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Intraoperative controlled hypotension improves surgical field visibility by reducing blood loss (efficacy) but poses potential risks linked to organ hypoperfusion (safety). The use of controlled hypotension persists despite increasing evidence of associations between intraoperative inadvertent hypotension and adverse outcomes. Therefore, we tested the hypothesis that the focus and results of intraoperative controlled hypertension research differ across anaesthesia and surgery investigators because of differing priorities. We systematically reviewed randomised trials comparing controlled hypotension with usual care with trials categorised by investigators' affiliation. We identified 48 eligible trials, of which 37 were conducted by anaesthesia investigators and 11 by surgery investigators. For the primary outcome, 54% of the anaesthesia-led trials focused on safety, whereas all (100%) surgery-led trials focused on efficacy (P =0.004). Compared with usual care, mean arterial pressure in controlled hypotension was 23% (95% confidence interval [CI] 17–29%) lower in anaesthesia trials and 30% (95% CI 14–37%) lower in surgery trials; estimated blood loss was 44% (95% CI 30–55%) less in anaesthesia trials and 38% (95% CI 30–49%) less in surgery trials. Overall, blood loss was reduced by 43% (95% CI 32–53%), and trial sequential analysis supported an efficacy conclusion. Mean arterial pressure and estimated blood loss reductions were associated (R2=0.41, P =0.002). All trials were underpowered for safety outcomes, and none adequately evaluated myocardial or renal injury. Anaesthesia researchers prioritised safety outcomes, whereas surgery researchers emphasised efficacy in controlled hypotension trials. Controlled hypotension significantly reduces blood loss. In contrast, safety outcomes were poorly studied. Given increasing observational evidence linking inadvertent hypotension to myocardial and renal injury, the safety of controlled hypotension remains to be addressed. PROSPERO (CRD42023450397). [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion To test if a New Zealand food–based Mediterranean diet (NZMedDiet) with behavioural intervention improves cardiometabolic health and wellbeing.A randomised controlled trial comparing 12 weeks of the NZMedDiet to usual diet in participants with increased cardiometabolic risk (metabolic syndrome severity score [MetSSS] > 0.35). The intervention group was provided with food and recipes to meet 75% of their energy requirements, supported by a behavioural intervention to improve adherence. The primary outcome measure was (MetSSS) after 12 weeks.Two hundred individuals with mean (SD) age 49.9 (10.9) years of which 62% women were enrolled with their household/whānau. After 12 weeks, the mean (SD) MetSSS was 1.0 (0.7) in the control (n = 98) and 0.8 (0.5) in the intervention (n = 102) group; estimated difference (95% confidence interval [CI]) of −0.05 (−0.16 to 0.06), p = 0.35. The Mediterranean diet score (PyrMDS) was greater in the intervention group 1.6 (1.1–2.1), p < 0.001, consistent with a change to a more Mediterranean dietary pattern. Weight reduced in the NZMedDiet group compared with control (−1.9 kg [−2.0 to −0.34]), p = 0.006 and wellbeing, assessed by the SF‐36 quality of life questionnaire, and improved across all domains. For example, the physical component summary score difference (95% CI) was 4.0 (2.4–5.7), p < 0.001, and the mental component summary score difference was 3.0 (0.7–5.2), p = 0.01.In participants with increased cardiometabolic risk, food provision with a Mediterranean dietary pattern and a behavioural intervention did not improve metabolic risk scores but was associated with reduced weight and improved quality of life. [ABSTRACT FROM AUTHOR]

Purpose: The primary goal of this randomised controlled trial was to investigate whether there are differences in the outcome between the Gamma3 nail and a sliding hip screw (SHS) regarding quality of life 1 year after surgery. Methods: In a controlled randomised trial, we compared the Gamma3 nail (Stryker) and a SHS (Omega, Stryker) in the treatment of 193 patients with pertrochanteric fractures. The follow-up period was 12 months. The outcomes included the surgical duration, health-related quality of life measured with the EQ-5D Index and a Visual Analogue Scale (VAS), the living situation and use of walking aid before trauma and 52 weeks after surgery; the Parker Mobility Score; the Harris Hip Score; and the revision, complication and mortality rates. Results: The Gamma3 group had a significantly shorter surgical duration than the SHS group (p < 0.0001). Implant-related complications were significantly lower in the Gamma3 group (p > 0.05). The revision rate was significantly lower in the Gamma3 group based on intention-to-treat (p = 0.0336) as well as as-treated (p = 0.0302) analyses. Otherwise, we did not find significant difference between the two groups regarding the EQ-5D Index and VAS scores, the Parker Mobility Score, the Harris Hip Score, the mortality rate, the use of walking aids and the living situation. Conclusion: There were no detectable differences between the groups in terms of quality of life and clinical scores 12 months after surgery. The surgical duration and revision rate were superior for the Gamma3 group. [ABSTRACT FROM AUTHOR]

