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K Groen, NWCJ van de Donk, CAM Stege, S Zweegman, IS Nijhof Department of Hematology, VU University Medical Center, Amsterdam, Netherlands Abstract: Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients. Keywords: carfilzomib, relapsed, refractory multiple myeloma, proteasome inhibitor

Abstract Crimean Congo hemorrhagic fever (CCHF) is a re-emerging tick-borne zoonosis that is caused by CCHF virus (CCHFV). The geographical distribution of the disease and factors that influence its occurrence are poorly known. We analysed historical records on its outbreaks in various countries across the sub-Saharan Africa (SSA) to identify hotspots and determine socioecological and demographicfactors associated with these outbreaks. We used data from historical outbreaks that were reported between 1981 and 2022 in various countries in SSA. To develop a common framework for merging the outbreak data and potential explanatory variables, we generated a common shapefile that combined Level 2 administrative units in all the countries. Several climatic, environmental, socioecological data were obtained from on-line GIS databases and extracted using the shapefile. The data were analysed using an approximate Bayesian hierarchical model using the R-INLA package. The outcome was a Boolean variable which indicated whether an administrative unit in the shapefile was affected in a given year or not. A neighborhood structure was also generated and used to account for spatial autocorrelation in the analysis. The final model that was obtained from the analysis was used to build a CCHF risk map. A total of 54 CCHF outbreaks were compiled across 414 districts in nine SSA countries. Factors that were positively associated with CCHF outbreaks included human population density, land area under grassland, bare soil cover and shrub cover. Conversely, high precipitation during wet months, elevated mean temperature and slope had negative effects. The risk map generated shows that CCHF occurrence risk is higher in arid and semi-arid land (ASAL) of West Africa, the Sahelian region, Central Africa, and the Eastern and Southern Africa region. The analysis identified ecological and demographic factors that are associated with CCHF outbreaks in SSA. This finding suggests the need to improve surveillance for the disease especially in the grasslands where the human population is increasing.

Background: Post-traumatic stress disorder (PTSD) is common in adults with intellectual disabilities. Often there are additional disorders such as substance use, mood and anxiety disorders. The current study focuses on the feasibility and initial efficacy of prolonged exposure (PE) for PTSD in adults with mild intellectual disabilities. The secondary effect of PE on additional mood, anxiety and substance use disorders is also examined. Methods: A single case experimental design (N = 12) with an A (baseline)-B (intervention) phase including a follow-up measurement after 3 months was conducted. Time series and single time points measurements were performed. Results: Six participants dropped-out. The results showed a significant decrease in PTSD symptoms and a significant decrease in additional symptoms (social avoidance, anxiety and stress), among participants who completed treatment. Conclusion: PE appears to be a feasible and effective treatment for PTSD in some adults with mild intellectual disabilities. Suggestions emerge from this study to make standard PE treatment more appropriate for adults with mild intellectual disabilities. Further research is needed to reduce drop-out in trauma treatment. Some suggestions for this are made in this study. Treatment of PTSD with PE did not appear to affect comorbid mood disorders. Further research is needed.

IntroductionSocial play behaviour facilitates the development of social, emotional and cognitive capacities, including resilience. Deprivation of social play in rats leads to alterations in anxiety, stress and social behaviour. The aim of this study was to elucidate the effects of social play deprivation, specifically on the responsivity to social and non-social challenges. We hypothesised that play deprivation leads to impairments in stress resilience later in life, particularly in social contexts. MethodsTo test this, play-deprived rats were compared with undeprived control rats for their responsivity to (1) a novel environment, (2) facing an aggressive male rat in its territory (resident-intruder test) and (3) an encounter with two unfamiliar conspecifics in a neutral, familiar environment (stranger encounter test). ResultsCorticosterone concentrations in response to these different stressors were comparable between play-deprived and control rats. Behavioural analysis revealed that play-deprived rats responded similar to undeprived controls when confronted with an aggressive rat in its territory. In the stranger encounter test, the unfamiliar strangers directed more play behaviour towards play-deprived animals than towards undeprived control animals. DiscussionTogether our results indicate that, except for subtle differences in play behaviour in a social challenging condition, play deprivation did not result in altered corticosterone responses to the different stressors. Our data add to the existing knowledge about the impact of social play for the development of resilient and social behaviour later in life.

