Search

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.

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.

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.

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).

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 Background Negative symptoms of schizophrenia are frequently associated with poor long term outcomes. Established interventions have little, if any, positive effects on negative symptoms. Arts Therapies such as Body Psychotherapy (BPT) have been suggested to reduce negative symptoms, but the existing evidence is limited. In a small exploratory trial a manualised form of group BPT led to significantly lower negative symptom levels both at the end of treatment and at 4 months follow-up as compared to supportive counseling. We designed a large multi-site trial to assess the effectiveness of a manualised BPT intervention in reducing negative symptoms, compared to an active control. Methods/Design In a randomised controlled trial, 256 schizophrenic outpatients with negative symptoms will be randomly allocated either to BPT or Pilates groups. In both conditions, patients will be offered two 90 minutes sessions per week in groups of about 8 patients over a period of 10 weeks. Outcomes are assessed at the end of treatment and at six months follow-up. The primary outcome is severity of negative symptoms, as measured by the Positive and Negative Symptom Scale (PANSS), whilst a range of secondary outcome measures include general psychopathology, social contacts, and quality of life. We will also assess the cost-effectiveness of the intervention. Discussion The study aims to evaluate the effectiveness of a promising form of group therapy which may help alleviate negative symptoms that are associated with unfavourable long-term outcomes and have so far been difficult to treat. If the trial is successful, it will add a new and effective option in the treatment of negative symptoms. Group BPT is manualised, might be attractive to many patients because of its unusual approach, and could potentially be rolled out to services at relatively little additional cost. Trial registration Current Controlled Trials ISRCTN84216587

Abstract Background Breathlessness is a common and distressing symptom affecting many patients with advanced disease both from malignant and non-malignant origin. A combination of pharmacological and non-pharmacological measures is necessary to treat this symptom successfully. Breathlessness services in various compositions aim to provide comprehensive care for patients and their carers by a multiprofessional team but their effectiveness and cost-effectiveness have not yet been proven. The Breathlessness Support Service (BSS) is a newly created multiprofessional and interdisciplinary outpatient service at a large university hospital in South East London. The aim of this study is to develop and evaluate the effectiveness and cost effectiveness of this multidisciplinary out–patient BSS for the palliation of breathlessness, in advanced malignant and non-malignant disease. Methods The BSS was modelled based on the results of qualitative and quantitative studies, and systematic literature reviews. A randomised controlled fast track trial (RCT) comprising two groups: 1) intervention (immediate access to BSS in addition to standard care); 2) control group (standard best practice and access to BSS after a waiting time of six weeks). Patients are included if suffering from breathlessness on exertion or at rest due to advanced disease such as cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), interstitial lung disease (ILD) or motor neurone disease (MND) that is refractory to maximal optimised medical management. Both quantitative and qualitative outcomes are assessed in face to-face interviews at baseline, after 6 and 12 weeks. The primary outcome is patients' improvement of mastery of breathlessness after six weeks assessed on the Chronic Respiratory Disease Questionnaire (CRQ). Secondary outcomes for patients include breathlessness severity, symptom burden, palliative care needs, service use, and respiratory measures (spirometry). For analyses, the primary outcome, mastery of breathlessness after six weeks, will be analysed using ANCOVA. Selection of covariates will depend on baseline differences between the groups. Analyses of secondary outcomes will include patients’ symptom burden other than breathlessness, physiological measures (lung function, six minute walk distance), and caregiver burden. Discussion Breathlessness services aim to meet the needs of patients suffering from this complex and burdensome symptom and their carers. The newly created BSS is different to other current services as it is run in close collaboration of palliative medicine and respiratory medicine to optimise medical care of patients. It also involves professionals from various medical, nursing, physiotherapy, occupational therapy and social work background. Trial registration ClinicalTrials.gov (NCT01165034)

