Chalder Fatigue Scale. Participants continued to improve between 6 and 12 months in both treatment arms, and there was little difference in physical function between the two treatment arms at 12 months. Fatigue In Teenagers on the interNET in the National Health Service participants had a small gain in QALYs (0.002, 95% CI −0.041 to 0.045) compared to Activity Management but substantially higher mean costs (£1047.51, 95% CI £624.61 to £1470.41). In the primary analysis, from an NHS perspective, at a threshold of £20,000 per QALY, the iNMB was −£1001.74 (95% CI −£2041.31 to £37.83), indicating that FITNET-NHS is unlikely to be cost-effective. The wide Cis show there is considerable uncertainty in this result. The subgroup analysis suggests that FITNET-NHS is more likely to be cost-effective among those with comorbid anxiety and depression at baseline. In the qualitative interviews, families felt online treatment could fit around everyday life and reduce the increase in symptoms that can accompany travelling to face-to-face appointments. However, some participants still preferred in-person treatment and found it difficult to build a rapport with therapists online. Personalised contact with a therapist was valued in both treatments and remains essential even in online treatment. The reading and writing required on the FITNET-NHS platform was difficult for younger children and those with cognitive symptoms such as brain fog; therefore, adaptations may be needed for these groups. Therapists felt they had to develop a different set of skills to engage patients online. Conclusions Despite the fact that adolescents are more likely to have better physical function at 6 months and attend more school (at 6 and 12 months) after receiving FITNET-NHS compared to Activity Management, FITNET-NHS is unlikely to be cost-effective. This study is consistent with previous RCTs that demonstrated the effectiveness of CBT for children and young people with ME/CFS. It is the first study to attempt to look at cost-effectiveness. The high additional cost of FITNET-NHS and limited substantial sustained impact mean that it may not be a cost-effective use of NHS funds. Alternatively, it is possible that the EQ-5D-Y is not sensitive enough to appropriately reflect the improvements in physical function and school attendance. Most participants in the FITNET-NHS group did not complete 80% or more of the recommended treatment modules. While our qualitative data suggest that FITNET-NHS was acceptable to most patients, it was considered burdensome by some. Implications for health care This study strengthens the evidence that CBT is effective for adolescents with ME/CFS and should be the first line of treatment offered. FITNET-NHS is an intensive treatment approach and is unlikely to be cost-effective. However, the online approach was popular with patients and families. Recommendations for research Would a shorter intervention with less intensive therapist input increase retention and reduce costs without jeopardising effectiveness? We need a validated health economic measure for children and young people that is sensitive to change. Further research needs to be conducted on the best method to deliver remote treatment. A large implementation study in the Netherlands suggested that many patients (and therapists) prefer a mixture of face-to-face and online treatment. Trial registration This trial is registered as ISRCTN18020851. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/109) and is published in full in Health Technology Assessment; Vol. 28, No. 70. See the NIHR Funding and Awards website for further award information.