Objective: To assess whether, in those requiring continuing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low‐dose oral misoprostol is superior to intravenous oxytocin. Design: Open‐label, superiority randomised trial. Setting: Government hospitals in India. Population: Women who were induced for hypertensive disease in pregnancy and had undergone cervical ripening with oral misoprostol, but required continuing stimulation after artificial membrane rupture. Methods: Participants received misoprostol (25 micrograms, orally, 2‐hourly) or titrated oxytocin through an infusion pump. All women had one‐to‐one care; fetal monitoring was conducted using a mixture of intermittent and continuous electronic fetal monitoring. Main outcome measures: Caesarean birth. Results: A total of 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced with the use of misoprostol (misoprostol, 84/260, 32.3%, vs oxytocin, 71/260, 27.3%; aOR 1.23; 95% CI 0.81–1.85; P = 0.33). The interval from randomisation to birth was somewhat longer with misoprostol (225 min, 207–244 min, vs 194 min, 179–210 min; aOR 1.137; 95% CI 1.023–1.264; P = 0.017). There were no cases of hyperstimulation in either arm. The rates of fetal heart rate abnormalities and maternal side effects were similar. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group; aOR 0.463; 95% CI 0.203–1.058; P = 0.068) and there were no neonatal deaths in the misoprostol group, compared with three neonatal deaths in the oxytocin arm. Women's acceptability ratings were high in both study groups. Conclusions: Following cervical preparation with oral misoprostol and membrane rupture, the use of continuing oral misoprostol for augmentation did not significantly reduce caesarean rates, compared with the use of oxytocin. There were no hyperstimulation or significant adverse events in either arm of the trial. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio‐renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio‐renal diseases and SGLT2 inhibitors has been explored through landmark trials and real‐world evidence (RWE) studies, demonstrating significant reductions in cardio‐renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real‐world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio‐renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower‐limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio‐renal protective effects in real‐world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long‐term effects and safety profiles. [ABSTRACT FROM AUTHOR]

Aims: To develop a clinical risk model to identify individuals at higher risk of developing new‐onset diabetes and who might benefit more from weight loss pharmacotherapy. Materials and Methods: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new‐onset diabetes. Twenty‐seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new‐onset diabetes. Results: During a median (interquartile range) follow‐up of 2.3 (1.8–2.7) years, new‐onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high‐density lipoprotein). The clinical risk model showed good discrimination (Harrell's C‐indices 0.802, 95% confidence interval [CI] 0.788–0.817 and 0.807, 95% CI 0.788–0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5‐year area under the curve was 81.2 [79.1–83.5]). While hazard ratios for new‐onset diabetes with a weight‐loss therapy were comparable across risk groups (annual risks of <1%, 1%–5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). Conclusions: The developed clinical risk model effectively predicts new‐onset diabetes, with potential implications for personalized patient care and therapeutic decision making. [ABSTRACT FROM AUTHOR]

Background: There is a pressing need to offer more accessible, evidence-based psychological interventions to secondary school students who are increasingly reporting difficulties with anxiety and low mood. The aim of this pragmatic randomised multiple baseline trial is to evaluate the efficacy of a school-based counselling intervention called Knowledge Insight Tools (KIT) for reducing anxiety and low mood in UK secondary school students. KIT is a flexible intervention delivered individually and informed by cognitive behavioural therapy (CBT). Methods: We will use a randomised multiple baseline design whereby young people will be randomly allocated to a baseline wait period of 3, 4, 5, 6, 7, or 8 weekly measurements, followed by receiving up to 10 weekly sessions of KIT delivered by trained, school-based practitioners. We aim to recruit 60 young people aged 11–18 who are primarily experiencing problems with low mood and/or anxiety from secondary schools across England and Scotland. We will assess child-reported anxiety, mood, and general psychological distress/coping with the Young Person's Clinical Outcomes in Routine Evaluation (YP-CORE), recorded at each session during the baseline and intervention phases. We will also assess child-reported anxiety and low mood with the Revised Children's Anxiety and Depression Scale (RCADS) at the beginning and end of treatment; practitioner-reported treatment fidelity with the KIT Fidelity Checklist; and practitioner-reported feasibility with an end-of-treatment Implementation Survey. We will analyse within-person and between-person change in YP-CORE scores across the baseline and intervention phases using visual analysis and piecewise multilevel growth curve models. We will also analyse pre-post changes in YP-CORE scores using randomisation tests, and reliable and clinically significant change using the RCADS scores. Discussion: The KIT trial is a pragmatic, randomised multiple baseline trial aimed at evaluating a school-based, individual CBT counselling intervention for reducing anxiety and low mood in UK secondary school students. Results will directly inform the provision of KIT in school-based counselling services, as well as the growing evidence-base for school-based CBT interventions. Trial registration: ClinicalTrials.gov NCT06188962. Retrospectively registered on 02/01/24. [ABSTRACT FROM AUTHOR]

Objective: To assess the effectiveness of an exercise intervention, in addition to standard care, in preventing or delaying insulin prescription in women with gestational diabetes mellitus (GDM). Design: Randomised controlled trial. Setting: University hospital. Population: Pregnant women at 25–35 weeks of gestation diagnosed with GDM. Methods: Women in the intervention group participated in weekly, supervised, 30–45 min exercise sessions and were encouraged to accumulate more than 5000 steps per day, tracked by a pedometer, in addition to receiving usual care. The control group received standard care only. Main outcome measure: Insulin prescription. Results: From February 2008 through April 2013, 109 women were randomized into the intervention group (n = 57) or the usual care group (n = 52). Two women in the intervention group were excluded from the analysis (one was randomised in error and one was lost to follow-up). Six women never attended the exercise sessions, and two attended fewer than two sessions. However, two-third of women were considered as compliant to the intervention (attended more than 50% of sessions and/or averaged more than 5000 steps/day). The incidence of insulin prescription did not differ between the groups: 31 women (56%) in the intervention group versus 24 women (46%) in the control group (RR 1.22, 95% CI 0.84 to 1.78). The median time from randomization to insulin prescription was also similar between groups (14 days in the intervention group and 13 days in the control group). Conclusion: This study did not demonstrate that an exercise program reduces or delays insulin prescription in women with GDM. Low adherence to the intervention, a small sample size, and the short duration of the program may explain the lack of observed benefit. Registered: At clinicaltrials.gov, NCT03174340, 02/06/2017 [ABSTRACT FROM AUTHOR]