Abstract Background Fatigue is common and has been shown to result in high economic costs to society. The aim of this study is to compare the cost-effectiveness of two active therapies, graded-exercise (GET) and counselling (COUN) with usual care plus a self-help booklet (BUC) for people presenting with chronic fatigue. Methods A randomised controlled trial was conducted with participants consulting for fatigue of over three months’ duration recruited from 31 general practices in South East England and allocated to one of three arms. Outcomes and use of services were assessed at 6-month follow-up. The main outcome measure used in the economic evaluation was clinically significant improvements in fatigue, measured using the Chalder fatigue scale. Cost-effectiveness was assessed using the net-benefit approach and cost-effectiveness acceptability curves. Results Full economic and outcome data at six months were available for 163 participants; GET = 51, COUN = 58 and BUC = 54. Those receiving the active therapies (GET and COUN) had more contacts with care professionals and therefore higher costs, these differences being statistically significant. COUN was more expensive and less effective than the other two therapies. The incremental cost-effectiveness ratio of GET compared to BUC was equal to £987 per unit of clinically significant improvement. However, there was much uncertainty around this result. Conclusion This study does not provide a clear recommendation about which therapeutic option to adopt, based on efficiency, for patients with chronic fatigue. It suggests that COUN is not cost-effective, but it is unclear whether GET represents value for money compared to BUC. Clinical Trial Registration number at ISRCTN register: 72136156

Abstract Background Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration ISRCTN21615909.

Abstract Background There is a consensus about the importance of 'recovery' in mental health services, but the evidence base is limited. Methods/Design A two centre, cluster randomised controlled trial. Participants are community-based mental health teams, and service users aged 18-65 years with a primary clinical diagnosis of psychosis. In relation to the REFOCUS Manual researchintorecovery.com/refocus, which describes a 12-month, pro-recovery intervention based on the REFOCUS Model, the objectives are: (1) To establish the effectiveness of the intervention described in the REFOCUS Manual; (2) To validate the REFOCUS Model; (3) To establish and optimise trial parameters for the REFOCUS Manual; and (4) To understand the relationship between clinical outcomes and recovery outcomes. The hypothesis for the main study is that service users in the intervention arm will experience significantly greater increases in measures of personal recovery (as measured by the QPR) compared to service users receiving care from control teams. The hypothesis for the secondary study is that black service users in the intervention arm will experience significantly greater increases in measures of personal recovery (as measured by the QPR) and client satisfaction (as measured by the CSQ) compared to Black service users receiving care from control teams. The intervention comprises treatment as usual plus two components: recovery-promoting relationships and working practices. The control condition is treatment as usual. The primary outcme is the Process of Recovery Questionnaire (QPR). Secondary outcomes are satisfaction, Goal setting - Personal Primary Outcome, hope, well-being, empowerment, and quality of life. Primary outcomes for the secondary study will be QPR and satisfaction. Cost data will be estimated, and clinical outcomes will also be reported (symptomatology, need, social disability, functioning). 29 teams (15 intervention and 14 control) will be randomised. Within each team, 15 services users will be randomly chosen, giving a total sample of 435 service users (225 in intervention and 210 in control). Power for the main study: 336 service users will give power to detect a medium effect size of 0.4 (alpha 0.05, power = 0.8) on both QPR sub-scales. Power for the secondary study: 89 participants will give power to detect an effect size of 0.67 on both QPR sub-scales and on CSQ. A range of approaches are used to minimise bias, although service users and clinicians cannot be blinded. Discussion This cluster-RCT will evaluate a pro-recovery intervention in community mental health teams. Trial registration ISRCTN: ISRCTN02507940

Abstract Background The national Cancer Reform Strategy recommends delivering care closer to home whenever possible. Cancer drug treatment has traditionally been administered to patients in specialist hospital-based facilities. Technological developments mean that nowadays, most treatment can be delivered in the out-patient setting. Increasing demand, care quality improvements and patient choice have stimulated interest in delivering some treatment to patients in the community, however, formal evaluation of delivering cancer treatment in different community settings is lacking. This randomised trial compares delivery of cancer treatment in the hospital with delivery in two different community settings: the patient's home and general practice (GP) surgeries. Methods/design Patients due to receive a minimum 12 week course of standard intravenous cancer treatment at two hospitals in the Anglia Cancer Network are randomised on a 1:1:1 basis to receive treatment in the hospital day unit (control arm), or their own home, or their choice of one of three neighbouring GP surgeries. Overall patient care, treatment prescribing and clinical review is undertaken according to standard local practice. All treatment is dispensed by the local hospital pharmacy and treatment is delivered by the hospital chemotherapy nurses. At four time points during the 12 week study period, information is collected from patients, nursing staff, primary and secondary care teams to address the primary end point, patient-perceived benefits (using the emotional function domain of the EORTC QLQC30 patient questionnaire), as well as secondary end points: patient satisfaction, safety and health economics. Discussion The Outreach trial is the first randomised controlled trial conducted which compares delivery of out-patient based intravenous cancer treatment in two different community settings with standard hospital based treatment. Results of this study may better inform all key stakeholders regarding potential costs and benefits of transferring clinical services from hospital to the community. Trial registration number ISRCTN: ISRCTN66219681