Background and objectives Schools play a crucial role in facilitating physical activity among children, but the COVID-19 pandemic has affected both children’s physical activity and the school environment. It is essential to understand between-school differences in children’s physical activity post lockdown, to determine if and how the role of schools has changed. Design and participants Active-6 is a natural experiment comparing postlockdown accelerometer-estimated physical activity to a pre-COVID-19 comparator group. Accelerometer and individual data were collected on 1296 children aged 10–11 pre-COVID-19 (2017–8), with school characteristics collected from the 50 schools they attended. Post lockdown, we collected accelerometer, individual and school data from 393 children in 23 of the same schools and 436 children in 27 of the same schools in 2021 (Wave 1) and 2022 (Wave 2), respectively. Methods Sources of variation (between-school, between-pupil and within-pupil) in child weekday moderate to vigorous physical activity at each wave were modelled using linear mixed-effects models with school-level wave random coefficients. We extended the model to estimate the proportion of between-school variation explained by school policy, curriculum and physical environment factors and school-aggregated pupil characteristics. We also explored the extent to which postlockdown differences in moderate to vigorous physical activity were mediated by individual or school factors. Results Between-school variation comprised 13% of the total variation pre-COVID-19, 7% in Wave 1 and 13% in Wave 2. School factors associated with moderate to vigorous physical activity were the following: whether physical education was compromised due to space (often: 9 minutes lower moderate to vigorous physical activity; sometimes: 5.4 minutes lower); high after-school club attendance (7 minutes higher moderate to vigorous physical activity for each additional club attended on average in the school); cycle training policy (4 minutes higher moderate to vigorous physical activity); and higher prevalence of active travel (1 minute higher moderate to vigorous physical activity for each 10% point increase in prevalence). These factors explained 22% of the between-school variation pre-COVID-19, and 72% at Wave 2. The relative importance changed, with cycle training policy and active travel being the most important pre-COVID-19 and cycle training policy, active after-school clubs and compromised physical education space most important in Wave 2. No factors were found to mediate the postlockdown differences in moderate to vigorous physical activity, except compromised physical education space, which had a suppressor effect in Wave 2. Limitations Only 27 of the initial 50 schools participated post lockdown, limiting our ability to make comparisons across waves. Sample sizes were additionally affected by missing data for some variables. Conclusions and future work While schools continue to play an important role in facilitating children’s physical activity, the factors that contribute to this have changed post-COVID-19, with cycle training, active after-school clubs and ensuring physical education is prioritised even when space is limited now explaining nearly three-quarters of the between-school variation in children’s moderate to vigorous physical activity. School-level interventions that focus on these areas, and policies that support them, may offer the potential to increase children’s physical activity. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847. Plain language summary What was the question? Schools are important in helping children to be physically active. How active children are differs between schools. We wanted to know whether this has changed after the COVID-19 lockdowns. We also looked at features of the school, like equipment in the playground or being active in lessons, that might explain these differences. What did we do? We collected activity data from 10- to 11-year-olds from 50 schools around Bristol (United Kingdom) before and after the COVID-19 lockdowns. Children also told us about how they travelled to school and whether they went to after-school sports or exercise clubs. We asked schools about their policies and lessons. Finally, we collected data on the playground and surroundings. What did we find? In the first 6 months after lockdowns, schools had a much smaller role in children’s activity. But after a year, schools were once again an important influence on how active children were. We found that the school features that affected children’s activity had changed. Before the pandemic, the things that helped children most to be active were learning to ride a bike at school, and walking or cycling to school. After the pandemic, offering lots of after-school sports clubs was more important. Schools that struggled with physical education lessons because of a lack of space had fewer active pupils. What does this mean? Schools continue to play an important role in helping children be active. But this role has changed after the lockdowns. In the future, schools could help keep children active by offering plenty of after-school clubs and help children to learn to ride a bike. Also, it is important to make sure that physical education lessons are a priority, even when there is not much space.