Background: In oncology, the suffering of patients and the burnout of health professionals are key issues. Mindfulness meditation is a holistic approach that can help to improve well-being. While numerous studies have shown the benefits of meditation for both patients and health professionals, the added value of offering shared meditation to groups of patients, health professionals and third persons has not been assessed. Beyond strengthening the relationship between carers and patients, opening up meditation sessions to third parties (neither carers nor patients) enables patients to escape the stigma of their illness. We previously conducted a pilot study that validated the feasibility and the relevance of shared meditation with a specifically designed programme. Methods/Design: IMPLIC-2 is a two-arm randomised study designed to assess the added value of this meditation programme (optimised following the pilot study), particularly for cancer patients (our target population). People motivated to follow the programme, without previous regular practice of meditation and able to participate in the sessions are eligible. The study will include 96 participants: 16 health professionals, 16 third persons and 64 patients. The latter will be randomized in two arms: the experimental arm ("Shared" meditation) consisting of 4 mixed groups of 8 patients, 4 health professionals and 4 third parties, and the control arm ("Patient" meditation) consisting of 2 groups of 16 patients. Validated questionnaires will be used to measure the effects of the programme, notably in terms of quality of life, perceived stress, feelings of self-efficacy, qualities of mindfulness and self-compassion, and carers' burn-out. Participants' perception of a change in their quality of life and satisfaction will be measured at the end of the programme. A complementary qualitative focus-group approach will be used to optimise implementation of the programme beyond the study. Discussion: The well-being of oncology patients would be improved. Dealing with overworked carers would have a beneficial impact on the way they interact with patients. In addition, encounters between the three types of population will allow otherness to be viewed differently and alleviate suffering by promoting collective humanity. Trial Registration: NCT06041607, registered: 09/18/2023. Protocol version: Version n°1.2 dated from 08/29/2023. [ABSTRACT FROM AUTHOR]

Aim: To perform a direct, double‐blind, randomised, crossover comparison of subcutaneous and intravenous glucagon‐like peptide‐1 (GLP‐1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP‐1‐based therapy. Materials and Methods: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP‐1 and intravenous saline, or intravenous GLP‐1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg−1·min−1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg−1·min−1 for intravenous). Plasma glucose, total and intact GLP‐1, insulin, C‐peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. Results: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP‐1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP‐1 increased dose‐dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP‐1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP‐1 clearance was higher for subcutaneous than intravenous GLP‐1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP‐1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). Conclusions: Subcutaneous GLP‐1 administration is much less efficient than intravenous GLP‐1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether treatment early after onset in bipolar disorder may improve the long‐term illness course. The early intervention in affective disorders (EIA) randomised controlled trial found that 2‐years treatment in a specialised mood disorder clinic combining evidence‐based pharmacological treatment with group psychoeducation improved clinical outcomes compared with standard treatment in patients with bipolar disorder discharged after their 1st, 2nd, or 3rd hospital admission. We aimed to assess the 16 years long‐term outcomes after randomisation of the participants in the EIA trial. Methods: Data were obtained by linking nation‐wide Danish population‐based registers. All 158 participants of the EIA trial (Trial Registration Number NCT00253071) were followed from time of randomisation (2005–2009) to end of study (31 December 2021). The primary outcome was risk of psychiatric readmission. Secondary outcomes were total admissions and costs, medication use, intentional self‐harm or suicide attempt or suicide, and socio‐economic measures. Results: The absolute mean risk of psychiatric readmission was 49.3% in the intervention group and 59.8% in the control group, with no statistically significant difference between the groups (b = −0.10, 95% CI: −0.26 to 0.047, p = 0.18). Compared with the control group, patients in the intervention group had numerically fewer total admission days (mean (SD) 44 (77) versus 62 (109)), lower total cost of psychiatric hospital admissions and hospital‐based outpatient visits (mean (SD) 22,001 (36793) euros versus 29,822 (52671) euros) and higher use of lithium and antipsychotics, but the differences were not statistically significant. Fewer patients in the intervention group had an event of intentional self‐harm or suicide attempt or suicide during follow‐up (OR 0.25, 95% CI: 0.15–0.40, p < 0.001) compared with the control group and more patients in the intervention group used antiepileptics (OR 2.21, 95% CI: 1.08–4.60, p = 0.031). Conclusion: Analyses of very long‐term outcomes of the EIA trial may potentially indicate a beneficial effect of the intervention at the long term but were likely underpowered to detect a more subtle effect and for most outcomes the differences between groups were not statistically significant. [ABSTRACT FROM AUTHOR]

Background: Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large‐scale randomised trials have yet investigated this hypothesis. Methods: LENS is a streamlined randomised double‐masked placebo‐controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non‐referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. Results: Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. Conclusions: LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid‐2024. Trial Registrations: NCT03439345; ISRCTN15073006; EuDRACT 2016–002656‐24. [ABSTRACT FROM AUTHOR]