Abstract Background Impairment in social functioning is a key component of personality disorder. Therefore psycho-education and problem solving (PEPS) therapy may benefit people with this disorder. Psycho-education aims to educate, build rapport, and motivate people for problem solving therapy. Problem solving therapy aims to help clients solve interpersonal problems positively and rationally, thereby improving social functioning and reducing distress. PEPS therapy has been evaluated with community adults with personality disorder in an exploratory trial. At the end of treatment, compared to a wait-list control group, those treated with PEPS therapy showed better social functioning, as measured by the Social Functioning Questionnaire (SFQ). A definitive evaluation is now being conducted to determine whether PEPS therapy is a clinically and cost-effective treatment for people with personality disorder Methods This is a pragmatic, two-arm, multi-centre, parallel, randomised controlled clinical trial. The target population is community-dwelling adults with one or more personality disorder, as identified by the International Personality Disorder Examination (IPDE). Inclusion criteria are: Living in the community (including residential or supported care settings); presence of one or more personality disorder; aged 18 or over; proficiency in spoken English; capacity to provide informed consent. Exclusion criteria are: Primary diagnosis of a functional psychosis; insufficient degree of literacy, comprehension or attention to be able to engage in trial therapy and assessments; currently engaged in a specific programme of psychological treatment for personality disorder or likely to start such treatment during the trial period; currently enrolled in any other trial. Suitable participants are randomly allocated to PEPS therapy plus treatment as usual (TAU) or TAU only. We aim to recruit 340 men and women. The primary outcome is social functioning as measured by the SFQ. A reduction (i.e., an improvement) of 2 points or more on the SFQ at follow-up 72 weeks post-randomisation is our pre-specified index of clinically significant change. Secondary outcomes include a reduction of unscheduled service usage and an increase in scheduled service usage; improved quality of life; and a reduction in mental distress. Discussion PEPS therapy has potential as an economical, accessible, and acceptable intervention for people with personality disorder. The results from this randomised controlled trial will tell us if PEPS therapy is effective and cost-effective. If so, then it will be a useful treatment for inclusion in a broader menu of treatment options for this group of service users. Trial Registration International Standard Randomised Controlled Trial Number - ISRCTN70660936

Abstract Background To describe patterns of recent health service utilisation, and consequent out-of-pocket expenses among older people in countries with low and middle incomes, and to assess the equity with which services are accessed and delivered. Methods 17,944 people aged 65 years and over were assessed in one-phase population-based cross-sectional surveys in geographically-defined catchment areas in nine countries - urban and rural sites in China, India, Mexico and Peru, urban sites in Cuba, Dominican Republic, Puerto Rico and Venezuela, and a rural site in Nigeria. The main outcome was use of community health care services in the past 3 months. Independent associations were estimated with indicators of need (dementia, depression, physical impairments), predisposing factors (age, sex, and education), and enabling factors (household assets, pension receipt and health insurance) using Poisson regression to generate prevalence ratios and fixed effects meta-analysis to combine them. Results The proportion using healthcare services varied from 6% to 82% among sites. Number of physical impairments (pooled prevalence ratio 1.37, 95% CI 1.26-1.49) and ICD-10 depressive episode (pooled PR 1.21, 95% CI 1.07-1.38) were associated with service use, but dementia was inversely associated (pooled PR 0.93, 95% CI 0.90-0.97). Other correlates were female sex, higher education, more household assets, receiving a pension, and health insurance. Standardisation for age, sex, physical impairments, depression and dementia did not explain variation in service use. There was a strong borderline significant ecological correlation between the proportion of consultations requiring out-of-pocket costs and the prevalence of health service use (r = -0.50, p = 0.09). Conclusions While there was little evidence of ageism, inequity was apparent in the independent enabling effects of education and health insurance cover, the latter particularly in sites where out-of-pocket expenses were common, and private health insurance an important component of healthcare financing. Variation in service use among sites was most plausibly accounted for by stark differences in the extent of out-of-pocket expenses, and the ability of older people and their families to afford them. Health systems that finance medical services through out-of-pocket payments risk excluding the poorest older people, those without a secure regular income, and the uninsured.

