To Trial or Not to Trial Before Spinal Cord Stimulation for Chronic Neuropathic Pain: The Patients' View From the TRIAL-STIM Randomized Controlled Trial.

Objectives Spinal cord stimulation (SCS) is an established treatment of chronic neuropathic pain. Although a temporary SCS screening trial is widely used to determine suitability for a permanent implant, its evidence base is limited. The recent TRIAL-STIM study (a randomized controlled trial at three centers in the United Kingdom) found no evidence that an SCS screening trial strategy provides superior patient outcomes as compared with a no trial approach. As part of the TRIAL-STIM study, we undertook a nested qualitative study to ascertain patients' preferences in relation to undergoing a screening trial or not. Materials and Methods We interviewed 31 patients sampled from all three centers and both study arms (screening trial/no trial) prior to SCS implantation, and 23 of these patients again following implantation (eight patients were lost to follow-up). Interviews were undertaken by telephone and audio-recorded, then transcripts were subject to thematic analysis. In addition, participants were asked to state their overall preference for a one-stage (no screening trial) versus two-stage (screening trial) implant procedure on a five-point Likert scale, before and after implantation. Results Emergent themes favoured the option for a one-stage SCS procedure. Themes identified include: saving time (off work, in hospital, attending appointments), avoiding the worry about having "loose wires" in the two-stage procedure, having only one period of recovery, and saving NHS resources. Participants' rated preferences show similar support for a one-stage procedure without a screening trial. Conclusions Our findings indicate an overwhelming preference among participants for a one-stage SCS procedure both before and after the implant, regardless of which procedure they had undergone. The qualitative study findings further support the TRIAL-STIM RCT results.

Self-management and HeAlth Promotion in Early-stage dementia with e-learning for carers (SHAPE): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: With an increasing number of people with dementia worldwide and limited advancement in medical treatments, the call for new and cost-effective approaches is crucial. The utility of self-management has been proven in certain chronic conditions. However, very little work has been undertaken regarding self-management in people with dementia. METHODS: The SHAPE trial will include 372 people with mild to moderate dementia to evaluate the effectiveness and cost-effectiveness of an educational programme combining approaches of self-management, health promotion, and e-learning for care partners. The study is a multi-site, single-randomised, controlled, single-blinded trial with parallel arms. The intervention arm is compared with treatment as usual. The intervention comprises a 10-week course delivered as group sessions for the participants with dementia. The sessions are designed to develop self-management skills and to provide information on the nature of the condition and the development of healthy behaviours in a supportive learning environment. An e-learning course will be provided for care partners which covers similar and complementary material to that discussed in the group sessions for the participant with dementia. DISCUSSION: This trial will explore the effect of the SHAPE group intervention on people with mild to moderate dementia in terms of self-efficacy and improvement in key health and mental health outcomes and cost-effectiveness, along with carer stress and knowledge of dementia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04286139, registered prospectively February 26, 2020, https://clinicaltrials.gov/ct2/show/NCT04286139.

Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial.

BACKGROUND: Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy-cognitive behavioural therapy (CBT)-is complex and costly. A simpler therapy-behavioural activation (BA)-might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. METHODS: In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity [Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19], antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat [mITT]) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol [PP]). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. FINDINGS: Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points [SD 7·5], BA 8·4 PHQ-9 points [7·0], mean difference 0·1 PHQ-9 points [95% CI -1·3 to 1·5], p=0·89; PP: CBT 7·9 PHQ-9 points [7·3]; BA 7·8 [6·5], mean difference 0·0 PHQ-9 points [-1·5 to 1·6], p=0·99). Two (1%) non-trial-related deaths (one [1%] multidrug toxicity in the BA group and one [1%] cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three [2%] participants in the BA group (two [1%] patients who overdosed and one [1%] who self-harmed) and eight (4%) participants in the CBT group (seven [4%] who overdosed and one [1%] who self-harmed). INTERPRETATION: We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. FUNDING: National Institute for Health Research.