Background The COVID-19 lockdowns had negative effects on children’s and adults’ mental and physical health. There is, however, a paucity of research that explores differences in health-related quality of life (HRQL) and well-being over time after the COVID-19 lockdowns had been lifted. Furlough during lockdowns, increases in unemployment, and the emerging cost-of-living crisis all put pressure on family finances, which could have a detrimental effect on HRQL and well-being. This study, part of the wider Active-6 study, explored how HRQL, capability well-being and family financial strain changed after the lockdowns, the relationship between these outcomes, and whether physical activity had any mediating effect on differences in HRQL and capability well-being. Methods Cross-sectional data were collected in May–December 2021 (Wave 1) and January–July 2022 (Wave 2). Children (aged 10–11) and their parent/carer were recruited from 23 to 27 schools in each wave, respectively, and completed validated questionnaires measuring HRQL (adults – EQ-5D-5L, children – CHU9D), capability well-being (adults – ICECAP-A) and family financial strain (adults – Family Economic Strain Scale, FESS). Children also completed questions on capability well-being. Weekday minutes of moderate-to-vigorous physical activity (MVPA) were measured using accelerometers. Mixed-effects regression models, adjusted for gender, age group (adults only), IMD and highest household education, were used to explore differences in HRQL and capability well-being between waves. In addition, the moderating effect of financial strain and the mediating effect of MVPA on HRQL and capability well-being were explored. Results Active-6 recruited 393 parent-child pairs in Wave 1 and 436 in Wave 2. There were no differences in HRQL (EQ-5D, CHU9D) and capability well-being (ICECAP-A) scores between waves, but financial strain was worse in Wave 2 compared to Wave 1 (FESS score difference 1.14 adjusted 95% CI 0.15 to 2.12). Increased financial strain was associated with lower (worse) EQ-5D-5L, CHU9D and ICECAP-A scores. There was no evidence of a mediating effect of MVPA. Limitations and future work Pre-COVID-19 data on HRQL were not collected, so analysis was limited to post-lockdown only. Participating parents were predominantly female and participation was lower among lower socio-economic groups, limiting our ability to explore inequalities. Intervention planning to increase physical activity and health and well-being during the COVID-19 recovery should consider the financial strain families are experiencing and the negative implications of financial strain on HRQL. Conclusions There were no differences in HRQL and capability well-being in children and adults after lockdowns lifted in 2021 and a year later in 2022. The results indicate increasing financial strain, which could reflect the UK’s ‘cost of living crisis’. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847. Plain language summary Why did we do this study? We know that the COVID-19 pandemic negatively affected people’s mental and physical health. But we don’t know how quality of life, well-being and pressure on family finances changed for people after the lockdowns were lifted and society reopened. We also wanted to know if these changes were related to how physically active people were. What did we do? Children and a parent/carer answered questions about their quality of life, well-being and family budget pressures. Physical activity data were also collected using devices worn on their waists. We did this in 2021, when society started to reopen after lockdowns, and a year later in 2022 when all restrictions were gone. We explored differences in quality of life, well-being and pressure on family finances between 2021 and 2022. We then looked at whether any of these differences were because of changes in physical activity, and if financial strain was related to quality of life. What did we find? We did not find any differences in quality of life or well-being between 2021 and 2022. Financial strain increased slightly. As financial strain increased, quality of life and well-being decreased. This was worse for those experiencing most financial difficulties. Physical activity did not seem to explain differences in quality of life. What does this mean? If family finances are stretched, it might be difficult for families to pay for activities that will help their children be more active. We have also found that family financial difficulties are related to quality of life and well-being.

Background Stroke or transient ischaemic attack patients are at increased risk of secondary vascular events. Antiplatelet medications, most commonly clopidogrel, are prescribed to reduce this risk. Factors including CYP2C19 genetic variants can hinder clopidogrel metabolism. Laboratory-based or point-of-care tests can detect these variants, enabling targeted treatment. Objective To assess the effectiveness of genetic testing to identify clopidogrel resistance in people with ischaemic stroke or transient ischaemic attack. Specific objectives: Do people tested for clopidogrel resistance, and treated accordingly, have a reduced risk of secondary vascular events? Do people with loss-of-function alleles associated with clopidogrel resistance have a reduced risk of secondary vascular events if treated with alternative interventions compared to clopidogrel? Do people with loss-of-function alleles associated with clopidogrel resistance have an increased risk of secondary vascular events when treated with clopidogrel? What is the accuracy of point-of-care tests for detecting variants associated with clopidogrel resistance? What is the technical performance and cost of CYP2C19 genetic tests? Is genetic testing for clopidogrel resistance cost-effective compared with no testing? Design Systematic review and economic model. Results Objective 1: Two studies assessed secondary vascular events in patients tested for loss-of-function alleles and treated accordingly. They found a reduced risk, but confidence intervals were wide (hazard ratio 0.50, 95% confidence interval 0.09 to 2.74 and hazard ratio 0.53, 95% confidence interval 0.24 to 1.18). Objective 2: Seven randomised controlled trials compared clopidogrel with alternative treatment in people with genetic variants. Ticagrelor was associated with a lower risk of secondary vascular events than clopidogrel (summary hazard ratio 0.76, 95% confidence interval 0.65 to 0.90; two studies). Objective 3: Twenty-five studies compared outcomes in people with and without genetic variants treated with clopidogrel. People with genetic variants were at an increased risk of secondary vascular events (hazard ratio 1.72, 95% confidence interval 1.43 to 2.08; 18 studies). There was no difference in bleeding risk (hazard ratio 0.98, 95% confidence interval 0.68 to 1.40; five studies). Objective 4: Eleven studies evaluated Genomadix Cube accuracy; no studies evaluated Genedrive. Summary sensitivity and specificity against laboratory reference standards were both 100% (95% confidence interval 94% to 100% and 99% to 100%). Objective 5: Seventeen studies evaluated technical performance of point-of-care tests. Test failure rate ranged from 0.4% to 19% for Genomadix Cube. A survey of 8/10 genomic laboratory hubs revealed variation in preferred technologies for testing, and cost per test ranging from £15 to £250. Most laboratories expected test failure rate to be