Abstract Background Breathlessness in advanced disease causes significant distress to patients and carers and presents management challenges to health care professionals. The Breathlessness Intervention Service (BIS) seeks to improve the care of breathless patients with advanced disease (regardless of cause) through the use of evidence-based practice and working with other healthcare providers. BIS delivers a complex intervention (of non-pharmacological and pharmacological treatments) via a multi-professional team. BIS is being continuously developed and its impact evaluated using the MRC's framework for complex interventions (PreClinical, Phase I and Phase II completed). This paper presents the protocol for Phase III. Methods/Design Phase III comprises a pragmatic, fast-track, single-blind randomised controlled trial of BIS versus standard care. Due to differing disease trajectories, the service uses two broad service models: one for patients with malignant disease (intervention delivered over two weeks) and one for patients with non-malignant disease (intervention delivered over four weeks). The Phase III trial therefore consists of two sub-protocols: one for patients with malignant conditions (four week protocol) and one for patients with non-malignant conditions (eight week protocol). Mixed method interviews are conducted with patients and their lay carers at three to five measurement points depending on randomisation and sub-protocol. Qualitative interviews are conducted with referring and non-referring health care professionals (malignant disease protocol only). The primary outcome measure is 'patient distress due to breathlessness' measured on a numerical rating scale (0-10). The trial includes economic evaluation. Analysis will be on an intention to treat basis. Discussion This is the first evaluation of a breathlessness intervention for advanced disease to have followed the MRC framework and one of the first palliative care trials to use fast track methodology and single-blinding. The results will provide evidence of the clinical and cost-effectiveness of the service, informing its longer term development and implementation of the model in other centres nationally and internationally. It adds to methodological developments in palliative care research where complex interventions are common but evidence sparse. Trial Registration ClinicalTrials.gov: NCT00678405 ISRCTN: ISRCTN04119516

Abstract Background Coronary heart disease and depression are both common health problems and by 2020 will be the two leading causes of disability worldwide. Depression has been found to be more common in patients with coronary heart disease but the nature of this relationship is uncertain. In the United Kingdom general practitioners are now being remunerated for case-finding for depression in patients with coronary heart disease, however it is unclear how general practitioners should manage these patients. We aim to explore the relationship between coronary heart disease and depression in a primary care population and to develop an intervention for patients with coronary heart disease and depression. Methods/design This programme of research will consist of 4 inter-related studies. A 4 year prospective cohort study of primary care patients with coronary heart disease will be conducted to explore the relationship between coronary heart disease and depression. Within this, a nested case-control biological study will investigate genetic and blood-biomarkers as predictors of depression in this sample. Two qualitative studies, one of patients' perspectives of treatments for coronary heart disease and co-morbid depression and one of primary care professionals' views on the management of patients with coronary heart disease and depression will inform the development of an intervention for this patient group. A feasibility study for a randomised controlled trial will then be conducted. Discussion This study will provide information on the relationship between coronary heart disease and depression that will allow health services to determine the efficiency of case-finding for depression in this patient group. The results of the cohort study will also provide information on risk factors for depression. The study will provide evidence on the efficacy and feasibility of a joint patient and professional led intervention and data necessary to plan a definitive randomised controlled trial of the intervention.