Potential for rapid antibody detection to identify tuberculous cattle with non-reactive tuberculin skin test results.

BACKGROUND: Bovine tuberculosis (TB) control programs generally rely on the tuberculin skin test (TST) for ante-mortem detection of Mycobacterium bovis-infected cattle. RESULTS: Present findings demonstrate that a rapid antibody test based on Dual-Path Platform (DPP®) technology, when applied 1-3 weeks after TST, detected 9 of 11 and 34 of 52 TST non-reactive yet M. bovis-infected cattle from the US and GB, respectively. The specificity of the assay ranged from 98.9% (n = 92, US) to 96.0% (n = 50, GB) with samples from TB-free herds. Multi-antigen print immunoassay (MAPIA) revealed the presence of antibodies to multiple antigens of M. bovis in sera from TST non-reactors diagnosed with TB. CONCLUSIONS: Thus, use of serologic assays in series with TST can identify a significant number of TST non-reactive tuberculous cattle for more efficient removal from TB-affected herds.

Clinical effectiveness and safety of adding a self-harm prevention app (BlueIce) to specialist mental health care for adolescents who repeatedly self-harm: A single blind randomised controlled trial (the BASH study).

No randomised controlled trials have evaluated whether the addition of a smartphone app to usual child and adolescent mental health care (CAMHS) can reduce self-harm in adolescents (<18 years) with repeated self-harm. We enrolled 170 participants aged 12-17, receiving CAMHS treatment who had self-harmed ≥2 in the past 12 months. Participants were randomised via an independent web-based system (1:1, minimised for gender, age, self-harm frequency, and depression severity) to treatment as usual (TAU) or treatment as usual plus BlueIce (TAU+BI). BlueIce is a self-harm prevention app that includes techniques from CBT and DBT that was co-designed with adolescents who self-harm. The primary outcome was change from baseline to 12-weeks on the self-harm scale of the Risk Taking and Self-Harm Inventory for Adolescents (RTSHIA), analysed by intention to treat (ITT). Emergency department attendances or admissions for self-harm were assessed over 6-months via a review of clinical records. Both groups improved but there were no statistically significant between group differences at 12 weeks or 6 months on the self-harm scale of the RTSHIA. There were fewer emergency department attendances and admissions in those who received the app, a finding that approached statistical significance. BlueIce can be helpful in some important aspects by contributing to fewer emergency department admissions and attendances. TRIAL REGISTRATION: Trial registration number ISRCTN10541045.

Acceptability, use and safety of the BlueIce self-harm prevention app: qualitative findings from the Beating Adolescent Self-Harm (BASH) randomised controlled trial.

BACKGROUND: Little is known about the social validity of self-harm prevention apps for young adolescents with severe mental health problems who repeatedly self-harm. OBJECTIVE: We assessed the acceptability, use and safety of BlueIce, a self-harm prevention app for young adolescents who self-harm. METHODS: Mixed methods study involving a content analysis of postuse interviews. Participants were a clinical group of 60 UK adolescents aged 12-17 with repeated self-harm, randomised to receive BlueIce. FINDINGS: BlueIce was used by 57/60 (95%) respondents with 47/57 (82%) using BlueIce when thinking about self-harm. 17/47 (36%) who were thinking about self-harm used it on more than six occasions with 36/47 (77%) reporting that BlueIce prevented at least one episode of self-harm. 33/47 (70%) reported occasions when they used the app but still went on to self-harm. Reasons why the app was not used or not helpful included feeling too distressed, a negative mindset, prior decision to self-harm or forgetting. BlueIce was rated 4.09 (SD=0.75) out of 5 stars, with high mean ratings out of 10 for ease of use (8.70, SD=1.37) and good for acceptability (7.68, SD=2.05) and helpfulness (6.77, SD=1.72). No respondent identified BlueIce as triggering any episode of self-harm. CONCLUSION: These findings are consistent with previous evaluations and highlight the acceptability, use and safety of BlueIce. Self-reports indicate that BlueIce prevented some episodes of self-harm. CLINICAL IMPLICATIONS: Our results highlight the acceptability of the BlueIce self-harm app for young adolescents who repeatedly self-harm.