Our research evaluates the effectiveness of a community musical learning exchange (MLE) that included group singing, guided conversations, and reflection. The respondents (N = 290) who participated in the MLE included members of the Soweto Gospel Choir (n = 17), Soweto Gospel Choir Crew (n = 3), prison choir incarcerated singers (n = 41), prison choir non-incarcerated singers (n = 41), and community guest-participants (n = 188). We studied: To what extent did respondents engage in singing and conversations during the learning exchange? To what degree did the respondents perceive the various components of the learning exchange helped them reflect upon the theme? What similarities and differences existed among various groups regarding these perceptions? Results suggest the MLE model was effective for intercultural sharing and most respondents engaged in singing and conversations. The guided conversations within a musical event were novel experiences, with the majority describing these as very effective components of the MLE. Respondents noted that both these guided conversations and spoken reflections prior to song selections from prison choir members and singing together most effectively helped them engage with the theme. We offer suggestions for musical leaders to implement MLEs and we make recommendations for future related research.

Introduction Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking.Methods and analysis RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period.Ethics and dissemination Ethics approval was obtained from the London—Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries.Trial registration number ISRCTN16473239.

Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

Purpose: This paper explores the school leadership career outcomes, timing and educator evaluation of those who complete the Massachusetts Performance Assessment for Leaders (PAL) in comparison with others who did not. It also compares outcomes for those with different PAL score completion requirements. Design/methodology/approach: Using PAL assessment results and state employment data for years 2015 through 2019, the authors examined trends and timing in PAL completers' career advancement into an initial school leader position (assistant principal or principal), by assessment cohort (based on assessment year and passing (cut) score requirements) and with who never had to complete the assessment for licensure (non-PAL completers). Using regression analysis, the authors evaluated potential race/ethnicity and gender differences in advancement. Using chi-square tests of association, the authors compared non-PAL and PAL completers on their demographic attributes and on retention and promotion from assistant principal and on their educator evaluation scores. The authors also examined differences in advancement based on the cut score requirements and preparation pathways. Findings: PAL completers made steady career advances over time and at faster rates than non-PAL completers. Further, PAL completers subject to higher cut score requirements advanced more quickly than those with lower or no score requirements. PAL completers' gender and race/ethnicity seemed to matter less in career advancement than was found in other studies. In 2019, almost half who advanced were employed in the same districts as they had been in 2014 and were more likely to be new leaders in urban districts. When compared with other career-related measures, PAL completers outperformed non-PAL completers who first became school leaders since 2014: they were more likely to be rated as exemplary on educator evaluation and more likely to be retained or promoted after two years in their first school leader position. Originality/value: Until now little research has existed on the career effects of licensure assessments. Because it requires candidates to demonstrate proficiency in core areas of school leadership work, the PAL assessment appears to be a superior means of screening initial school leaders (based on rate of hiring) and of signaling future performance (based on subsequent educator evaluation ratings) than other assessment forms (such as the School Leader Licensure Assessment [SLLA] exam).

