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The calls for reasoning and proof to have a prominent place in secondary mathematics classrooms raise the question of knowledge that teachers need to support student learning of reasoning and proof. Several conceptualizations of Mathematical Knowledge for Teaching Proof (MKT-P) have been proposed over the years, yet some key questions about the nature of MKT-P remain unclear, such as whether MKT-P is a special kind of knowledge specific to teaching or whether it is just common mathematics knowledge. Another question is whether MKT-P can be improved through targeted intervention. Our study attempts to respond to both questions. An MKT-P questionnaire was administered to in-service secondary teachers, undergraduate mathematics and computer science (M&CS) majors, and pre-service secondary teachers before and after taking a capstone course Mathematical Reasoning and Proving for Secondary Teachers. The results suggest that MKT-P is indeed a specialized type of knowledge, which can be improved through targeted intervention.

Abstract Background Genomic epidemiology has helped reconstruct the global and regional movement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still a lack of understanding of SARS-CoV-2 spread in some of the world’s least developed countries (LDCs). Methods To begin to address this disparity, we studied the transmission dynamics of the virus in Bangladesh during the country’s first COVID-19 wave by analysing case reports and whole-genome sequences from all eight divisions of the country. Results We detected > 50 virus introductions to the country during the period, including during a period of national lockdown. Additionally, through discrete phylogeographic analyses, we identified that geographical distance and population -density and/or -size influenced virus spatial dispersal in Bangladesh. Conclusions Overall, this study expands our knowledge of SARS-CoV-2 genomic epidemiology in Bangladesh, shedding light on crucial transmission characteristics within the country, while also acknowledging resemblances and differences to patterns observed in other nations.

Abstract The move away from transmission-based lecturing toward a more student-centred active learning approach is well evidenced in STEM higher education. However, the examination of active learning has generally remained confined to formal timetabled contexts, with assumptions made that students independently manage the transition between timetabled and non-timetabled learning. This paper introduces research findings from a mixed methods study that used an ecological approach when investigating student transitions between a formal lecture theatre and adjacent informal breakout space in a UK STEM university. Using quantitative occupancy monitoring data to analyse usage patterns of both spaces, in combination with qualitative ethnographic observations and field interviews, permitted a purposeful exploration of student engagement with transitions within and between the two learning spaces. The ecological approach aided the discovery of spatial, pedagogic and agentic transitions and tensions, which subsequently informed strategic modification of space across the institution to facilitate the adoption of active learning pedagogy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) now arise in the context of heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron BA.1 genomes, we identified >6,000 introductions of the antigenically distinct VOC into England and analyzed their local transmission and dispersal history. We find that six of the eight largest English Omicron lineages were already transmitting when Omicron was first reported in southern Africa (22 November 2021). Multiple datasets show that importation of Omicron continued despite subsequent restrictions on travel from southern Africa as a result of export from well-connected secondary locations. Initiation and dispersal of Omicron transmission lineages in England was a two-stage process that can be explained by models of the countrys human geography and hierarchical travel network. Our results enable a comparison of the processes that drive the invasion of Omicron and other VOCs across multiple spatial scales.

Mathematics teacher education programs in the United States are charged with preparing prospective secondary teachers (PSTs) to teach reasoning and proving across grade levels and mathematical topics. Although most programs require a course on proof, PSTs often perceive it as disconnected from their future classroom practice. Our design research project developed a capstone course "Mathematical Reasoning and Proving for Secondary Teachers" and systematically studied its effect on PSTs' content and pedagogical knowledge specific to proof. This paper focuses on one course module--"Quantification and the Role of Examples in Proving," a topic which poses persistent difficulties to students and teachers alike. The analysis suggests that after the course, PSTs' content and pedagogical knowledge of the role of examples in proving increased. We provide evidence from multiple data sources: pre-and post-questionnaires, PSTs' responses to the in-class activities, their lesson plans, reflections on lesson enactment, and self-report. We discuss design principles that supported PSTs' learning and their applicability beyond the study context.

Abstract Background Two million people in the UK are living with or beyond cancer and a third of them report poor quality of life (QoL) due to problems such as fatigue, fear of cancer recurrence, and concerns about returning to work. We aimed to develop and evaluate an intervention based on acceptance and commitment therapy (ACT), suited to address the concerns of cancer survivors and in improving their QoL. We also recognise the importance of exercise and vocational activity on QoL and therefore will integrate options for physical activity and return to work/vocational support, thus ACT Plus (+). Methods We will conduct a multi-centre, pragmatic, theory driven, randomised controlled trial. We will assess whether ACT+ including usual aftercare (intervention) is more effective and cost-effective than usual aftercare alone (control). The primary outcome is QoL of participants living with or beyond cancer measured using the Functional Assessment of Cancer Therapy: General scale (FACT-G) at 52 weeks. We will recruit 344 participants identified from secondary care sites who have completed hospital-based treatment for cancer with curative intent, with low QoL (determined by the FACT-G) and randomise with an allocation ratio of 1:1 to the intervention or control. The intervention (ACT+) will be delivered by NHS Talking Therapies, specialist services, and cancer charities. The intervention consists of up to eight sessions at weekly or fortnightly intervals using different modalities of delivery to suit individual needs, i.e. face-to-face sessions, over the phone or skype. Discussion To date, there have been no robust trials reporting both clinical and cost-effectiveness of an ACT based intervention for people with low QoL after curative cancer treatment in the UK. We will provide high quality evidence of the effectiveness and cost-effectiveness of adding ACT+ to usual aftercare provided by the NHS. If shown to be effective and cost-effective then commissioners, providers and cancer charities will know how to improve QoL in cancer survivors and their families. Trial registration ISRCTN: ISRCTN67900293 . Registered on 09 December 2019. All items from the World Health Organization Trial Registration Data Set for this protocol can be found in Additional file 2 Table S1.