Clinical effectiveness of a modified muscle sparing posterior technique compared with a standard lateral approach in hip hemiarthroplasty for displaced intracapsular fractures (HemiSPAIRE): a multicenter, parallel-group, randomized controlled trial.

Objectives: Assess the effect of a modified muscle sparing posterior approach; SPAIRE (Save Piriformis and Internus, Repairing Externus), in hip hemiarthroplasty for displaced intracapsular fractures on postoperative mobility and function compared with a standard lateral approach. Design: Pragmatic, superiority, multicenter, parallel-group, randomized controlled trial (with internal pilot). Participants, ward staff, and research staff conducting postoperative assessments were blinded to allocation. A CTU allocated treatments centrally using computer-generated lists. Setting: Six hospitals in Southwest England, recruiting November 25, 2019-April 25, 2022. Participants: 244 adults (≥60 years) requiring hip hemiarthroplasty (122 allocated to each approach). 90 and 85 participants allocated to SPAIRE and lateral, respectively, had primary outcome data within the prespecified data collection window. Interventions: Surgery using SPAIRE or standard lateral approach. Follow-up 3 days and 120 days postoperation. Main outcome measure: Oxford Hip Score (OHS), via telephone at 120 days. Secondary outcomes: function and mobility (3 days), pain (3 days, 120 days), discharge destination, length of hospital stay, complications and mortality (within 120 days), quality of life and place of residence (120 days). Results: Participants' mean age was 84.6 years (SD 7.2); 168 (69%) were women. Primary outcome: little evidence of a difference in OHS at 120 days; adjusted mean difference (SPAIRE-lateral) -1.23 (95% CI -3.96 to 1.49, p=0.37). Secondary outcomes: indication of lower participant-reported pain at 3 days in SPAIRE arm; no differences between arms for remaining outcomes. Conclusions: Participants' mobility and function are similar in the short term (3 days) and longer term (120 days), whether receiving the SPAIRE or lateral approach. Neither approach confers benefit over the other in terms of length of hospital stay, return to prefracture residence, survival within 120 days, or quality of life at 120 days. Participants receiving SPAIRE approach may experience less pain in the early postoperative period. Modifying the posterior approach in hip hemiarthroplasty to the SPAIRE approach gives equivalent patient outcomes to the lateral approach within 120 days. Trial registration number: NCT04095611.

Development of an enzyme-linked immunosorbent assay for the diagnosis of feline tuberculosis.

Cases of feline tuberculosis (TB) can be challenging to diagnose. Currently, this is achieved through a combination of mycobacterial culture, polymerase chain reaction (PCR), or interferon-gamma release assay (IGRA); however, these each have limitations. There is limited data regarding the use of humoral immunodiagnostics for TB in cats. Therefore, we sought to develop an enzyme-linked immunosorbent assay (ELISA) to further facilitate the diagnosis of feline TB. A comparative PPD (purified protein derivative) antibody ELISA was optimised for use on serum and plasma, and was tested against samples from 14 cats with culture-confirmed TB and 24 uninfected controls. Selection of an appropriate positive cut-off value based on receiver-operator characteristic curve analysis gave test sensitivity of 64.3 % and specificity of 100 %. When tested on further samples from cats with strongly suspected mycobacteriosis, 32.9 % (23/70) were antibody positive. Notably, positive results were recorded in cats that failed to respond to the IGRA, and in one PCR and IGRA negative cat. No positive responses were identified in cats with non-tuberculous mycobacterial infections, or with non-mycobacterial diseases (n = 12). Therefore, antibody-based diagnostics may be useful adjunctive tests for cases of TB missed by the IGRA, helping protect both feline and, in turn, human health.

Evaluation of Antibody Tests for Mycobacterium bovis Infection in Pigs and Deer.