Abstract Background Children’s physical activity in England is more dependent on active clubs after the COVID-19 pandemic. However, it is unclear how the COVID-19 pandemic and related cost-of-living crisis have impacted on active club participation, costs and provision. This mixed-methods natural experiment explored school-based and community-based active clubs after lockdowns, using a unique combination of data sources to highlight implications for policy and practice post-COVID-19. Methods Cross-sectional questionnaire data on school and community active clubs were collected from 10-11-year-old children pre-COVID-19 in 2017-18 (N = 1,296; 50 schools), in 2021 (N = 393; 23 schools), and 2022 (N = 463; 27 schools). Club participation and attendance frequency were modelled using logistic and Poisson mixed effects models, adjusted for child age, gender and household education. In 2021 and 2022, parents reported expenditure on community-based clubs and schools provided data on school-based club provision, with data summarised descriptively. Qualitative data were collected in 2021 and 2022, with one-to-one interviews with school staff (N = 18) and parents (N = 43), and twelve child focus groups (N = 92), and analysed using the framework method. Results School-based active club participation was higher in 2022 compared to pre-pandemic (50% /43%), while community-based club participation was lower (74%/80%). Children attended 0.3 fewer clubs per week. Those from lower education households were less likely to participate in both types of active clubs, and girls less likely to attend community clubs. In 2022, the median cost of community and school club sessions were £6.67 and £3.88 respectively, with 52% of school-based clubs free to parents. Schools offered an average of 3.4 active clubs per week for 10-11-year-olds in 2022, with 34% partly/wholly subsidised. Qualitative analysis highlighted the impact of the cost-of-living crisis and COVID-19 pandemic on family resources, encouraging a shift to more affordable and convenient school-based active clubs, which negatively impacted the community-based active club environment. However, many schools struggled to meet this increased demand. Conclusions Findings emphasise the importance for policymakers to support schools to meet increased demand for clubs and community clubs to increase affordable and convenient physical activity opportunities. Targeted support is needed to prevent socioeconomic and gender inequalities.

Abstract Background Health economic research is still facing significant problems regarding the standardization and international comparability of health care services. As a result, comparative effectiveness studies and cost-effectiveness analyses are often not comparable. This study is part of the PECUNIA project, which aimed to improve the comparability of economic evaluations by developing instruments for the internationally standardized measurement and valuation of health care services for mental disorders. The aim of this study was to identify internationally relevant services in the health and social care sectors relevant for health economic studies for mental disorders. Methods A systematic literature review on cost-of-illness studies and economic evaluations was conducted to identify relevant services, complemented by an additional grey literature search and a search of resource use measurement (RUM) questionnaires. A preliminary long-list of identified services was explored and reduced to a short-list by multiple consolidation rounds within the international research team and an external international expert survey in six European countries. Results After duplicate removal, the systematic search yielded 15,218 hits. From these 295 potential services could be identified. The grey literature search led to 368 and the RUM search to 36 additional potential services. The consolidation process resulted in a preliminary list of 186 health and social care services which underwent an external expert survey. A final consolidation step led to a basic list of 56 services grouped into residential care, daycare, outpatient care, information for care, accessibility to care, and self-help and voluntary care. Conclusions The initial literature searches led to an extensive number of potential service items for health and social care. Many of these items turned out to be procedures, interventions or providing professionals rather than services and were removed from further analysis. The resulting list was used as a basis for typological coding, the development of RUM questionnaires and corresponding unit costs for international mental health economic studies in the PECUNIA project.