Abstract Background There is a large treatment gap with few community services for people with schizophrenia in low income countries largely due to the shortage of specialist mental healthcare human resources. Community based rehabilitation (CBR), involving lay health workers, has been shown to be feasible, acceptable and more effective than routine care for people with schizophrenia in observational studies. The aim of this study is to evaluate whether a lay health worker led, Collaborative Community Based Care (CCBC) intervention, combined with usual Facility Based Care (FBC), is superior to FBC alone in improving outcomes for people with schizophrenia and their caregivers in India. Methods/Design This trial is a multi-site, parallel group randomised controlled trial design in India. The trial will be conducted concurrently at three sites in India where persons with schizophrenia will be screened for eligibility and recruited after providing informed consent. Trial participants will be randomly allocated in a 2:1 ratio to the CCBC+FBC and FBC arms respectively using an allocation sequence pre-prepared through the use of permuted blocks, stratified within site. The structured CCBC intervention will be delivered by trained lay community health workers (CHWs) working together with the treating Psychiatrist. We aim to recruit 282 persons with schizophrenia. The primary outcomes are reduction in severity of symptoms of schizophrenia and disability at 12 months. The study will be conducted according to good ethical practice, data analysis and reporting guidelines. Discussion If the additional CCBC intervention delivered by front line CHWs is demonstrated to be effective and cost-effective in comparison to usually available care, this intervention can be scaled up to expand coverage and improve outcomes for persons with schizophrenia and their caregivers in low income countries. Trial registration The trial is registered with the International Society for the Registration of Clinical Trials and the allocated unique ID number is ISRCTN 56877013.

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.

Abstract Background A public health response is essential to meet the multidimensional needs of patients and families affected by HIV disease in sub-Saharan Africa. In order to appraise curret provision of HIV care and support in East Africa, and to provide evidence-based direction to future care programming, and Public Health Evaluation was commissioned by the PEPFAR programme of the US Government. Methods/Design This paper described the 2-Phase international mixed methods study protocol utilising longitudinal outcome measurement, surveys, patient and family qualitative interviews and focus groups, staff qualitative interviews, health economics and document analysis. Aim 1) To describe the nature and scope of HIV care and support in two African countries, including the types of facilities available, clients seen, and availability of specific components of care [Study Phase 1]. Aim 2) To determine patient health outcomes over time and principle cost drivers [Study Phase 2]. The study objectives are as follows. 1) To undertake a cross-sectional survey of service configuration and activity by sampling 10% of the facilities being funded by PEPFAR to provide HIV care and support in Kenya and Uganda (Phase 1) in order to describe care currently provided, including pharmacy drug reviews to determine availability and supply of essential drugs in HIV management. 2) To conduct patient focus group discussions at each of these (Phase 1) to determine care received. 3) To undertake a longitudinal prospective study of 1200 patients who are newly diagnosed with HIV or patients with HIV who present with a new problem attending PEPFAR care and support services. Data collection includes self-reported quality of life, core palliative outcomes and components of care received (Phase 2). 4) To conduct qualitative interviews with staff, patients and carers in order to explore and understand service issues and care provision in more depth (Phase 2). 5) To undertake document analysis to appraise the clinical care procedures at each facility (Phase 2). 6) To determine principle cost drivers including staff, overhead and laboratory costs (Phase 2). Discussion This novel mixed methods protocol will permit transparent presentation of subsequent dataset results publication, and offers a substantive model of protocol design to measure and integrate key activities and outcomes that underpin a public health approach to disease management in a low-income setting.

Abstract Background Emerging trends and new policies suggest that more cancer patients might die at home in the future. However, not all have equal chances of achieving this. Furthermore, there is lack of evidence to support that those who die at home experience better care and a better death than those who die as inpatients. The QUALYCARE study aims to examine variations in the quality and costs of end-of-life care, preferences and palliative outcomes associated with dying at home or in an institution for cancer patients. Methods/Design Mortality followback survey (with a nested case-control study of home vs. hospital deaths) conducted with bereaved relatives of cancer patients in four Primary Care Trusts in London. Potential participants are identified from death registrations and approached by the Office for National Statistics in complete confidence. Data are collected via a postal questionnaire to identify the informal and formal care received in the three months before death and the associated costs, relatives' satisfaction with care, and palliative outcomes for the patients and their relatives. A well-established questionnaire to measure relatives' views on the care integrates four brief and robust tools - the Client Service Receipt Inventory, the Palliative Outcome Scale, the EQ-5 D and the Texas Revised Inventory of Grief. Further questions assess patients and relatives' preferences for place of death. The survey aims to include 500 bereaved relatives (140 who experienced a home death, 205 a hospital death, 115 a hospice death and 40 a nursing home death). Bivariate and multivariate analyses will explore differences in place of death and place of end-of-life care, in preferences for place of death, patients' palliative outcomes and relatives' bereavement outcomes, in relation to place of death. Factors influencing death at home and the costs of end-of-life care by place of death will be identified. Discussion Collecting data on end-of-life care retrospectively from bereaved relatives has ethical, practical and scientific challenges. QUALYCARE has been carefully designed to address these challenges in a robust and ethically sound population-based survey. By discovering variations in the underlying individual reality of place of death for people dying from cancer and their families, this study will advance our understanding of end-of-life care and, we hope, improve care for cancer patients and their families in the future. Trial registration National Institute of Health Research (NIHR) Clinical Research Network Portfolio. UKCRN7041.