Background: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. Methods: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. Results: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009–2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03–2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. Conclusion: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports. [ABSTRACT FROM AUTHOR]

Abstract Objective To assess the effectiveness of an exercise intervention, in addition to standard care, in preventing or delaying insulin prescription in women with gestational diabetes mellitus (GDM). Design Randomised controlled trial. Setting University hospital. Population Pregnant women at 25–35 weeks of gestation diagnosed with GDM. Methods Women in the intervention group participated in weekly, supervised, 30–45 min exercise sessions and were encouraged to accumulate more than 5000 steps per day, tracked by a pedometer, in addition to receiving usual care. The control group received standard care only. Main outcome measure Insulin prescription. Results From February 2008 through April 2013, 109 women were randomized into the intervention group (n = 57) or the usual care group (n = 52). Two women in the intervention group were excluded from the analysis (one was randomised in error and one was lost to follow-up). Six women never attended the exercise sessions, and two attended fewer than two sessions. However, two-third of women were considered as compliant to the intervention (attended more than 50% of sessions and/or averaged more than 5000 steps/day). The incidence of insulin prescription did not differ between the groups: 31 women (56%) in the intervention group versus 24 women (46%) in the control group (RR 1.22, 95% CI 0.84 to 1.78). The median time from randomization to insulin prescription was also similar between groups (14 days in the intervention group and 13 days in the control group). Conclusion This study did not demonstrate that an exercise program reduces or delays insulin prescription in women with GDM. Low adherence to the intervention, a small sample size, and the short duration of the program may explain the lack of observed benefit. Registered At clinicaltrials.gov, NCT03174340, 02/06/2017

Abstract Background There is a pressing need to offer more accessible, evidence-based psychological interventions to secondary school students who are increasingly reporting difficulties with anxiety and low mood. The aim of this pragmatic randomised multiple baseline trial is to evaluate the efficacy of a school-based counselling intervention called Knowledge Insight Tools (KIT) for reducing anxiety and low mood in UK secondary school students. KIT is a flexible intervention delivered individually and informed by cognitive behavioural therapy (CBT). Methods We will use a randomised multiple baseline design whereby young people will be randomly allocated to a baseline wait period of 3, 4, 5, 6, 7, or 8 weekly measurements, followed by receiving up to 10 weekly sessions of KIT delivered by trained, school-based practitioners. We aim to recruit 60 young people aged 11–18 who are primarily experiencing problems with low mood and/or anxiety from secondary schools across England and Scotland. We will assess child-reported anxiety, mood, and general psychological distress/coping with the Young Person’s Clinical Outcomes in Routine Evaluation (YP-CORE), recorded at each session during the baseline and intervention phases. We will also assess child-reported anxiety and low mood with the Revised Children’s Anxiety and Depression Scale (RCADS) at the beginning and end of treatment; practitioner-reported treatment fidelity with the KIT Fidelity Checklist; and practitioner-reported feasibility with an end-of-treatment Implementation Survey. We will analyse within-person and between-person change in YP-CORE scores across the baseline and intervention phases using visual analysis and piecewise multilevel growth curve models. We will also analyse pre-post changes in YP-CORE scores using randomisation tests, and reliable and clinically significant change using the RCADS scores. Discussion The KIT trial is a pragmatic, randomised multiple baseline trial aimed at evaluating a school-based, individual CBT counselling intervention for reducing anxiety and low mood in UK secondary school students. Results will directly inform the provision of KIT in school-based counselling services, as well as the growing evidence-base for school-based CBT interventions. Trial registration ClinicalTrials.gov NCT06188962. Retrospectively registered on 02/01/24.

Abstract Background In oncology, the suffering of patients and the burnout of health professionals are key issues. Mindfulness meditation is a holistic approach that can help to improve well-being. While numerous studies have shown the benefits of meditation for both patients and health professionals, the added value of offering shared meditation to groups of patients, health professionals and third persons has not been assessed. Beyond strengthening the relationship between carers and patients, opening up meditation sessions to third parties (neither carers nor patients) enables patients to escape the stigma of their illness. We previously conducted a pilot study that validated the feasibility and the relevance of shared meditation with a specifically designed programme. Methods/Design IMPLIC-2 is a two-arm randomised study designed to assess the added value of this meditation programme (optimised following the pilot study), particularly for cancer patients (our target population). People motivated to follow the programme, without previous regular practice of meditation and able to participate in the sessions are eligible. The study will include 96 participants: 16 health professionals, 16 third persons and 64 patients. The latter will be randomized in two arms: the experimental arm (“Shared” meditation) consisting of 4 mixed groups of 8 patients, 4 health professionals and 4 third parties, and the control arm (“Patient” meditation) consisting of 2 groups of 16 patients. Validated questionnaires will be used to measure the effects of the programme, notably in terms of quality of life, perceived stress, feelings of self-efficacy, qualities of mindfulness and self-compassion, and carers’ burn-out. Participants' perception of a change in their quality of life and satisfaction will be measured at the end of the programme. A complementary qualitative focus-group approach will be used to optimise implementation of the programme beyond the study. Discussion The well-being of oncology patients would be improved. Dealing with overworked carers would have a beneficial impact on the way they interact with patients. In addition, encounters between the three types of population will allow otherness to be viewed differently and alleviate suffering by promoting collective humanity. Trial Registration NCT06041607, registered: 09/18/2023. Protocol version Version n°1.2 dated from 08/29/2023.