This study addressed the need in Great Britain for supplementary blood tests for deer and pig herds under movement restrictions due to confirmed Mycobacterium bovis infection-to enhance the overall sensitivity and reliability of tuberculosis (TB) testing and contribute to an exit strategy for these herds. We evaluated four antibody tests (lateral flow DPP VetTB Assay for Cervids, M. bovis IDEXX ELISA, Enferplex Cervid and Porcine antibody tests and an in-house comparative PPD ELISA) using serum samples from defined cohorts of TB-infected and TB-free deer and pigs. TB-infected deer included two separate cohorts; farmed deer that had received a tuberculin skin test less than 30 days prior, and park deer that had received no prior skin test. In this way, we were able to assess the effect of the skin test anamnestic boost upon antibody test sensitivity. We tested a total of 402 TB-free pigs and 416 TB-free deer, 77 infected farmed deer and 105 infected park deer, and 29 infected pigs (including 2 wild boar). For deer, we found an equivalent high performance of all four tests: specificity range 98.8-99.5% and sensitivity range 76.6-85.7% for skin test-boosted infected deer, and 51.4-58.1% for non-boosted infected deer. These data suggest an overall approximate 25% increase in test sensitivity for infected deer following a skin test boost. For pigs, the tests again had equivalent high specificity of 99-99.5% and a sensitivity range of 62.1-86.2%, with substantial agreement for three of the four tests. Retrospective application of the ELISA tests to individual culled park deer and wild boar that showed no obvious evidence of TB at larder inspection identified a significant seropositivity within wild boar suggestive of low-level M. bovis infection that would otherwise not have been detected. Overall this investigation provided a robust evaluation of four antibody tests, which is essential to generate confidence in test performance before a wider deployment within TB control measures can be considered.

Evaluation of the prehospital use of a Valsalva assist device in the emergency treatment of supraventricular tachycardia (EVADE SVT): study protocol for a stepped wedge cluster randomised controlled trial.

INTRODUCTION: Patients with episodes of supraventricular tachycardia (SVT), a common heart arrhythmia, are often attended by ambulance services. International guidelines advocate treatment with the Valsalva manoeuvre (VM), but this simple physical treatment has a low success rate, with most patients requiring conveyance to hospital. The Valsalva Assist Device (VAD) is a simple device that might help practitioners and patients perform a more effective VM and reduce the need for patients to be taken to hospital. METHODS AND ANALYSIS: This stepped wedge cluster randomised controlled trial, conducted within a UK ambulance service, compares the current standard VM with a VAD-delivered VM in stable adult patients presenting to the ambulance service with SVT. The primary outcome is conveyance to hospital; secondary outcomes measures include cardioversion rates, duration of ambulance care and number of subsequent episodes of SVT requiring ambulance service care. We plan to recruit approximately 800 patients, to have 90% power to detect an absolute reduction in conveyance rate of 10% (from 90% to 80%) between the standard VM (control) and VAD-delivered VM (intervention). Such a reduction in conveyance would benefit patients, the ambulance service and receiving emergency departments. It is estimated potential savings would pay for devices for the entire ambulance trust within 7 months. ETHICS AND DISSEMINATION: The study has been approved by the Oxford Research Ethics Committee (reference 22/SC/0032). Dissemination will be through peer-reviewed journal publication, presentation at national and international conferences and by the Arrhythmia Alliance, a patient support charity. TRIAL REGISTRATION NUMBER: ISRCTN16145266.

A randomised controlled trial to investigate the clinical effectiveness and cost effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) for depressed non-responders to Increasing Access to Psychological Therapies (IAPT) high-intensity therapies: study protocol.