Background Despite the effectiveness of cognitive remediation, it is not widely implemented because we do not know whether teams will accept it, how much therapist time is needed, whether there are factors which predict lower benefits, whether it is cost-effective and what is required for large-scale roll-out. Objective To understand the factors that will enhance implementation and benefits of cognitive remediation in Early Intervention Services. Design Four work packages: (1) focus groups and interviews exploring the development of satisfaction and preference measures for staff and service users; participant team interviews to collect data, before and after introducing cognitive remediation, to understand team dynamics; (2) an observational study of a newly developed therapist e-training programme; (3) a multiarm multistage four-arm randomised controlled trial comparing different amounts of therapist input with Treatment as Usual; and (4) an analysis of trial data to understand potential mediating and moderating factors that affect treatment benefits. Setting Early Intervention Services in the United Kingdom National Health Service. Participants Staff and service users in touch with Early Intervention Services. Interventions For the e-training, we piloted and then provided an e-learning system for training cognitive remediation therapists. For the randomised trial, we provided a cognitive remediation software programme (CIRCuiTS™,King’s College London, London) that was delivered in three conditions, all offering up to 42 sessions of cognitive remediation. The conditions were: Intensive (one to one with a therapist), Group treatment with a therapist, Independent with drop-in sessions. Main outcome measures Work package 1: We developed two satisfaction measures and tested a team dynamic model. Work package 2: Feasibility and acceptability questionnaire, time to complete e-training modules. Work package 3: The personal recovery measure – Goal Attainment Scale. Results Work package 1: The service user satisfaction with cognitive remediation was reliable and valid. Although it did not show statistically significant differences between the arms of the trial, the most preferred methods (Group and Intensive) had higher associated satisfaction. Team leadership and especially a flattened hierarchy, resources and time were identified as vital for implementation. Our team dynamic model supported the importance of leadership in influencing organisational climate, which then affected staff attitudes. However, this was only significant before staff had any experience of their patients receiving cognitive remediation. Although the sample was much smaller after therapy, this may indicate that experience of the beneficial therapy changes team dynamics. Work package 2: The e-training modules were completed by 43% of the recruited participants. They judged the training to be feasible and acceptable, but it did take longer to complete than expected. COVID-19 with the increased workload may have had some effects, but our data exploration shows that it was individuals who had most recently qualified who had the best outcomes. This may be because of a lighter workload or that they were more used to online training. Adaptations suggested are now being implemented. Work package 3: Following the interim analysis we closed two arms – Independent therapy and Treatment as Usual. Four hundred and forty-eight patients consented and 377 were eligible and completed baseline assessment. They were randomised: Group 134, Independent 65, Intensive 112 and Treatment as Usual 66. At post therapy, there were no differences between Group and Intensive or between Independent and Treatment as Usual, but the combined Group and Intensive versus Treatment as Usual was significant (mean difference: 5.734; standard error = 1.958; p = 0.003; lower confidence interval = 1.898 to upper confidence interval = 9.571). Our economic analysis showed that Group and Intensive cognitive remediation were not different with respect to quality-adjusted life-years (difference £150, 95% confidence interval –£1132 to £1905). Both conferred significant benefit compared with standard care (Group and Treatment as Usual: difference £257, 95% confidence interval –£1694 to £2615; Intensive vs. Treatment as Usual: difference £260, 95% CI –£1654 to £2239). Their cost–benefit for quality-adjusted life-year improvement was well below the National Institute for Health and Care Excellence threshold for adopting the intervention to National Health Service services. Work package 4: Cognition had a small mediation effect, and negative symptoms moderated the transfer of cognitive benefits to goal attainment. Limitations The trial suffered from recruitment difficulties which were overcome when we switched from block to individual randomisation. The final target was large enough to test our main outcomes and moderating and mediating variables. Conclusions Cognitive remediation should be provided in the National Health Service, involving a trained therapist on a Group or Intensive format with team and training support. Future work We have a large database and will continue to investigate factors that affect cognitive remediation benefits. Study registration This study is registered as ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0612-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 4. See the NIHR funding and Awards website for further award information. Plain language summary Cognitive problems in people with schizophrenia predict functional recovery even with the best-possible rehabilitation opportunities. One psychological treatment, cognitive remediation can improve both cognitive and functional recovery, such as in social relationships and occupational achievements. We investigated the optimal way of delivering computerised cognitive remediation in Early Intervention Services by incorporating service user and staff views. Our work involved exploring what treatment factors are important to service users, developing two bespoke cognitive remediation satisfaction measures for service users and service providers. Our investigation of team dynamics suggested that a more flexible leadership style together with increasing resources might be most suited to successful delivery. One challenge for large-scale roll-out of cognitive remediation is therapist training opportunities, so we developed an online programme and then tested it in the United Kingdom and, with a few adaptations, it can be provided to the National Health Service. Although cognitive remediation is effective, we do not know how much therapist time produces therapy benefits, so we conducted a trial comparing three options for cognitive remediation treatment that differed in the amount of the therapist time (Independent, Group and Intensive). We compared these options with a no-treatment group. We investigated benefits of each option in 377 participants from Early Intervention Services. The main benefit assessed was whether participants could achieve their personal goals that were set before therapy began. Although we found no change in a social or occupational functioning scale rated by an observer, the Group and Intensive cognitive remediation produced significant achievements in the participants’ own personal goals compared with those who did not receive therapy or who carried out therapy on their own. We also found that any cognitive remediation therapy option improved thinking skills. Group and Intensive therapy were also cost-effective. Overall, cognitive remediation was acceptable and well liked by service users, so all our data suggest that it should be more easily accessible in the National Health Service. Scientific summary Cognitive remediation (CR) therapy is a psychological intervention targeting cognitive dysfunction associated with psychosis with the goal of improving functional outcomes. Cognitive remediation can improve cognitive and functional recovery, as well as increasing confidence and motivation. Evidence from the largest meta-analysis demonstrated that these effects are durable. National Health Service Early Intervention for psychosis services provide care soon after a diagnosis of psychosis to optimise recovery. Embedding CR in those services may confer long-lasting benefits such as improved social relationships and the opportunity to work or take part in further education. The overarching aim of the Enhancing Cognition and quality of Life in early PSychosiEs (ECLIPSE) research programme was to determine the optimal method of introducing computerised CR therapy (CIRCuiTS™) into NHS Early Intervention Services (EIS) considering improvement in cognitive and social function and cost-effectiveness. The programme was centred on work package 3 (WP3), a randomised, blinded multiarm multisite controlled trial comparing three CR implementation methods with each other and with routine clinical care [Treatment as Usual (TAU)]. To aid the interpretation of WP3 and bolster our recommendations to the NHS, WP1 included a series of studies investigating: patient and staff satisfaction with CR; preference for the methods of CR delivery; and the influence of team organisational climate. Although the CR was computerised and can be completed independently, its effects are boosted via learning, practice and feedback supervised by a therapist. WP2 was a series of studies to design and test an online CR therapist training package to use in their individual teams. Finally, WP4 examined mediators and moderators of the trial results to inform teams about how the clinical features of their individual patients may influence the effect of CR. In WP3, the CR modalities were: Intensive 1 : 1 therapist supervision; Group supervision with one therapist; and Independent (self-determined with infrequent access to therapist supervision). Participants were recruited from EIS in 12 mental health trusts, linked to 6 universities and serving diverse urban/rural populations. They were clinically stable and presented with a non-affective psychotic episode not