Background Childhood overweight and obesity prevalence steeply increased during recent decades, prompting the development of many digital behavioral dietary interventions (DBDIs). However, a coherent overview is lacking, which is crucial for delineating research in this field.Objective This scoping review outlines the landscape of DBDIs for improving dietary behaviors in children and adolescents, including delivery modes, design and development approaches, behavioral theory, and outcomes assessed. Secondary objectives involved examining the integration of behavior change techniques (BCTs) and identifying outcomes favoring DBDIs.Methods Following PRISMA guidelines, PsycInfo, PubMed, and Scopus were systematically searched for evaluated DBDIs. Two reviewers independently screened titles and abstracts; one performed full-text screening. Studies included had a digital component, targeted dietary behavior, focused on children or adolescents, and evaluated effects on behavior change, health, or process evaluation outcomes. One reviewer extracted data, including general information, theoretical underpinning, and outcomes assessed, while BCTs were coded independently by two reviewers. DBDIs were deemed favorable if significant improvements were observed in all outcomes (p ≤ .05).Results From 51 included studies, 41 DBDIs were identified, including app-based (37%), web-based (29%), computer-based (27%), text-message-based (5%), and combined technology tools (2%). Stakeholders were involved in the design of 59% of DBDIs, with 5% using co-design methodologies. Studies evaluated behavior change outcomes (86%), process evaluation outcomes (59%), and health outcomes (20%). DBDIs included an average of 6.2 BCTs, primarily ‘Feedback on behavior’ (56%) and ‘Non-specific reward’ (46%). Among experimental studies, 15% yielded favorable results, 58% mixed results, and 28% no favorable results.Discussion This review outlines the diverse landscape of DBDIs, highlighting various technological delivery modes and outcomes assessed. Methodological variations and limitations challenge consistent effectiveness assessment. Future research should prioritize rigorous study designs to understand efficacy and identify effective BCTs among diverse pediatric populations. Leveraging co-design methods may enhance engagement and effectiveness.

Background The use of peer support workers to support suicidal adolescents is underdeveloped. This study focuses on the effects of a one-year intervention with peer support workers on a chronically suicidal adolescent residing in a secure residential youth care facility in the Netherlands. Moreover, we explore the mechanisms that underpin the role of peer support workers in detail. Method This study employed a single case study design. We conducted seven semi-structured interviews with staff, peer support workers, and a chronically suicidal adolescent. The interviews were analysed using a thematic analysis. Results The results indicate that the suicidal tendencies of the adolescent decreased significantly one year after the peer support intervention compared to the initial baseline. Working mechanisms that underpinned the peer support intervention emphasized building meaningful and trust-based relationships, providing recognition and hope, and practical support from a recovery-oriented perspective. Conclusion The results suggest that peer support has a beneficial impact on the adolescent and treatment teams. Peer support workers contribute to a sense of belonging and connection, coping with suicidality, rediscovering life goals, and improving adolescent self-management. Barriers and facilitators to implementing peer support workers are also discussed.

Niels WCJ van de Donk,1,2 Güllü Görgün,1 Richard WJ Groen,1,3 Jana Jakubikova,1 Constantine S Mitsiades,1 Teru Hideshima,1 Jacob Laubach,1 Inger S Nijhof,2 Reinier A Raymakers,2 Henk M Lokhorst,2 Paul G Richardson,1 Kenneth C Anderson11Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2Department of Hematology, 3Department of Cell Biology, University Medical Center Utrecht, Utrecht, The NetherlandsAbstract: Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy.Keywords: lenalidomide, multiple myeloma, immunomodulatory drugs, relapse treatment, refractory disease

Purpose of the article – The article aims to provide guidance to governments, companies and civil society for real-world sustainable market transformations. Research methodology – Sustainable market transformations (SMTs) are key to creating long-term sustainable development. Literature on sustainable market transformations focuses on how markets can move from unsustainable to more sustainable. We apply the Sustainable Market Transformation Framework (SMTF) to the Oil & Gas sector in Europe (2017-2022). To analyse whether and in which way a sustainable market transition is unfolding, we use Lessig’s Modalities theory (1998). Lessig identifies four regulators— Market, Law, Architecture and Norm —that influence behaviour of individuals and organisations. Findings –While the regulator Law has actioned the sector towards Phase 1, it is the interplay between the Norm and Market that dictates the pace. Since 2019, a shift occurred, underscoring the primacy of the regulator Norm as the principal driver of industry behavior. The role of Architecture proves to be more of a passive factor. It is the nuanced interplay between the regulator Norm and Market that ultimately shapes the speed and direction of the companies within the sector during 2017-2022. Practical implications – We recommend that strong influence be exerted by governments, other companies, civil society organizations to influence the cultural Norms in the sector. The regulator Law can assist therein as Law can directly and indirectly drive the other three regulators. Originality/Value – The findings provide guidance for real-world sustainable market transformations. It also deepens the conceptual understanding of the SMTF by developing a research protocol that can be used by other researchers to examine other (high-risk) sectors over time.