BACKGROUND: Major depression represents a pressing challenge for health care. In England, Increasing Access to Psychological Therapies (IAPT) services provide evidence-based psychological therapies in a stepped-care approach to patients with depression. While introduction of these services has successfully increased access to therapy, estimates suggest that about 50% of depressed patients who have come to the end of the IAPT pathway still show significant levels of symptoms. This study will investigate whether Mindfulness-Based Cognitive Therapy (MBCT), a group intervention combining training in mindfulness meditation and elements from cognitive therapy, can have beneficial effects in depressed patients who have not responded to high-intensity therapy in IAPT. It will seek to establish the effectiveness and cost-effectiveness of MBCT as compared to the treatment these patients would usually receive. METHODS: In a 2-arm randomised controlled trial, patients who currently meet the criteria for major depressive disorder and who have not sufficiently responded to at least 12 sessions of IAPT high-intensity therapy will be allocated, at a ratio of 1:1, to receive either MBCT (in addition to treatment as usual [TAU]) or continue with TAU only. Assessments will take place at baseline, 10 weeks and 34 weeks post-randomisation. The primary outcome will be reduction in depression symptomatology 34 weeks post-randomisation as assessed using the Public Health Questionnaire-9 (PHQ-9). Secondary outcomes will include depressive symptomatology at 10 weeks post-randomisation and other clinical outcomes measured at 10-week and 34-week follow-up, along with a series of binarised outcomes to indicate clinically significant and reliable change. Evaluations of cost-effectiveness will be based on assessments of service use costs collected using the Adult Service Use Schedule and health utilities derived from the EQ-5D. DISCUSSION: This trial will add to the evidence base for the use of MBCT in depressed treatment non-responders. It will constitute the first trial to test MBCT following non-response to psychological therapy, with results providing a direct estimate of efficacy within the IAPT pathway. As such, its results will offer an important basis for decisions regarding the adoption of MBCT for non-responders within IAPT. TRIAL REGISTRATION: ClinicalTrials.gov NCT05236959. Registered on 11 February 2022. ISRCTN 17755571. Registered on 2 February 2021.

Early Laser for Burn Scars (ELABS): protocol for a multi-centre randomised, controlled trial of both the effectiveness and cost-effectiveness of the treatment of hypertrophic burn scars with Pulsed Dye Laser and standard care compared to standard care alone [version 1; peer review: 2 approved].

This paper outlines the protocol for a study that is being carried out at multiple centres across the UK in the next three years. It is a Research for Patient Benefit (RfPB) study funded by the National Institute for Healthcare Research (NIHR). The aim is to assess the effectiveness of treating hypertrophic burns scars with pulsed dye laser (PDL) at an early stage of scar formation. The objective is to improve Quality of Life for the patient by improving both the appearance and quality of burn scarring, as well as reducing its psychological impact. This is a parallel-arm randomised, controlled trial to compare PDL and standard care against standard care alone. The difference is measured between baseline and six-month follow-up. Recruits are within three months of healing from a burn injury; with wounds showing a defined potential for hypertrophic scarring. A total of 120 patients are recruited in a multi-centre study; with randomisation in a 1:1 allocation to each arm. The treatment arm receives 3 PDL treatments at six-week intervals in addition to standard care, whereas the control arm receives standard care alone. The primary outcome is the patient-rated part of the Patient and Observer Scar Scale (POSAS). Psychological and psycho-social impact is evaluated using the CARe burn scale (UWE, Bristol) and Quality Adjusted Life Years (QALY) is determined using the Short-Form Health Survey (SF-12). The study evaluates both the cost-effectiveness through an economic analysis and the patient-reported experience of the treatment by phone interviews.

Performance of the imPulse device for the detection of atrial fibrillation in hospital settings.