Background Poor adherence to photoprotection from ultraviolet radiation in the rare disease xeroderma pigmentosum can be life-threatening due to heightened risk of skin cancers. This novel, two-phase research programme used mixed methods to investigate photoprotection in xeroderma pigmentosum, and its psychosocial impact, to develop an intervention to improve photoprotection. Objective(s) Phase I: To identify barriers to optimal photoprotection. Phase II: To design and test a personalised psychological intervention to improve photoprotection. Design Phase I: Interview study; n-of-1 photoprotection study; objective measurement of ultraviolet radiation exposure study; international cross-sectional survey. Phase II: Consensus conference to synthesise findings and determine targets/priorities for intervention; intervention development using Intervention mapping; randomised controlled trial to test efficacy, cost-effectiveness and intervention mechanisms. Settings for Phases I and II National Xeroderma Pigmentosum Service, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom; Specialist xeroderma pigmentosum clinics in Regensburg, Germany, Japan, Tunisia; Patient support organisations in France and USA. Participants Children < 16 (Phase I only) and adults (> 16) diagnosed with xeroderma pigmentosum. Intervention (Phase II) XPAND is a seven-session personalised psychological intervention designed to be facilitated by non-psychologists, delivered in spring to summer 2018 versus wait list control (intervention in spring to summer 2019). Main trial outcome measure (Phase II) Average daily ultraviolet radiation dose to the face calculated by combining objective ultraviolet radiation exposure with self-reported photoprotection. Results Phase I: Varying levels of photoprotection were found, with most participants doing less than clinically recommended. The international survey (N = 156) and estimation of ultraviolet radiation dose-to-face (N = 41) found that adults had worse photoprotection than the ‘cared for’ sample, but that overall the total dose-to-face was similar in the two groups because the ‘cared for’ group were outside more. The n-of-1 study (N = 20) showed that fluctuations in protection were associated with time of day, weekday versus weekend, environmental risk perceptions and symptoms resulting from exposure, self-regulatory and psychological constructs. The qualitative study (N = 25) identified three modes of adaptation to photoprotection: (1) ‘dominated’, (2)‘integrated’ and (3) ‘resistant’. Modifiable drivers of photoprotection behaviour were identified in the survey studies, including belief-based predictors and the important role of habits. These combined findings informed the development and targets of the XPAND intervention. Phase II: The intervention group (n = 6) had significantly lower daily average ultraviolet radiation dose-to-face (primary outcome) compared to control (n = 7) (−0.25 Standard Erythemal Dose, p 16 years with a confirmed diagnosis of XP, sufficient English language comprehension and no cognitive impairment completed the measures themselves. Parents/caregivers of children (