Abstract Background The promotion of care pathways in the recent Governmental health policy reports of Lord Darzi is likely to increase efforts to promote the use of care pathways in the NHS. Evidence on the process of pathway implementation, however, is sparse and variations in how organisations go about the implementation process are likely to be large. This paper summarises what is known about factors which help or hinder clinicians in adopting and putting care pathways into practice, and which consequently promote or hinder the implementation of scientific evidence in clinical practice. Discussion Care pathways can provide patients with clear expectations of their care, provide a means of measuring patient's progress, promote teamwork on a multi-disciplinary team, facilitate the use of guidelines, and may act as a basis for a payment system. In order to achieve adequate implementation, however, facilitators and barriers must be considered, planned for, and incorporated directly into the pathway with full engagement among clinical and management staff. Barriers and/or facilitators may be present at each stage of development, implementation and evaluation; and, barriers at any stage can impede successful implementation. Important considerations to be made are ensuring the inclusion of all types of staff, plans for evaluating and incorporating continuous improvements, allowing for organisational adaptations and promoting the use of multifaceted interventions. Summary Although there is a dearth of information regarding the successful implementation of care pathways, evidence is available which may be applied when implementing a care pathway. Multifaceted interventions which incorporate all staff and facilitate organisational adaptations must be seriously considered and incorporated alongside care pathways in a continuous manner. In order to better understand the mechanism upon which care pathways are effective, however, more research specifically addressing conditions under which providers become engaged in using care pathways is needed.

Abstract Background Nearly 1 in 10 in the population experience fatigue of more than six months at any one time. Chronic fatigue is a common reason for consulting a general practitioner, and some patients report their symptoms are not taken seriously enough. A gap in perceptions may occur because doctors underestimate the impact of fatigue on patients' lives. The main aim of the study is to explore the economic impact of chronic fatigue in patients seeking help from general practitioners and to identify characteristics that explain variations in costs. Methods The design of study was a survey of patients presenting to general practitioners with unexplained chronic fatigue. The setting were 29 general practice surgeries located in the London and South Thames regions of the English National Health Service. Use of services over a six month period was measured and lost employment recorded. Regression models were used to identify factors that explained variations in these costs. Results The mean total cost of services and lost employment across the sample of 222 patients was £3878 for the six-month period. Formal services accounted for 13% of this figure, while lost employment accounted for 61% and informal care for 26%. The variation in the total costs was significantly related to factors linked to the severity of the condition and social functioning. Conclusions The economic costs generated by chronic fatigue are high and mostly borne by patients and their families. Enquiry about the functional consequences of fatigue on the social and occupational lives of patients may help doctors understand the impact of fatigue, and make patients feel better understood.