Abstract Background Bespoke self-report resource-use measures (RUMs) are commonly developed or adapted for each new randomised controlled trial. Consequently, RUMs lack standardisation and validation is rarely conducted. A new generic RUM, ModRUM, has been developed using a rigorous process, including consultation with health economists and patients. ModRUM includes a concise core healthcare module, designed to be included in all trials, and depth-adding questions, which can replace or be added to core questions as needed. Modules covering other sectors are under development. The aim of this study was to test the acceptability, feasibility, and criterion and construct validity of the healthcare module of ModRUM. Methods Patients who had a recent appointment at their GP practice were invited to complete ModRUM (core module or core module with depth questions), a characteristics form and the EQ-5D-5L. Acceptability was assessed via response rates and questionnaire completion time. Feasibility was assessed by reviewing issues observed in participants’ responses and question completion rates. Construct validity was tested via hypothesis testing and known-group analyses, using Wilcoxon rank-sum and Kruskal–Wallis tests, and a generalised linear model. Criterion validity was tested by comparing ModRUM results with primary care medical records. Sensitivity, specificity, and agreement using Lin’s concordance correlation coefficient (pc) were estimated. Results One hundred patients participated from five GP practices in the South-West of England. Acceptability was higher for the core module (20% versus 10% response rate). Question completion rates were high across both versions (> 90%). Some support was observed for construct validity, with results suggesting that healthcare costs differ dependent on the number of long-term conditions (p 0.83), while specificity varied (0.33–0.88). There was a good level of agreement for GP contacts and costs, and prescribed medication costs (pc > 0.6). Conclusion This study provided preliminary evidence of the acceptability, feasibility, and criterion and construct validity of ModRUM. Further testing is required within trials and with groups that were less well represented in this study.

The disruptive potential of artificial intelligence (AI) has been on the minds of many professionals since the public launch of ChatGPT in late 2022. Just as previous technological revolutions deeply [...]

Abstract Background Policymakers in sub-Saharan Africa (SSA) face challenging decisions regarding the allocation of health resources. Economic evaluations can help decision makers to determine which health interventions should be funded and or included in their benefits package. A major problem is whether the evaluations incorporated data from sources that are reliable and relevant to the country of interest. We aimed to review the quality of the data sources used in all published economic evaluations for cardiovascular disease and diabetes in SSA. Methods We systematically searched selected databases for all published economic evaluations for CVD and diabetes in SSA. We modified a hierarchy of data sources and used a reference case to measure the adherence to reporting and methodological characteristics, and descriptively analysed author statements. Results From 7,297 articles retrieved from the search, we selected 35 for study inclusion. Most were modelled evaluations and almost all focused on pharmacological interventions. The studies adhered to the reporting standards but were less adherent to the methodological standards. The quality of data sources varied. The quality level of evidence in the data domains of resource use and costs were generally considered of high quality, with studies often sourcing information from reliable databases within the same jurisdiction. The authors of most studies referred to data sources in the discussion section of the publications highlighting the challenges of obtaining good quality and locally relevant data. Conclusions The data sources in some domains are considered high quality but there remains a need to make substantial improvements in the methodological adherence and overall quality of data sources to provide evidence that is sufficiently robust to support decision making in SSA within the context of UHC and health benefits plans. Many SSA governments will need to strengthen and build their capacity to conduct economic evaluations of interventions and health technology assessment for improved priority setting. This capacity building includes enhancing local infrastructures for routine data production and management. If many of the policy makers are using economic evaluations to guide resource allocation, it is imperative that the evidence used is of the feasibly highest quality.

Abstract Background One in seven UK children have obesity when starting school, with higher prevalence associated with deprivation. Most pre-school children do not meet UK recommendations for physical activity and nutrition. Formal childcare settings provide opportunities to deliver interventions to improve nutritional quality and physical activity to the majority of 3–4-year-olds. The nutrition and physical activity self-assessment for childcare (NAP SACC) intervention has demonstrated effectiveness in the USA with high acceptability in the UK. The study aims to evaluate the effectiveness and cost-effectiveness of the NAP SACC UK intervention to increase physical activity, reduce sedentary time and improve nutritional intake. Methods Multi-centre cluster RCT with process and economic evaluation. Participants are children aged 2 years or over, attending UK early years settings (nurseries) for ≥ 12 h/week or ≥ 15 h/week during term time and their parents, and staff at participating nurseries. The 12-month intervention involves nursery managers working with a Partner (public health practitioner) to self-assess policies and practices relating to physical activity and nutrition; nursery staff attending one physical activity and one nutrition training workshop and setting goals to be achieved within 6 months. The Partner provides support and reviews progress. Nursery staff receive a further workshop and new goals are set, with Partner support for a further 6 months. The comparator is usual practice. Up to 56 nurseries will be stratified by area and randomly allocated to intervention or comparator arm with minimisation of differences in level of deprivation. Primary outcomes: accelerometer-assessed mean total activity time on nursery days and average total energy (kcal) intake per eating occasion of lunch and morning/afternoon snacks consumed within nurseries. Secondary outcomes: accelerometer-assessed mean daily minutes of moderate-to-vigorous physical activity and sedentary time per nursery day, total physical activity on nursery days compared to non-nursery days, average serving size of lunch and morning/afternoon snacks in nursery per day, average percentage of core and non-core food in lunch and morning/afternoon snacks, zBMI, proportion of children who are overweight/obese and child quality-of-life. A process evaluation will examine fidelity, acceptability, sustainability and context. An economic evaluation will compare costs and consequences from the perspective of the local government, nursery and parents. Trial registration ISRCTN33134697, 31/10/2019.