Background: Atrial fibrillation (AF) increases thromboembolism and stroke risk; this can be reduced by oral anticoagulation, but only if AF is detected. A portable, point-of-care device, capable of accurately detecting and identifying AF, could reduce workload and diagnostic delay by minimizing need for follow-up 12-lead electrocardiogram (ECGs). Objective: To assess the diagnostic performance of the Plessey imPulse lead I ECG device compared with a 12-lead ECG in detecting AF. Methods: Cross-sectional diagnostic accuracy study. Participants underwent simultaneous 12-lead ECG and imPulse device recordings. The imPulse device reports AF to be "probable," "possible," "unlikely," or "uncontrolled AF unlikely." imPulse and ECG reference results were cross-tabulated; sensitivity, specificity, positive/negative predictive values, and positive/negative likelihood ratios with 95% confidence interval (CI) were estimated based on different imPulse device report categorizations and heart rate subgroups. Results: A total of 217 participants were recruited (mean age 70.2 [standard deviation 12.7]), 56% male, 57% outpatients, 43% inpatients) and 199 were included in analyses. AF was diagnosed on ECG for 41 of 199 (20.6%) participants and reported by imPulse as possible, probable, or uncontrolled AF unlikely present for 49 of 199 (24.6%). Sensitivity and specificity for imPulse detection of possible, probable, or uncontrolled AF unlikely vs unlikely, compared with ECG, were 80.5% (95% CI, 65.1%-91.2%) and 89.9% (84.1%-94.1%), respectively. When probable or uncontrolled AF unlikely were compared vs possible or unlikely AF, sensitivity and specificity were 63.4% (46.9%-77.9%) and 98.1% (94.6%-99.6%), respectively. Conclusion: The imPulse device has moderate sensitivity and good specificity compared with ECG AF detection in a hospital setting.

Detailed statistical analysis plan for a randomised controlled trial of the effects of a modified muscle sparing posterior technique (SPAIRE) in hip hemiarthroplasty for displaced intracapsular fractures on post-operative function compared to a standard lateral approach: HemiSPAIRE.

BACKGROUND: The HemiSPAIRE trial is being conducted to determine whether a modified muscle sparing technique (SPAIRE-"Save Piriformis and Internus, Repairing Externus") in hip hemiarthroplasty brings clinical benefits compared to the standard lateral technique in adults aged 60 years or older, with a displaced intracapsular hip fracture. This article describes the detailed statistical analysis plan for the trial.  METHODS AND DESIGN: HemiSPAIRE is a definitive, pragmatic, superiority, multicentre, randomised controlled trial (with internal pilot) with two parallel groups. Participants, ward staff and all research staff involved in post-operative assessments are blinded to allocation. This article describes in detail (1) the primary and secondary outcomes; (2) the statistical analysis principles, including a survivor average causal effect (SACE) method chosen specifically to address the issue of potential bias from differential survival between trial arms, which was seen from data review by the Trial Steering Committee, the participants that will be included in each analysis, the covariates that will be included in each analysis, and how the results will be presented; (3) planned main analysis of the primary outcome; (4) planned analyses of the secondary outcomes; and (5) planned additional analyses of the primary and secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04095611. Registered on 19 September 2019.

Beating Adolescent Self-Harm (BASH): a randomised controlled trial comparing usual care versus usual care plus a smartphone self-harm prevention app (BlueIce) in young adolescents aged 12-17 who self-harm: study protocol.

INTRODUCTION: A mobile app, BlueIce, was codesigned with young people with a history of self-harm to provide them with more accessible and available evidence-based support at times of distress. A preliminary evaluation found that BlueIce was acceptable, safe and used by young people and helped to reduce self-harm. The present study is designed to assess the effectiveness and cost-effectiveness of adding BlueIce to usual Child and Adolescent Mental Health Service (CAMHS). METHODS AND ANALYSIS: This study is a single-blind, randomised controlled trial comparing usual CAMHS care with usual care plus BlueIce. A total of 138 adolescents aged 12-17 with current or a history of self-harm will be recruited through the Oxford Health National Health Service (NHS) Foundation Trust via their CAMHS clinician. The primary outcome is self-harm at 12 weeks assessed using the Risk Taking and Self-Harm Inventory for Adolescents. Secondary outcomes include mood, anxiety, hopelessness, general behaviour, sleep and impact on everyday life at 12 weeks and 6 months. Health-related quality of life and healthcare resource utilisation data will be collected at baseline, 12 weeks and 6 months. Postuse interviews at 12 weeks will determine the acceptability, safety and usability of BlueIce. ETHICS AND DISSEMINATION: The study was approved by the NHS South Central-Oxford B NHS Research Ethics Committee (19/SC/0212) and by the Health Research Authority (HRA) and Health and Care Research Wales. Findings will be disseminated in peer review open-access journals and at academic conferences. TRIAL REGISTRATION NUMBER: ISRCTN10541045.