Objective: The transversus abdominis plane (TAP) block and local anaesthetic infiltration (LAI) of port sites provide adequate analgesia after laparoscopic cholecystectomy (LC). Little is known if the two techniques affect the day-case (DC) rate of LC. We tested the appropriateness of the research design in view of a larger randomised controlled trial (RCT) – laparoscopic-assisted right subcostal TAP block plus local anaesthetic wound infiltration (STALA) versus LAI. Subjects and Methods: Sixty patients having DC LC were randomised into STALA and LAI. Participants received bupivacaine 0.5% 30 mL. Pain scores were evaluated with the Visual Analogue Scale (VAS) score, at 1 h post-surgery and at discharge. Need of postoperative intravenous (IV) opioids, DC rate, and Quality of Recovery-15 questionnaires were compared between groups and were considered as measures of efficacy of the interventions and follow-up in a definitive trial. Results: Twenty-nine participants were randomised to STALA, and 31 to LAI. Subjects in LAI group were all women (p = 0.0007) and younger (43.8 vs. 37.7 years, p = 0.023). Median VAS scores were 0 versus 1 at 1 h (p = 0.60), 0 versus 1.5 at discharge (p = 0.55). The need of IV opioids was 15/29 (51.7%) versus 13/31 (41.9%; p = 0.60). The DC rate was 93.1% versus 93.5% (p = 0.39). Fifty (83.3%) participants responded the questionnaires. Conclusions: The laparoscopically guided right subcostal TAP block provided no additional benefit to LAI on pain control after LC and DC rate. Despite the appropriate design, our findings do not support a larger RCT. [ABSTRACT FROM AUTHOR]

This randomised double-blind placebo-controlled trial evaluated the efficacy and safety of fermented gold kiwi (FGK) in improving gastrointestinal health. A total of 100 participants were enrolled and randomly assigned to treatment or placebo groups. Over 8 weeks, the participants consumed an FGK or placebo preparation daily. Primary outcomes included changes in gastrointestinal symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS) and the Korean version of the Nepean Dyspepsia Index (NDI-K), as well as quality of life assessed using the Functional Dyspepsia-related Quality of Life questionnaire. The FGK group showed significant improvements in GSRS and NDI-K total and subdomain scores compared with the placebo group. Moreover, the quality of life scores were significantly better in the FGK group than in the placebo group. Safety evaluations revealed no significant adverse events or clinically meaningful changes upon assessing laboratory test results. This study demonstrated that FGK is a safe and effective dietary supplement for improving gastrointestinal health in adults with gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Opioids are commonly added to local anaesthetic for subarachnoid block for caesarean section due to their synergistic effects. The physiochemical characteristics of opioids suggest premixing with hyperbaric bupivacaine may limit their distribution within the CSF. We studied the effect of a separate injection with a combination of bupivacaine, morphine and fentanyl on block characteristics, haemodynamic changes, postoperative pain and patient satisfaction. Method: Following ethical approval and informed consent, a prospective double-blinded randomised controlled trial was performed in a university hospital. A total of 126 patients undergoing caesarean section were randomised to two groups. In group M, the premixed group, patients received 12 mg of hyperbaric bupivacaine, 20 mcg of fentanyl and 100 mcg of morphine injected as a single mixture. In group S, the separate injection group, patients received the same drugs in separate injections. Measurements included haemodynamics, block distribution, intra- and postoperative pain, as well as patient satisfaction. Results: Patients in both groups had similar block height, time to maximum sensory block, time to block regression and motor block. However, haemodynamics were different between the groups. The proportion of systolic hypotension episodes was greater in group S [159/1320 (12.05%)] than group M [113/1452 (7.78%)], with P = 0.0002. Moreover, a greater amount of ephedrine was administered in group S than group M, with values 12.09 (8.1) and 9.09 (8.5) mg respectively (P = 0.001). Additionally, postoperative pain, as measured by the Visual Analogue Scale (VAS), was greater in group M, with a VAS of 4.6 (1.7), vs. group S, which recorded a VAS of 3.8 (2.0) (P = 0.017). Conclusion: Sequential injection of intrathecal opioids and hyperbaric bupivacaine resulted in greater early haemodynamic instability and slightly better postoperative analgesia without any difference in block height or patient satisfaction. Clinical trial registration: NCT04403724. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the effectiveness of the digital and gamified WellWe intervention on parental self-efficacy for healthy behaviours and mindfulness in parenting at the comprehensive health checks of 4-year-old children. Methods: Two-arm cluster, randomised, controlled trial with a 4-month follow-up.The data were collected from parents of 4-year-old children. Cluster randomisation was done at the municipality level. Fifteen child health clinics within 4 municipalities located in Southwest Finland were randomly allocated to either an intervention (WellWe intervention) or a control group (usual care). The outcome measures included the Parental Self-Efficacy for Healthy Behaviours (PDAP) and Mindfulness in Parenting (MIPQ) questionnaires. Data were collected at baseline, after the intervention and at the 4-month follow-up. Results: Initially a total of 110 parents (50 in the intervention and 60 in the control group) participated in the study. At the end of the study, there were 33 parents involved, with 12 in the intervention group and 21 in the control group. Parental self-efficacy and mindfulness in parenting showed no statistically significant difference between the groups or within the groups at the different time points. Conclusions: The results of the study showed no difference between the intervention and the usual care. The commitment of the subjects was lower than expected. The intervention could be improved by placing a greater focus on engaging and motivating both families and public health nurses (PHNs). Therefore, when refining the intervention further, it's important to involve the target group more actively in the design of both content and delivery. [ABSTRACT FROM AUTHOR]