Abstract Background The COVID-19 pandemic significantly impacted children’s physical activity. Recent evidence indicated children’s accelerometer-measured physical activity levels have, on average, returned to near pre-pandemic levels in 2022, though sedentary behaviour remains higher. However, insufficient physical activity levels among children continues to be a critical public health issue in the UK, with only 41% meeting physical activity guidelines. This study aimed to provide in-depth analysis of how the pandemic has shaped children’s physical activity patterns beyond the short-term periods following lockdowns and identify the new challenges to engaging children in physical activity. Methods One-to-one interviews with parents (n = 22), school staff (n = 9), and six focus groups with children aged 10–11 years (n = 45) were conducted between February and July 2022. Topics explored changes to children’s physical activity and sedentary behaviour patterns, including screen-viewing, and factors influencing any changes. The framework method was used for analysis. Results Five themes were generated. Theme 1 described residual lockdown habits, including increased screen-viewing within the home, while activities outside the home continued to feel less spontaneous. Theme 2 highlighted an interrupted development of social, emotional, and physical skills among children compared to what would be expected pre-pandemic. This coincided with Theme 3 which reflected increased mental health challenges among families, creating complex barriers to children’s physical activity. A new normal for child physical activity was evoked and explored in Theme 4, with greater dependence on structured and organised activities. However, Theme 5 highlighted that girls and children with lower socio-economic position may be especially at risk of decreased physical activity. Conclusions There is a new normal for children’s physical activity that is characterised by increased dependence on structured and organised physical activities, such as active clubs, and less on unstructured and spontaneous physical activities, such as physical play. While this may suit many children, girls and children from lower socio-economic households face barriers to participating in the new normal. It is important that affordable and equitable opportunities are provided to all children to prevent physical activity and health inequalities.

Background: Prior work examined the relationship between teacher preparation programs (TPPs) and teacher attrition and turnover. However, such research aggregated all types of non-traditional certification programs (non-TCPs) into a single non-TCP group. This practice masks some critical differences among non-TCPs, and could send a misleading message to stakeholders and policymakers. Purpose: Our study builds on prior studies and empirically investigates the relationship between the types of TPPs and beginning teachers' attrition and turnover behaviors in Texas public schools using a detailed non-TCP typology. Our study provides information about variation in attrition and turnover rates among non-TCPs and highlights the types of non-TCPs that exhibited different turnover and attrition patterns. Research Design: Using longitudinal administrative data and detailed data on preparation program type obtained from the Texas Education Agency, we estimated a series of logistic regression models and discrete-time hazard models with district fixed effects, school random effects, and school-by-year random effects. Findings: Non-TCP teachers were more likely to leave the profession or the district than TCP teachers for the first few years. Yet, by the end of the fourth year, attrition and turnover rates converged between TCP and non-TCP teachers. Among non-TCP teachers, teachers from district-administered programs and programs operated by private nonprofit organizations exhibited different attrition and turnover behaviors than other non-TCP teachers. Conclusion: Given the differential turnover and attrition rates among non-TCP teachers, district and school administrators may design tailored activities and programs that could meet the varying needs of teachers from different types of preparation programs.