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.

This study aims to impact the responsible management practices of factories in the Ready-Made Garment (RMG) sector in Bangladesh. Collaborative research with our main partner - the BGMEA University for Fashion and Technology (BUFT) - on responsible management has contributed to the embedding of ethical practices in the RMG sector. More specifically, in a first stage of this program, the collaborative knowledge development is ingrained in the degree and executive education programs of BUFT - impacting about a quarter of the professionals entering the RMG sector in Bangladesh - and has informed the practices and policies of professional bodies, such as BGMEA in Bangladesh, MODINT in the Netherlands and the International Apparel Federation (IAF). Furthermore, in a second stage of this program, research on sustainability hot spots in the RMG value chain has influenced decision-making of the European Committee in relation to their sustainability policies. It substantially advanced the understanding of how European non-development policies and regulations aimed at private and public market actors contribute to or undermine sustainable development policies. The project delivered practical tools and innovative regulatory reform proposals with substantial potential for greater policy-coherence for development, thereby contributing to an integral approach focusing on a shift towards responsibility.

Abstract Background In Europe, feline vector-borne infections are gaining importance because of the changing climate, expanding habitats of potential vectors and expanding pathogen reservoirs. The main objective of this study was to assess the prevalence of vector-borne pathogens (VBPs) in stray cats in Zaragoza, Spain, and to investigate potential risk factors for infection, including feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV). Methods Blood samples from stray cats presented to the veterinary faculty in Zaragoza between February 2020 and 2022 were tested by polymerase chain reaction (PCR) for the presence of Anaplasma phagocytophilum, Anaplasma platys, Bartonella henselae, Ehrlichia canis, Rickettsia spp., haemotropic Mycoplasma spp., Hepatozoon spp., Leishmania infantum, piroplasms and microfilariae at the LABOKLIN laboratory. The cats were also tested for FeLV and FIV by PCR. Results Nearly half of the cats (158/332, 47.6%) were positive for at least one VBP. Hepatozoon spp. were detected in 25.6%, haemotropic Mycoplasma spp. in 22.9%, B. henselae in 9.3% and L. infantum in 2.1% of the cats. Male sex had a statistically significant association with test results for haemotropic Mycoplasma spp. (odds ratio 1.38 [1.21;1.57]); regionality with Hepatozoon spp., B. henseale and FIV; and seasonality with Hepatozoon spp., haemotropic Mycoplasma spp., L. infantum and FeLV (P ≤ 0.05 each). A strong positive correlation was reported for the amount of rainfall and the number of cats that tested positive for Hepatozoon spp. (ρ = 753, P = 0.05). None of the cats tested positive for A. phagocytophilum, A. platys, E. canis, Rickettsia spp., piroplasms, or microfilariae. Co-infections with multiple VBPs were detected in 56 out of 332 cats (16.9%). Thirty-one of the 332 cats included in the study (9.3%) tested positive for FeLV (6.9%) and for FIV (3.6%). In 20/31 cats (64.5%) that tested positive for FeLV/FIV, coinfections with VBP were detected (P = 0.048, OR 2.15 [0.99; 4.64]). Conclusions VBPs were frequently detected in stray cats in Zaragoza. In particular, regionality and seasonality had a statistically significant association with PCR results for most VBPs included in the study. Graphical Abstract

Abstract The apicomplexan parasite Theileria annulata is transmitted by Hyalomma ticks and causes an acute lymphoproliferative disease that is invariably lethal in exotic cattle breeds. The unique ability of the schizont stage of T. annulata to transform infected leukocytes to a cancer-like phenotype and the simplicity of culturing and passaging T. annulata-transformed cells in vitro have been explored for live vaccine development by attenuating the transformed cells using lengthy serial propagation in vitro. The empirical in vivo evaluation of attenuation required for each batch of long-term cultured cells is a major constraint since it is resource intensive and raises ethical issues regarding animal welfare. As yet, the molecular mechanisms underlying attenuation are not well understood. Characteristic changes in gene expression brought about by attenuation are likely to aid in the identification of novel biomarkers for attenuation. We set out to undertake a comparative transcriptome analysis of attenuated (passage 296) and virulent (passage 26) bovine leukocytes infected with a Tunisian strain of T. annulata termed Beja. RNA-seq was used to analyse gene expression profiles and the relative expression levels of selected genes were verified by real-time quantitative PCR (RT-qPCR) analysis. Among the 3538 T. annulata genes analysed, 214 were significantly differentially expressed, of which 149 genes were up-regulated and 65 down-regulated. Functional annotation of differentially expressed T. annulata genes revealed four broad categories of metabolic pathways: carbon metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum and biosynthesis of secondary metabolites. It is interesting to note that of the top 40 genes that showed altered expression, 13 were predicted to contain a signal peptide and/or at least one transmembrane domain, suggesting possible involvement in host-parasite interaction. Of the 16,514 bovine transcripts, 284 and 277 showed up-regulated and down-regulated expression, respectively. These were assigned to functional categories relevant to cell surface, tissue morphogenesis and regulation of cell adhesion, regulation of leucocyte, lymphocyte and cell activation. The genetic alterations acquired during attenuation that we have catalogued herein, as well as the accompanying in silico functional characterization, do not only improve understanding of the attenuation process, but can also be exploited by studies aimed at identifying attenuation biomarkers across different cell lines focusing on some host and parasite genes that have been highlighted in this study, such as bovine genes (CD69, ZNF618, LPAR3, and APOL3) and parasite genes such as TA03875.