BackgroundInterest in the application of predictive risk models (PRMs) in health care to identify people most likely to experience disease and treatment-related complications is increasing. In cancer care, these techniques are focused primarily on the prediction of survival or life-threatening toxicities (eg, febrile neutropenia). Fewer studies focus on the use of PRMs for symptoms or supportive care needs. The application of PRMs to chemotherapy-related symptoms (CRS) would enable earlier identification and initiation of prompt, personalized, and tailored interventions. While some PRMs exist for CRS, few were translated into clinical practice, and human factors associated with their use were not reported. ObjectiveWe aim to explore patients’ and clinicians’ perspectives of the utility and real-world application of PRMs to improve the management of CRS. MethodsFocus groups (N=10) and interviews (N=5) were conducted with patients (N=28) and clinicians (N=26) across 5 European countries. Interactions were audio-recorded, transcribed verbatim, and analyzed thematically. ResultsBoth clinicians and patients recognized the value of having individualized risk predictions for CRS and appreciated how this type of information would facilitate the provision of tailored preventative treatments or supportive care interactions. However, cautious and skeptical attitudes toward the use of PRMs in clinical care were noted by both groups, particularly in relationship to the uncertainty regarding how the information would be generated. Visualization and presentation of PRM information in a usable and useful format for both patients and clinicians was identified as a challenge to their successful implementation in clinical care. ConclusionsFindings from this study provide information on clinicians’ and patients’ perspectives on the clinical use of PRMs for the management of CRS. These international perspectives are important because they provide insight into the risks and benefits of using PRMs to evaluate CRS. In addition, they highlight the need to find ways to more effectively present and use this information in clinical practice. Further research that explores the best ways to incorporate this type of information while maintaining the human side of care is warranted. Trial RegistrationClinicalTrials.gov NCT02356081; https://clinicaltrials.gov/study/NCT02356081

The SARS-CoV-2 Delta (Pango lineage B.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide1,2. The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virus genomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chains that later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing-and not the number of importations-were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventions to reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529).

Abstract Background Rates of compulsory (also known as involuntary) detention under mental health legislation have been rising over several decades in countries including England. Avoiding such detentions should be a high priority given their potentially traumatic nature and departure from usual ethical principles of consent and collaboration. Those who have been detained previously are at high risk of being detained again, and thus a priority group for preventive interventions. In a very sparse literature, interventions based on crisis planning emerge as having more supporting evidence than other approaches to preventing compulsory detention. Method We have adapted and manualised an intervention previously trialled in Zürich Switzerland, aimed at reducing future compulsory detentions among people being discharged following a psychiatric admission that has included a period of compulsory detention. A co-production group including people with relevant lived and clinical experience has co-designed the adaptations to the intervention, drawing on evidence on crisis planning and self-management and on qualitative interviews with service users and clinicians. We will conduct a randomised controlled feasibility trial of the intervention, randomising 80 participants to either the intervention in addition to usual care, or usual care only. Feasibility and acceptability of the intervention and trial procedures will be assessed through process evaluation (including rates of randomisation, recruitment, and retention) and qualitative interviews. We will also assess and report on planned trial outcomes. The planned primary outcome for a full trial is repeat compulsory detention within one year of randomisation, and secondary outcomes include compulsory detention within 2 years, and symptoms, service satisfaction, self-rated recovery, self-management confidence, and service engagement. A health economic evaluation is also included. Discussion This feasibility study, and any subsequent full trial, will add to a currently limited literature on interventions to prevent involuntary detention, a goal valued highly by service users, carers, clinicians, and policymakers. There are significant potential impediments to recruiting and retaining this group, whose experiences of mental health care have often been negative and traumatising, and who are at high risk of disengagement. Trial registration ISRCTN, ISRCTN11627644. Registered 25th May 2022, https://www.isrctn.com/ISRCTN11627644 .

Abstract Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach’s alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design.

The application of inertial force actuators (IFAs) to vehicle dynamics is investigated. These are modeled as translational motors with a small proof mass attached at one end, such that forces applied by the actuator to the vehicle result in displacement of the proof mass in inertial space. IFAs would provide specific benefits compared to traditional active suspensions, which exhibit deleterious effects on secondary vehicle signals while pursuing their primary objectives. Since IFAs can be high power and generate high force magnitudes, and are constrained only by their internal stroke and force limits, their application is well suited for zero-mean band-limited white noise inputs such as a vehicle roadway. The suspension control problem is studied with the incorporation of IFAs in cooperation with traditional actuators in order to meet the vehicle objectives hierarchy. Modern and classical control theory investigate the application of IFAs to control various vehicle output signals.

Abstract Experiences of trauma in childhood and adulthood are highly prevalent among service users accessing acute, crisis, emergency, and residential mental health services. These settings, and restraint and seclusion practices used, can be extremely traumatic, leading to a growing awareness for the need for trauma informed care (TIC). The aim of TIC is to acknowledge the prevalence and impact of trauma and create a safe environment to prevent re-traumatisation. This scoping review maps the TIC approaches delivered in these settings and reports related service user and staff experiences and attitudes, staff wellbeing, and service use outcomes. We searched seven databases (EMBASE; PsycINFO; MEDLINE; Web of Science; Social Policy and Practice; Maternity and Infant Care Database; Cochrane Library Trials Register) between 24/02/2022-10/03/2022, used backwards and forwards citation tracking, and consulted academic and lived experience experts, identifying 4244 potentially relevant studies. Thirty-one studies were included. Most studies (n = 23) were conducted in the USA and were based in acute mental health services (n = 16). We identified few trials, limiting inferences that can be drawn from the findings. The Six Core Strategies (n = 7) and the Sanctuary Model (n = 6) were the most commonly reported approaches. Rates of restraint and seclusion reportedly decreased. Some service users reported feeling trusted and cared for, while staff reported feeling empathy for service users and having a greater understanding of trauma. Staff reported needing training to deliver TIC effectively. TIC principles should be at the core of all mental health service delivery. Implementing TIC approaches may integrate best practice into mental health care, although significant time and financial resources are required to implement organisational change at scale. Most evidence is preliminary in nature, and confined to acute and residential services, with little evidence on community crisis or emergency services. Clinical and research developments should prioritise lived experience expertise in addressing these gaps.