Diagnostic accuracy of the interferon-gamma release assay (IGRA) for cases of feline mycobacteriosis.

The aim of this study was to evaluate the sensitivity and specificity of the interferon-gamma release assay (IGRA) for diagnosing infections with members of the Mycobacterium (M.) tuberculosis-complex (MTBC) and non-tuberculous mycobacteria (NTM) in domestic cats, and to generate defined feline-specific cut-off values using receiver operating characteristic (ROC) curve analysis to improve test performance. Records of 594 cats that had been tested by IGRA were explored to identify individuals that had a culture and/or polymerase chain reaction (PCR)-confirmed case of mycobacterial disease, and those that had a final diagnosis of non-mycobacterial disease. A total of 117 cats - 80 with mycobacterial disease and 37 diagnosed with a condition other than mycobacteriosis - were identified for further detailed analysis. This population was used to estimate test sensitivity and specificity, as well as likelihood ratios for the IGRA to correctly identify a cat with or without mycobacterial disease. Agreement between IGRA results and culture/PCR using current and proposed new cut-off values was also determined. ROC analysis of defined confirmed infected and non-mycobacterial disease control cats allowed an adjustment of current test cut-offs that increased the overall test sensitivity for MTBC infections from 83.1 % (95 % confidence interval [CI]: 71.5-90.5 %) to 90.2 % (95 % CI: 80.2-95.4%), and M. bovis infection from 43 % (95 % CI: 28.2-60.7%) to 68 % (95 % CI: 51.4-82.1%) while maintaining high test specificity (100 % in both cases). Overall agreement between IGRA results and culture/PCR, while recognising that neither culture nor PCR tests have perfect sensitivity, improved from weak (κ = 0.57) to moderate (κ = 0.71) using new proposed IGRA test cut-off values. Application of these results, based upon the statistical analysis of accumulated test data, can improve the diagnostic performance of the feline IGRA, particularly for identifying infections with M. bovis, without compromising specificity.

Effects of a modified muscle sparing posterior technique in hip hemiarthroplasty for displaced intracapsular fractures on postoperative function compared to a standard lateral approach (HemiSPAIRE): protocol for a randomised controlled trial.

INTRODUCTION: Currently National Institute for Health and Care Excellence clinical guidelines in the UK suggest that surgeons performing partial hip replacements (hemiarthroplasty) should consider using the lateral approach. Alternatively, a newer, modified posterior approach using a muscle sparing technique named 'Save Piriformis and Internus, Repairing Externus' (SPAIRE) can be used leaving the major muscles intact. This randomised controlled trial (RCT) aims to compare the SPAIRE approach to the standard lateral approach, to determine if it allows patients to mobilise better and experience improved function after surgery. METHODS AND ANALYSIS: HemiSPAIRE is a two-arm, assessor-blinded, definitive pragmatic RCT with nested pilot and qualitative studies. Two hundred and twenty-eight participants with displaced intracapsular fractures requiring hip hemiarthroplasty will be individually randomised 1:1 to either the SPAIRE, or control (standard lateral approach) surgical procedure. Outcomes will be assessed at postoperative day 3 (POD3) and 120 (POD120). The primary outcome measure will be level of function and mobility using the Oxford Hip Score at POD120. Secondary outcomes include: De Morton Mobility Index (DEMMI), Cumulated Ambulatory Score and Numeric Pain Rating Scale (NPRS) at POD3; DEMMI, NPRS and EQ-5D-5L at POD120, complications, acute and total length of hospital stay, and mortality. Primary analysis will be on an intention-to-treat basis. Participant experiences of the impact of surgery and recovery period will be examined via up to 20 semi-structured telephone interviews. ETHICS AND DISSEMINATION: The protocol has been approved by Yorkshire and the Humber-Bradford Leeds Research Ethics Committee. Recruitment commenced in November 2019. Findings will be disseminated via research articles in peer-reviewed journals, presentations at conferences, public involvement events, patient groups and media releases. A summary of the trial findings will be shared with participants at the end of the study. TRIAL REGISTRATION NUMBER: NCT04095611.