Abstract Background Supplementary prescribing for mental health nurses was first introduced in the UK in 2003. Since then, a number of studies have reported stakeholders' perceptions of the success of the initiative. However, there has been little experimental research conducted into its effectiveness. This paper reports findings from the first known study to compare the cost and clinical impact of mental health nurse supplementary prescribing to independent medical prescribing. Methods A post-test control group experimental design was used to compare the treatment costs, clinical outcomes and satisfaction of patients in receipt of mental health nurse supplementary prescribing with a matched group of patients in receipt of independent prescribing from consultant psychiatrists. The sample comprised 45 patients in receipt of mental health nurse supplementary prescribing for a minimum of six months and a matched group (by age, gender, diagnosis, and chronicity) of patients prescribed for by psychiatrists. Results There were no significant differences between patients in the nurse supplementary prescribers' group and the independent prescribers' group in terms of medication adherence, health status, side effects, and satisfaction with overall care. Total costs per patient for service use were £803 higher for the nurse prescribers' group but this difference was not significant (95% confidence interval -£1341 to £3020). Conclusions No significant differences were found between the health and social outcomes of patients in the mental health nurse supplementary prescribers' group, and those prescribed for by the independent medical prescribers. The cost appraisal also showed that there was no significant difference in the costs of the two types of prescribing, although the pattern of resources used differed between patients in the two prescriber groups. The results suggest that mental health nurse supplementary prescribers can deliver similar health benefits to patients as consultant psychiatrists without any significant difference in patients' service utilisation costs.

Abstract Background Multiple Sclerosis (MS) is an incurable, chronic, potentially progressive and unpredictable disease of the central nervous system. The disease produces a range of unpleasant and debilitating symptoms, which can have a profound impact including disrupting activities of daily living, employment, income, relationships, social and leisure activities, and life goals. Adjusting to the illness is therefore particularly challenging. This trial tests the effectiveness of a Cognitive Behavioural intervention compared to Supportive Listening to assist adjustment in the early stages of MS. Methods/Design This is a two arm randomized multi-centre parallel group controlled trial. 122 consenting participants who meet eligibility criteria will be randomly allocated to receive either Cognitive Behavioral Therapy or Supportive Listening. Eight one hour sessions of therapy (delivered over a period of 10 weeks) will be delivered by general nurses trained in both treatments. Self-report questionnaire data will be collected at baseline (0 weeks), mid-therapy (week 5 of therapy), post-therapy (15 weeks) and at six months (26 weeks) and twelve months (52 weeks) follow-up. Primary outcomes are distress and MS-related social and role impairment at twelve month follow-up. Analysis will also consider predictors and mechanisms of change during therapy. In-depth interviews to examine participants' experiences of the interventions will be conducted with a purposively sampled sub-set of the trial participants. An economic analysis will also take place. Discussion This trial is distinctive in its aims in that it aids adjustment to MS in a broad sense. It is not a treatment specifically for depression. Use of nurses as therapists makes the interventions potentially viable in terms of being rolled out in the NHS. The trial benefits from incorporating patient input in the development and evaluation stages. The trial will provide important information about the efficacy, cost-effectiveness and acceptability of the interventions as well as mechanisms of psychosocial adjustment. Trial registration Current Controlled Trials ISRCTN91377356

Abstract Background This study aims to build a measure for assessing and reviewing the living conditions, care and human rights of people with longer term mental health problems in psychiatric and social care institutions. Protection of their human rights is imperative since impaired mental capacity secondary to mental illness can make them vulnerable to abuse and exploitation from others. They also constitute a major resource pressure for mental health services, social services, informal carers and society as a whole. Methods/Design This study uses an iterative methodology to develop a toolkit to assess internationally agreed domains of care that are considered most important for recovery. These domains are identified by collating results from: i) a systematic review of the literature on institutional care for this service user group; ii) a review of the relevant care standards in each participating country; iii) Delphi exercises in partner countries with mental health professionals, service users, carers and advocates. Common domains and cross-cutting themes are agreed by the principal researchers and an international expert panel. Items are developed to assess these domains and incorporated into the toolkit which is designed to be administered through a face to face interview with the institution's manager. The toolkit is refined in response to inter-rater reliability testing, feedback from interviewers and interviewees regarding its utility, and feedback from key stakeholders in each country about its ability to deliver information that can be used within each country's established systems for quality assessment and review. Cross-validation of the toolkit ratings against service users' quality of life, autonomy and markers of recovery tests whether it can deliver a proxy-measure of the service users' experiences of care and the institution's promotion of their human rights and recovery. The ability of the toolkit to assess the "value for money" delivered by institutions is investigated by comparing toolkit ratings and service costs. Discussion The study will deliver the first international tool for the assessment of the quality of institutional care for people with longer term mental health problems that is accurate, reliable, informative, useful and easy to use.

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.

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.

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.