Introduction Ethnic minorities (also called racialised groups) are more likely to experience severe mental illness (SMI). People with SMI are more likely to experience multimorbidity (MM), making psychosis among racialised groups more likely to lead to MM, poor outcomes, disability and premature mortality.Methods and analysis This National Institute for Health and Care Research-funded study (151887) seeks to use innovative participatory methods including photovoice and biographical narrative interviews in urban and rural areas of England to assemble experience data. These data will be subjected to polytextual thematic analysis, and alongside pictures and captions, will inform an experienced-based co-design of interventions, the implementation of which will be evaluated. There will be an economic analysis and a process evaluation of the implementation.Ethics and dissemination This programme of work has received ethical (IRAS 322421; Newcastle North Tyneside Research Ethics Committee 23/NE/0143) and sponsor approval. The findings will be disseminated in galleries showing the creative work, as lay and academic summaries and infographics; as practice briefings for practitioners, commissioners and policy makers; peer-reviewed publications.Trial registration number https://www.researchregistry.com/browse-the-registry%23home/registrationdetails/649c08111c037d0027b17d17/

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

The United Kingdoms COVID-19 epidemic during early 2020 was one of worlds largest and was unusually well represented by virus genomic sampling. We determined the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes, including 26,181 from the UK sampled throughout the countrys first wave of infection. Using large-scale phylogenetic analyses combined with epidemiological and travel data, we quantified the size, spatiotemporal origins, and persistence of genetically distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown tended to be larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, whereas lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.

Characterisation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic diversity through space and time can reveal trends in virus importation and domestic circulation and permit the exploration of questions regarding the early transmission dynamics. Here, we present a detailed description of SARS-CoV-2 genomic epidemiology in Ecuador, one of the hardest hit countries during the early stages of the coronavirus-19 pandemic. We generated and analysed 160 whole genome sequences sampled from all provinces of Ecuador in 2020. Molecular clock and phylogeographic analysis of these sequences in the context of global SARS-CoV-2 diversity enable us to identify and characterise individual transmission lineages within Ecuador, explore their spatiotemporal distributions, and consider their introduction and domestic circulation. Our results reveal a pattern of multiple international importations across the country, with apparent differences between key provinces. Transmission lineages were mostly introduced before the implementation of non-pharmaceutical interventions, with differential degrees of persistence and national dissemination.

Powertrains for vehicles are transitioning from the internal combustion engine to electric motors. Electric motors have the ability to both output traction and generative braking torque. Furthermore, electric motor powertrains have a smaller size compared to the internal combustion engine powertrain. This opens up thepossibility of different configurations of powertrain layouts. This paper explores an electric vehicle model with motors on both the front and the rear axles. The planar vehicle model with varying motor torque distribution is simulated to validate its handling dynamics.