Healthy Parent Carers: feasibility randomised controlled trial of a peer-led group-based health promotion intervention for parent carers of disabled children.

BACKGROUND: Parent carers of children with special educational needs or disability are at higher risk of poor mental and physical health. The need for a tailored, peer-led group programme was raised by parent carers, who co-developed the Healthy Parent Carers programme with researchers. This study aimed to test the feasibility of programme delivery in community settings, and the feasibility and acceptability of a randomised controlled trial design. METHODS: Participants were individually randomised with concealed allocation to a structured group programme and access to online resources (intervention), or access to the online resources only (control). Measures of wellbeing and secondary and economic outcomes were collected before randomisation, immediately post-intervention, and 6 months post-intervention. Descriptive statistics on recruitment and attrition, demographics, attendance, and fidelity of intervention delivery were analysed with feedback on the acceptability of the trial design. RESULTS: One hundred and ninety-three parent carers expressed an interest in taking part. Ninety-two participants recruited from across six sites were randomised (47 intervention, 45 control). Lead and assistant facilitators were trained and delivered the group sessions. Sixteen (34%) participants in the intervention arm did not attend any sessions, and attendance varied across sites and sessions. One participant withdrew post-randomisation, and 83 (90%) participants completed outcome measures at the six-month follow-up. CONCLUSIONS: The study demonstrated that it was feasible to deliver the programme in community settings. The number of parent carers who expressed interest signifies the need for such a programme and the feasibility of recruiting to a definitive trial. Loss to follow-up was low. Further research is needed to explore ways to reduce barriers to participation in person and assess the feasibility and acceptability of programme content and delivery for more ethnically diverse groups, and potentially using interpreters. Given the Covid-19 pandemic and delivery format feedback, there is also a need to investigate remote or blended delivery strategies. Although the results indicate that a definitive trial is feasible, programme impact would be strengthened through exploration of these uncertainties. TRIAL REGISTRATION: ISRCTN, ISRCTN15144652 , registered on 25 October 2018, ClinicalTrials.gov , NCT03705221 , registered on 15 October 2018.

Comparison of Serological Assays for the Detection of SARS-CoV-2 Antibodies.

SARS-CoV-2 virus was first detected in late 2019 and circulated globally, causing COVID-19, which is characterised by sub-clinical to severe disease in humans. Here, we investigate the serological antibody responses to SARS-CoV-2 infection during acute and convalescent infection using a cohort of (i) COVID-19 patients admitted to hospital, (ii) healthy individuals who had experienced 'COVID-19 like-illness', and (iii) a cohort of healthy individuals prior to the emergence of SARS-CoV-2. We compare SARS-CoV-2 specific antibody detection rates from four different serological methods, virus neutralisation test (VNT), ID Screen® SARS-CoV-2-N IgG ELISA, Whole Antigen ELISA, and lentivirus-based SARS-CoV-2 pseudotype virus neutralisation tests (pVNT). All methods were able to detect prior infection with COVID-19, albeit with different relative sensitivities. The VNT and SARS-CoV-2-N ELISA methods showed a strong correlation yet provided increased detection rates when used in combination. A pVNT correlated strongly with SARS-CoV-2 VNT and was able to effectively discriminate SARS-CoV-2 antibody positive and negative serum with the same efficiency as the VNT. Moreover, the pVNT was performed with the same level of discrimination across multiple separate institutions. Therefore, the pVNT is a sensitive, specific, and reproducible lower biosafety level alternative to VNT for detecting SARS-CoV-2 antibodies for diagnostic and research applications. Our data illustrate the potential utility of applying VNT or pVNT and ELISA antibody tests in parallel to enhance the sensitivity of exposure to infection.

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection.

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.