Abstract Background Evidence from the UK from the early stages of the covid-19 pandemic showed that people with Intellectual Disabilities (ID) had higher rates of covid-19 mortality than people without ID. However, estimates of the magnitude of risk vary widely; different studies used different time periods; and only early stages of the pandemic have been analysed. Existing analyses of risk factors have also been limited. The objective of this study was to investigate covid-19 mortality rates, hospitalisation rates, and risk factors in people with ID in England up to the end of 2021. Methods Retrospective cohort study of all people with a laboratory-confirmed SARS-CoV-2 infection or death involving covid-19. Datasets covering primary care, secondary care, covid-19 tests and vaccinations, prescriptions, and deaths were linked at individual level. Results Covid-19 carries a disproportionately higher risk of death for people with ID, above their already higher risk of dying from other causes, in comparison to those without ID. Around 2,000 people with ID had a death involving covid-19 in England up to the end of 2021; approximately 1 in 180. The covid-19 standardized mortality ratio was 5.6 [95% CI 5.4, 5.9]. People with ID were also more likely to be hospitalised for covid-19 than people without ID. The main determinants of severe covid-19 outcomes (deaths and/or hospitalisations) in both populations were age, multimorbidity and vaccination status. The key factor responsible for the higher risk of severe covid-19 in the ID population was a much higher prevalence of multimorbidity in this population. AstraZeneca vaccine was slightly less effective in preventing severe covid-19 outcomes among people with ID than among people without ID. Conclusions People with ID should be considered a priority group in future pandemics, such as shielding and vaccinations.

The aim of this project was to examine older adults and their next-of-kins’ experiences of using smart home technology. The technology unobtrusively monitors the older adult’s physical functional ability to undertake their daily activities at home. Using a case study approach, the participants comprised three family units: three older adults with a history of long-term co-morbidities and who lived alone, along with their next-of-kin (n=4). The older adults were all female aged between 72- 82 years of age, while the four next-of-kin were all females aged between 40 and 55 years of age. Participants experiences of using the smart home technology was evaluated at three- and eight-months post-installation via in-depth one-to-one interviews with the older adults and their next-of-kin. The older adults described how the smart home sensors reduced their levels of anxiety because they were ‘not feeling alone’. Likewise, their next-of-kin described how the sensors gave them an insight to their older relatives’ activities of daily living, as well as the challenges they experienced. The findings highlighted the benefit of smart home technologies in terms of helping older adults and their next-of-kin monitor their daily activities, reduce social isolation, and adopt positive health and behavioural changes.

Abstract Nearly a century after the first reports of Rift Valley fever (RVF) were documented in Kenya, questions on the transmission dynamics of the disease remain. Specifically, data on viral maintenance in the quiescent years between epidemics is limited. We implemented a cross-sectional study in northern Kenya to determine the seroprevalence, risk factors, and ecological predictors of RVF in humans and livestock during an interepidemic period. Six hundred seventy-six human and 1,864 livestock samples were screened for anti-RVF Immunoglobulin G (IgG). Out of the 1,864 livestock samples tested for IgG, a subset of 1,103 samples was randomly selected for additional testing to detect the presence of anti-RVFV Immunoglobulin M (IgM). The anti-RVF virus (RVFV) IgG seropositivity in livestock and humans was 21.7% and 28.4%, respectively. RVFV IgM was detected in 0.4% of the livestock samples. Participation in the slaughter of livestock and age were positively associated with RVFV exposure in humans, while age was a significant factor in livestock. We detected significant interaction between rainfall and elevation's influence on livestock seropositivity, while in humans, elevation was negatively associated with RVF virus exposure. The linear increase of human and livestock exposure with age suggests an endemic transmission cycle, further corroborated by the detection of IgM antibodies in livestock.