Design Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms No significant differences in other secondary endpoints or adverse events. Limitations Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information. Plain language summary Although kidney transplantation is the gold-standard treatment for kidney failure, thousands of transplants fail each year due to damage by the immune system. Finding circulating antibodies against the transplant can identify patients at high risk of failure. Under-treatment with immunosuppressive drugs plays a part in promoting the damage and increasing immunosuppression can slow progression in some but not all patients. In the Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation OuTSMART trial, we screened kidney transplant patients for circulating antibodies then, in the intervention arm, counselled everyone on the importance of taking immunosuppression, before optimising treatments to ‘best available’. We recruited > 2000 patients and split them into two groups randomly; in the first we revealed antibody results, encouraged adherence and tailored treatment to a combination of three drugs called tacrolimus, mycophenolate, and prednisolone, in a regimen that was judged optimal for each. In the second group, we did not release the antibody test results to patients or their doctors, and all treatment decision were based on local standard of care. At the end, we compared the numbers of transplant failures in each group. We confirmed that patients with antibodies were at higher risk of transplant failure, but found no differences in failures between those in whom we had intervened compared to those treated by standard of care. Although more developed rejection after standard care, there were no differences in the other things we measured, including the numbers who died, developed diabetes, infections or cancer and no differences in the number who developed new side effects. We therefore conclude that there is no basis for optimising drug treatment in those with antibodies at risk of transplant failure. Instead, novel treatments are needed. This trial will influence current practice around the world and hopefully incentivise research into new strategies to prevent transplant failure. Scientific summary Background Kidney transplants do not last for the natural lifespan of most recipients, and many patients eventually suffer progressive decline in transplant function leading to graft failure and need to return to dialysis. Around the world, this problem is significant, as 3% of kidney transplant patients return to dialysis each year. The single biggest cause of allograft dysfunction leading to transplant failure is immune-mediated damage and a prevalent hypothesis in the field is that inappropriately low levels of immunosuppression, either physician-led or due to patient non-adherence, is an important contributor to the initiation and progression of this immune-mediated damage. There are still no effective treatments for allograft dysfunction that is proven to be due to immune-mediated damage. Enhancing baseline immunosuppression appears to stabilise graft function in some patients. Two recent randomised trials of the anti-CD20 monoclonal antibody rituximab showed no impact, although both were stopped prematurely as they were underpowered. More recent reports indicate that anti-IL-6 monoclonals show promise at stabilising estimated Glomerular Filtration Rate (eGFR), but these have yet to be tested in large randomised trials. Since the development of circulating antibodies (Ab) against human leucocyte antigens (HLA) has been validated as a strong prognostic biomarker of kidney transplant failure, and there is genuine equipoise about whether increasing or optimising immunosuppression can benefit patients at risk of transplant failure, in the OuTSMART trial we tested the hypothesis that screening for these Ab followed by optimising oral immunosuppression treatment, could prevent allograft failure. Objectives Primary Determine the time to graft failure in patients testing positive for HLA Ab at baseline or within 32 months of randomisation who receive an optimised anti-rejection medication intervention with prednisolone, tacrolimus (Tac) and mycophenolate mofetil (MMF) (‘treatment’), compared to a control group who test positive for HLA Ab at baseline or within 32 months post-randomisation who remain on their established immunotherapy and whose clinicians are not aware of their Ab status. The primary endpoint was to be assessed remotely when 43 months post-randomisation was achieved by all. Secondary Determine the time to graft failure in patients randomised to ‘unblinded’ HLA Ab screening, compared to a control group randomised to ‘blinded’ HLA Ab screening. Determine whether treatment influences patient survival. Determine whether ‘treatment’ influences the development of graft dysfunction as assessed by presence of proteinuria (protein:creatinine ratio > 50 or albumin:creatinine ratio > 35) and change in eGFR. Determine whether ‘treatment’ influences the rates of acute rejection in these groups. Determine the adverse effect profiles of ‘treatment’ in this group, in particular whether they are associated with increased risk of infection, malignancy or diabetes mellitus. Determine the cost-effectiveness of routine screening for HLA Ab and prolonging transplant survival using this screening/treatment protocol. Determine the impact of biomarker screening and ‘treatment’ on the patients’ adherence to drug therapy and their perceptions of risk to the health of the transplant. Methods OuTSMART was an investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Eligible patients were recipients of cross-match negative transplants aged 18–75, more than 1 year post-transplant with an eGFR ≥30 ml/min willing to consent to the screening/treatment process. Patients were excluded if they were recipients of cross-match positive transplant requiring HLA desensitisation to remove Ab, recipients of additional solid organ transplants (e.g. pancreas, heart, etc.), had a history of malignancy (except non-melanomatous lesions restricted to the skin), had recent acute rejection, had a history of hepatitis B, C or human immunodeficiency virus (HIV), were known to have HLA Ab and received specific treatment for that Ab, had known hypersensitivity to any of the investigational medicinal products (IMPs), had known hereditary disorders of carbohydrate metabolism, were pregnant at the time of consent, or were females who refused to consent to using suitable contraception through the trial. Additionally, patients enrolled in any other studies involving administration of another IMP at time of recruitment were excluded. Stratified randomisation was 1 : 1 to two arms, blinded standard care (SC) or unblinded biomarker-led care (BLC). Randomisation was stratified first by the result from blood test screening for HLA Ab. The HLA Ab+ patients were further screened with single antigen beads to determine whether donor-specific Ab (DSA) were present or whether the only Ab detected was non-DSA. Thus, biomarker stratification led to three groups within each arm (DSA+, non-DSA+ and HLA Ab-neg). The second stratification was based on current immunosuppression, to ensure balanced numbers already on Tac or MMF in each group. The final stratification was by site. Patients in the SC arm were blinded to their biomarker status, as were their physicians, and remained on baseline immunotherapy, whereas patients in the BLC arm were told their HLA Ab status and were offered intervention. HLA Ab-negative patients in either arm remained on their existing immunotherapy and were rescreened for new HLA Abs every 8 months. Those patients who become positive during subsequent screening rounds were moved to the appropriate HLA Ab positive groups (DSA+ or non-DSA+) for final data analysis. All patients in the unblinded arm found to be positive on second or subsequent rounds were offered the same intervention as those patients who were positive in the first screening round, and these were intensively followed up for an additional 32 months from the time they become positive. Thus the maximum amount of time any single patient remained in intensive follow-up was 64 months. New patients were recruited to the study at each successive screening round. Intervention in the unblinded HLA Ab + patients consisted of informing patients of their HLA Ab status, followed by, in those with DSA or non-DSA, an interview to encourage medication adherence followed by medication changes to optimised doses of Tac, MMF and Prednisolone. Medication changes were tailored to each individual and failure to change, or to tolerate changes was not regarded as treatment failure, so some patients stayed on the same drug regimen. Patients with DSA and non-DSA were offered the same intervention. The primary outcome was originally transplant failure rates over 3 years, but this was changed to time to graft failure after an audit revealed that the prevalence and incidence rates of HLA Ab + patients were less than expected when planning the trial. With a planned minimum follow-up period of 43 months, the trial had 80% power to detect a hazard ratio (HR) of 0.49 in donor-specific antibody+ patients. Secondary endpoints were collected at 32 months and included patient death/survival, rates of biopsy-proven acute rejection, diabetes, infection and cancer, a health economic analysis and formal assessment of adherence. Results Recruitment started in September 2013. Over 37 months, 5519 patients were screened for eligibility and 2037 were randomised (1028 to unblinded BLC and 1009 to double-blinded SC). We identified 198 with DSA and 818 with non-DSA, and at the end of screening, there were 1021 in the Ab-neg groups. Baseline variables were well-matched between groups at the end of Ab-screening. Forty-five per cent of the DSA detected were directed against HLA-DQB antigens. Although the majority of patients were taking Tac (73%), MMF (67%) or prednisolone (55%), only 22% with DSA and 27% with non-DSA were taking all three drugs. Baseline immunosuppression use was balanced across arms and did not change during the trial in the SC arm. Ninety-seven per cent of HLA Ab+ recruits in the BLC arm had the formal interview, and the proportion taking all three drugs in the BLC arm increased to 54% (DSA) and 44% (non-DSA). There were 34 graft failures in HLA Ab+ recruits in the SC arm over the course of the study compared to 42 in the BLC arm. The HRs for graft failure in BLC DSA+ and non-DSA+ groups were 1.54 [95% confidence interval (CI) 0.72 to 3.30] and 0.97 (0.54 to 1.74), respectively, providing no evidence of a difference. The data for DSA+ groups confirmed that the presence of DSA was associated with an increased risk of graft failure, but non-DSA were not associated with graft failure compared to patients without Ab. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 : (1.02, 95% CI 0.72 to 1.44). The HR for the secondary endpoint biopsy-proven rejection in the overall unblinded BLC group was 0.5 (95% CI 0.27 to 0.94; p = 0.03), but there were no significant differences in patient survival, biopsy-proven rejection, proven infections, malignancies, diabetes, development of proteinuria or mean eGFRs at the end of the trial. After adjusting for baseline quality of life, there was no significant gain of quality-adjusted life-year (QALY) in the BLC arm, but an incremental cost-effectiveness ratio per QALY that was significantly higher than the threshold set by the National Institute for Health and Care Excellence. Our analysis of adherence revealed significantly improved adherences for all three drugs in the BLC DSA+ group. Conclusions Thus, we conclude that the development of DSA (but not non-DSA) is associated with an increased risk of graft failure, but there is no evidence to support the primary hypothesis, that optimisation of immunosuppression in DSA+ patients can prevent this from happening. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Spatiotemporal bias in genome sampling can severely confound discrete trait phylogeographic inference. This has impeded our ability to accurately track the spread of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, despite the availability of unprecedented numbers of SARS-CoV-2 genomes. Here, we present an approach to integrate individual travel history data in Bayesian phylogeographic inference and apply it to the early spread of SARS-CoV-2. We demonstrate that including travel history data yields i) more realistic hypotheses of virus spread and ii) higher posterior predictive accuracy compared to including only sampling location. We further explore methods to ameliorate the impact of sampling bias by augmenting the phylogeographic analysis with lineages from undersampled locations. Our reconstructions reinforce specific transmission hypotheses suggested by the inclusion of travel history data, but also suggest alternative routes of virus migration that are plausible within the epidemiological context but are not apparent with current sampling efforts.