Background: EMPA–KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. Methods: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. Results: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64–0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66–0.86), and 33 vs. 64 (0.49, 0.32–0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. Conclusions: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan. [ABSTRACT FROM AUTHOR]

For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0–36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7–35.9 Gy). IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial. • The standard tumour bed radiotherapy dose used for neuroblastoma is 21 Gy. • The optimal dose is uncertain, and a higher dose may lead to better local control. • Organ-at-risk tolerance may limit the desired dose to the target volume. • Intensity-modulated arc therapy facilitates better delivery of higher doses. [ABSTRACT FROM AUTHOR]

Background: After an initial recommendation from the World Health Organisation, trials of patients hospitalised with COVID-19 often include an ordinal clinical status outcome, which comprises a series of ordered categorical variables, typically ranging from 'Alive and discharged from hospital' to 'Dead'. These ordinal outcomes are often analysed using a proportional odds model, which provides a common odds ratio as an overall measure of effect, which is generally interpreted as the odds ratio for being in a higher category. The common odds ratio relies on the assumption of proportional odds, which implies an identical odds ratio across all ordinal categories; however, there is generally no statistical or biological basis for which this assumption should hold; and when violated, the common odds ratio may be a biased representation of the odds ratios for particular categories within the ordinal outcome. In this study, we aimed to evaluate to what extent the common odds ratio in published COVID-19 trials differed to simple binary odds ratios for clinically important outcomes. Methods: We conducted a systematic review of randomised trials evaluating interventions for patients hospitalised with COVID-19, which used a proportional odds model to analyse an ordinal clinical status outcome, published between January 2020 and May 2021. We assessed agreement between the common odds ratio and the odds ratio from a standard logistic regression model for three clinically important binary outcomes: 'Alive', 'Alive without mechanical ventilation', and 'Alive and discharged from hospital'. Results: Sixteen randomised clinical trials, comprising 38 individual comparisons, were included in this study; of these, only 6 trials (38%) formally assessed the proportional odds assumption. The common odds ratio differed by more than 25% compared to the binary odds ratios in 55% of comparisons for the outcome 'Alive', 37% for 'Alive without mechanical ventilation', and 24% for 'Alive and discharged from hospital'. In addition, the common odds ratio systematically underestimated the odds ratio for the outcome 'Alive' by –16.8% (95% confidence interval: –28.7% to –2.9%, p = 0.02), though differences for the other outcomes were smaller and not statistically significant (–8.4% for 'Alive without mechanical ventilation' and 3.6% for 'Alive and discharged from hospital'). The common odds ratio was statistically significant for 18% of comparisons, while the binary odds ratio was significant in 5%, 16%, and 3% of comparisons for the outcomes 'Alive', 'Alive without mechanical ventilation', and 'Alive and discharged from hospital', respectively. Conclusion: The common odds ratio from proportional odds models often differs substantially to odds ratios from clinically important binary outcomes, and similar to composite outcomes, a beneficial common OR from a proportional odds model does not necessarily indicate a beneficial effect on the most important categories within the ordinal outcome. [ABSTRACT FROM AUTHOR]