The benefits of using video in teacher education as a tool for reflection and for developing professional expertise have long been recognized. Recent introduction of 360 video technology holds promise to extend these benefits as it allows prospective teachers to reflect on their own performance by considering the classroom from multiple perspectives. This study examined nine prospective secondary teachers' (PSTs) noticing and self-reflection on the 360 recordings of their own teaching. The PSTs, enrolled in a capstone course "Mathematical Reasoning and Proving for Secondary Teachers," taught a proof-oriented lesson to small groups of students in local schools while capturing their teaching with 360 video cameras. We analyzed the PSTs' written comments on their video and reflection reports to identify the categories of noticing afforded by the 360 technology as well as the instances of PSTs' learning. The results point to the powerful potential of 360 videos for supporting PSTs' self-reflection and professional growth.

Introduction: There is growing evidence that prehabilitation programmes effectively improve the physical and psychological conditions of cancer patients awaiting treatment. During the pandemic, people with cancer were classed as vulnerable. To reduce risk to this population Kent and Medway Prehabilitation service transformed into a TeleHealth format. The aim of this study is to assess the impact on health-related quality of life (HRQoL) and the costs of a digital multimodal prehabilitation programme. Methods: HRQoL was measured with the EQ-5D and quality-adjusted life years (QALYs) were calculated. Costs of the prehabilitation service and inpatient care were calculated. Comparisons were made between different levels of prehabilitation received. Results: A sample of 192 individuals was included in the study Mean HRQoL improved from 69.53 at baseline to 85.71 post-rehabilitation, a 23% increase. For each additional week of prehabilitation care in cancer patients, the model predicts that the total QALYS increase by 0.02, when baseline utility is held constant. Conclusions: Prehabilitation is associated with improved HRQoL and QALYs. Our model of a multimodal digital prehabilitation program can be beneficial for patients and reduce costs for healthcare facilities even when the patients attend only a few sessions.

The discovery of analog LixNbO2 memristors revealed a promising new memristive mechanism wherein the diffusion of Li+ rather than O2- ions enables precise control of the resistive states. However, directly correlating lithium concentration with changes to the electronic structure in active layers remains a challenge and is required to truly understand the underlying physics. Chemically delithiated single crystals of LiNbO2 present a model system for correlating lithium variation with spectroscopic signatures from operando soft x-ray spectroscopy studies of device active layers. Using electronic structure modeling of the x-ray spectroscopy of LixNbO2 single crystals, we demonstrate that the intrinsic memristive behavior in LixNbO2 active layers results from field-induced degenerate p-type doping. We show that electrical operation of LixNbO2-based memristors is viable even at marginal Li deficiency and that the analog memristive switching occurs well before the system is fully metallic. This study serves as a benchmark for material synthesis and characterization of future LixNbO2-based memristor devices and suggests that valence change switching is a scalable alternative that circumvents the electroforming typically required for filamentary-based memristors.

Understanding student interaction in learning spaces is an ongoing challenge. The move away from didactic lecture delivery towards more active and hybrid learning renders this challenge ever more difficult. Researching pedagogic use of informal learning space, which is not formally timetabled or controlled, is always challenging because it is interacted with only transiently by both students and teachers. This paper introduces a mixed methods, phenomenological approach used in recent research to investigate campus learning spaces in face-to-face learning contexts. The full mixed methods approach combined space occupancy monitoring data with naturalistic ethnographic observation, field interviews and, where appropriate, more formal in-depth interviews to provide an effective way of understanding student and teacher engagement with learning spaces. Convergent use of these qualitative and quantitative methods yielded data which informed the application of subsequent methods, and the investment of researcher, pedagogic and infrastructural resource. In this paper we argue that as learning outside of formal teaching spaces increases, these mixed methods enable better, more efficient monitoring of pedagogic use of informal learning spaces. The mixed method can be adapted depending on the question being addressed and has the potential to inform resource allocation and investment into pedagogic and infrastructural change.

Background Creative arts practice can enhance the depth and quality of mental health research by capturing and foregrounding participants’ lived experience. Creative methods are emotionally activating and promote multiple perspectives, tolerating ambiguities and uncertainties, which are shared and even celebrated.Key arguments Methods such as photovoice use imagery to elucidate narratives that are not easily captured by more traditional interview-based research techniques. However, the use of creative methods and participatory research remains novel as there is little guidance of how to navigate conceptual, practical, and analytical challenges.Conclusion This paper considers these challenges, and puts forward practical and theory informed recommendations, using as study of photovoice methods for investigating ethnic inequalities in the use of the mental health act (Co-Pact) as a case study.

Abstract Mental health problems have a substantial economic impact across the world. Those who have their problems detected may receive therapies (usually medication or psychological) or who packages of care (for example, early intervention or residential support). Some problems are transient while others will remain across the life course. Costs are closely associated with care received and it may be that costs need to rise in order to provide adequate support. Economic costs also occur due to lost opportunities such as work and leisure. This talk will summarise recent estimates of the cost of mental health problems in a number of countries. Establishing total costs does not tell us how to use limited resources. This requires the use of economic evaluation methods such as cost-effectiveness and cost-utility analyses. There is a growing evidence base from such evaluations for many psychological and pharmacological interventions and recent key findings will be discussed. The need for long-term, life course approaches to economic evaluation of mental health interventions will be proposed. Disclosure of Interest None Declared

Abstract Background Poor social circumstances can induce, exacerbate and prolong symptoms of mental health conditions, while having a mental health condition can also lead to worse social outcomes. Many people with mental health conditions prioritise improvement in social and functional outcomes over reduction in clinical symptoms. Interventions that improve social circumstances in this population should thus be considered a priority for research and policy. Methods This rapid evidence synthesis reports on randomised controlled trials of interventions to improve social circumstances across eight social domains (Housing and homelessness; money and basic needs; work and education; social isolation and connectedness; family, intimate and caring relationships; victimisation and exploitation; offending; and rights, inclusion and citizenship) in people with mental health conditions. Economic evaluations were also identified. A comprehensive, stepped search approach of the Cochrane library, MEDLINE, Embase, PsycINFO, Web of Science and Scopus was conducted. Results One systematic review and 102 randomised controlled trials were included. We did not find RCT evidence for interventions to improve family, intimate and caring relationships and only one or two trials for each of improving money and basic needs, victimisation and exploitation, and rights, inclusion and citizenship. Evidence from successful interventions in improving homelessness (Housing First) and employment (Individual Placement and Support) suggests that high-intensity interventions which focus on the desired social outcome and provide comprehensive multidisciplinary support could influence positive change in social circumstances of people with mental health conditions. Objective social isolation could be improved using a range of approaches such as supported socialisation and social skills training but interventions to reduce offending showed few benefits. Studies with cost and cost-effectiveness components were generally supportive of interventions to improve housing and vocational outcomes. More research is needed to ensure that social circumstances accompanied by high risks of further exacerbation of mental health conditions are adequately addressed. Conclusions Although there is a large body of literature examining how to support some aspects of life for people with mental health conditions, more high-quality evidence is required in other social domains. Integration into mental health services of interventions targeting social circumstances could significantly improve a number of social outcomes.

Limited genomic sampling in many high-incidence countries has impeded studies of severe respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic epidemiology. Consequently, critical questions remain about the generation and global distribution of virus genetic diversity. We investigated SARS-CoV-2 transmission dynamics in Gujarat, India, during the state’s first epidemic wave to shed light on spread of the virus in one of the regions hardest hit by the pandemic. By integrating case data and 434 whole-genome sequences sampled across 20 districts, we reconstructed the epidemic dynamics and spatial spread of SARS-CoV-2 in Gujarat. Our findings indicate global and regional connectivity and population density were major drivers of the Gujarat outbreak. We detected >100 virus lineage introductions, most of which appear to be associated with international travel. Within Gujarat, virus dissemination occurred predominantly from densely populated regions to geographically proximate locations that had low population density, suggesting that urban centers contributed disproportionately to virus spread.

Summary: Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure. Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients. Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54–1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection. Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy. Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).