Background Cardiac rehabilitation improves health and quality of life and reduces risk of further cardiac events. Twenty-eight per cent of cardiac rehabilitation patients experience clinically significant anxiety and 19% suffer depression. Such patients are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. The available psychological treatments for cardiac patients have small effects on anxiety and depression and quality of life; therefore, more effective treatments are needed. Research shows that a thinking style dominated by rumination and worry maintains anxiety and depression. A psychological intervention (metacognitive therapy) effectively reduces this style of thinking and alleviates depression and anxiety in mental health settings. The PATHWAY study evaluated two versions of metacognitive therapy applied in cardiac rehabilitation services. Objectives The primary aim was to improve psychological outcomes for cardiac rehabilitation patients. We evaluated two formats of metacognitive therapy: (1) a group-based face-to-face intervention delivered by cardiac rehabilitation staff (group-based metacognitive therapy) and (2) a paper-based, self-directed intervention (home-based metacognitive therapy). Each was compared with usual cardiac rehabilitation alone in separate randomised controlled trials. Design A randomised feasibility trial (work stream 1) and a full-scale randomised controlled trial (work stream 2) evaluated group-metacognitive therapy, while separate feasibility and full-scale trials (work stream 3 and work stream 3+, respectively) evaluated home-based metacognitive therapy. A cost-effectiveness analysis of group-metacognitive therapy was conducted, along with stated preference surveys and qualitative studies examining patient psychological needs and therapists’ perspectives on metacognitive therapy. Setting Seven NHS cardiac rehabilitation services across the north-west of England. Participants Adults aged ≥ 18 years who met cardiac rehabilitation eligibility criteria, scored ≥ 8 on depression or anxiety subscales of the Hospital Anxiety and Depression Scale, and were able to read, understand and complete questionnaires in English. Interventions Work stream 1 and work stream 2 – a 6-week group-metacognitive therapy intervention delivered by cardiac rehabilitation staff plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Group-metacognitive therapy was delivered once per week for 6 weeks, with each session lasting 90 minutes. Work stream 3 and work stream 3+ – home-based metacognitive therapy plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Home-metacognitive therapy was a paper-based manual that included six modules and two supportive telephone calls delivered by cardiac rehabilitation staff. Main outcome measures The Hospital Anxiety and Depression Scale total score at 4-month follow-up was the primary outcome in all trials. A range of secondary outcomes were also evaluated. Results Our qualitative study with 46 patients across three cardiac rehabilitation services suggested that cardiac rehabilitation patients’ psychological needs were not met by current approaches and that metacognitive therapy might offer an improved fit with their psychological symptoms. The internal pilot feasibility study (work stream 1; n = 54) demonstrated that a full-scale randomised controlled trial was feasible and acceptable and confirmed our sample size estimation. A subsequent full-scale, single-blind randomised controlled trial (work stream 2; n = 332) showed that adding group-based metacognitive therapy to cardiac rehabilitation was associated with statistically significant improvements on the Hospital Anxiety and Depression Scale (primary outcome) in anxiety and depression compared with cardiac rehabilitation alone at 4-month (adjusted mean difference −3.24, 95% confidence interval −4.67 to −1.81, p < 0.001; standardised mean difference 0.52) and 12-month follow-up (adjusted mean difference −2.19, 95% confidence interval −3.72 to −0.66, p = 0.005; standardised mean difference 0.33). The cost-effectiveness analysis suggested that group-metacognitive therapy was dominant, that it could be cost saving (net cost −£219, 95% confidence interval −£1446 to £1007) and health increasing (net quality-adjusted life-year 0.015, 95% confidence interval −0.015 to 0.045). However, confidence intervals were wide and overlapped zero, indicating high variability in the data and uncertainty in the estimates. A pilot feasibility trial (work stream 3; n = 108) supported a full-scale trial of home-metacognitive therapy and was extended (work stream 3+; n = 240). In the full trial, the adjusted mean difference on the Hospital and Anxiety and Depression Scale favoured the metacognitive therapy + cardiac rehabilitation arm (adjusted mean difference −2.64, 95% confidence interval −4.49 to −0.78, p = 0.005; standardised mean difference 0.38), with statistically significant greater improvements in anxiety and depression in home-metacognitive therapy plus cardiac rehabilitation than in cardiac rehabilitation alone at 4-month follow-up. A stated preference survey on clinic-delivered psychological therapy (not specific to metacognitive therapy) indicated a preference for including psychological therapy as part of cardiac rehabilitation. Participants favoured individual therapy, delivered by cardiac rehabilitation staff, with information provided prior to therapy and at a lower cost to the NHS. A pilot stated preference study focused on preferences for home- or clinic-based psychological therapy. Preferences were stronger for home-based therapy than for centre-based, but this was not statistically significant and participants highly valued receiving therapy and having reduced waiting times. Limitations Limitations include no control for additional contact as part of metacognitive therapy to estimate non-specific effects. Work stream 3+ did not include 12-month follow-up and therefore the long-term effects of home-based metacognitive therapy are unknown. The health economics analysis was limited by sample size and large amount of missing data in the final follow up. Findings from the qualitative study cannot necessarily be generalised. Conclusions Both group-based and home-based metacognitive therapy were associated with significantly greater reductions in anxiety and depression symptoms at 4 months, compared with cardiac rehabilitation alone. The results in group-based metacognitive therapy appeared to be stable over 12 months. Introducing metacognitive therapy into cardiac rehabilitation has the potential to improve mental health outcomes. Future work Future studies should evaluate the long-term effects of home-metacognitive therapy and the effect of metacognitive therapy against other treatments offered in cardiac rehabilitation. Given the uncertainty in the economic evaluation, further work is needed to determine the cost-effectiveness of metacognitive therapy. Trial registration Work stream 1/work stream 2: NCT02420431 and ISRCTN74643496; work stream 3: NCT03129282; work stream 3+: NCT03999359. The trial is registered with clinicaltrials.gov NCT03999359. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-1211-20011) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary Depression and anxiety are common among cardiac rehabilitation patients. Cardiac patients with anxiety and depression are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. Current talking-based therapies have small effects on anxiety and depression in patients with cardiovascular disease. It is important that more effective treatments for mental health are added to cardiac rehabilitation. We applied two versions of a recent treatment called metacognitive therapy in cardiac rehabilitation: a group version and a home-based (self-help) paper-based manual. The programme had three work streams conducted across seven NHS trusts. In work stream 1, we ran a pilot trial showing that adding group-metacognitive therapy to cardiac rehabilitation was feasible and acceptable A full-scale trial (work stream 2) followed, and this showed that adding group-metacognitive therapy to cardiac rehabilitation was associated with greater improvement in anxiety and depression than cardiac rehabilitation alone. In work stream 3, we created a home-based version of metacognitive therapy and ran a feasibility trial, which was extended to a full-scale trial and showed that home-metacognitive therapy plus cardiac rehabilitation was associated with improved anxiety and depression outcomes compared with cardiac rehabilitation alone. Interview studies of patients’ needs, treatment preferences and reactions to treatment were included, and our patient and public involvement group advised the research team throughout the trial. The originator of metacognitive therapy, Adrian Wells, was the chief investigator of the study and is the director of the Metacognitive Therapy Institute. He has funding for the study ‘Implementing Group Metacognitive Therapy in Cardiac Rehabilitation Services (PATHWAY-Beacons; NIHR29567)’ as chief investigator. To maintain objectivity along with the trial statistician and research assistants he did not know patient treatment allocation, data were managed by a separate clinical trials unit and a plan for analysis was devised before analysis took place. Project oversight and monitoring were undertaken by an independent Trial Steering Committee. Scientific summary Background Cardiac rehabilitation (CR) aims to improve heart disease patients’ health and quality of life and reduce the risk of further cardiac events: 28% of cardiac patients have clinically significant anxiety and 19% have depression. Such patients are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. Available psychological treatments for patients with heart disease have small effects on improving anxiety, depression and quality of life. Therefore, more effective treatments for depression and anxiety need to be explored and made available in CR services. Research in mental health contexts shows that a style of thinking dominated by rumination and worry maintains distress. A psychological intervention [metacognitive therapy (MCT)] reduces this style of thinking and alleviates depression and anxiety. The PATHWAY study evaluated two versions of MCT applied in heart disease patients attending CR: (1) a 6-week intervention delivered face to face in a group setting by CR staff (group-based MCT) and (2) a paper-based, six-module, self-directed intervention (home-based MCT). Objectives The primary aim is to improve access to more effective psychological interventions for the range of heart disease patients attending CR services. The specific objectives were to: conduct a pilot randomised controlled trial (RCT) of group-based MCT (Group-MCT) to evaluate the acceptability and feasibility of delivering the intervention to CR patients who have symptoms of anxiety and depression establish evidence of the effectiveness and cost-effectiveness of Group-MCT in CR in a full-scale RCT produce a rigorous, well-specified Group-MCT package develop a home-based metacognitive intervention (Home-MCT) for CR patients with depression and/or anxiety establish the feasibility and acceptability of integrating Home-MCT into the CR pathway in a pilot RCT establish provisional evidence of the effectiveness and cost-effectiveness of Home-MCT develop a protocol and manual for Home-MCT to inform a full-scale RCT conduct a full-scale RCT evaluating the effectiveness of Home-MCT. Methods We conducted a randomised controlled pilot trial and a full-scale RCT comparing usual CR alone against CR plus group-based MCT [work stream (WS) 1 and WS2; n = 332)]. We also conducted a randomised controlled pilot trial and a full-scale RCT of home-based metacognitive therapy (WS3 and WS3+; n = 240). All trials included integrated qualitative (n = 52) and economic evaluations (n = 339; stated preference survey). Participants A total of seven NHS trusts that provided a routine CR service participated in the research, with the number of participants and specific sites varying by trial. Work streams 1 and 2 explored the acceptability and effectiveness of Group-MCT integrated into usual CR in hospital settings, whereas WS3 and WS3+ explored the acceptability and effectiveness of Home-MCT integrated into usual CR in hospital and community settings. Work stream 1 recruited participants from three NHS trusts in north-west England. Participant recruitment for WS2 took place in five NHS trusts across north-west England. WS3 and WS3+ patients were recruited from CR services at five NHS hospital trusts across north-west England. Participating CR patients in all trials had to score ≥ 8 on the anxiety and/or depression subscale of the Hospital Anxiety and Depression Scale (HADS), be aged ≥ 18 years and meet the British Association for Cardiovascular Prevention and Rehabilitation criteria for attending CR. Participants were randomly allocated in a one-to-one ratio to receive either MCT plus usual CR or usual CR only using a randomisation procedure that balanced the trial arms with respect to gender, HADS scores and trial sites. Interventions Group-MCT: a 6-week manualised MCT intervention delivered face to face in a group setting. Therapists were CR staff who were not mental health specialists (e.g. clinical psychologists) but were trained to deliver the intervention. The intervention was developed by Adrian Wells based on the metacognitive model of psychological disorder and uses effective metacognitive therapy methods tested in mental health settings. Home-MCT: a paper-based, self-directed MCT intervention consisting of six modules in a treatment manual following a structure and content like that of the group-based MCT intervention. Adrian Wells provided pre-trial training for staff but was not involved in the ongoing supervision of staff delivering the intervention to maintain blinding and objectivity. Outcome measures The primary outcome was HADS total score at 4 months, with HADS total scores at 12 months as a secondary outcome (WS1 and WS2, i.e. Group-MCT only). Other secondary outcomes were the separate HADS anxiety and depression subscales, traumatic stress symptoms, and psychological mechanisms including metacognitive beliefs and repetitive negative thinking. For both interventions, qualitative interviews were conducted to assess patients’ emotional experiences and needs following cardiac events, and their understanding and experience of MCT. In Group-MCT, practitioners were interviewed to understand their experience of delivering the intervention and their understanding of patients’ responses to it and patients’ emotional needs. Statistical analysis For the pilot studies, statistical analysis was principally descriptive. We assessed the acceptability of adding Group-MCT and Home-MCT to usual CR regarding rates of recruitment into the study, attrition by the primary end point, and numbers of MCT and CR modules/sessions completed. The feasibility of conducting a full RCT was assessed against the completion of follow-up questionnaires, adequate variability in the outcome measures, and re-estimation of the required sample size based on pilot study findings. Therapist adherence to the Group-MCT treatment protocol was also assessed. The full-scale RCTs of Group-MCT and Home-MCT were designed to detect a standardised mean difference (SMD) between trial arms of 0.4 in HADS total score at 4-month follow-up with 90% power, based on effect sizes reported for other psychological interventions for depression. Analysis was conducted following a prespecified plan detailing the analytic models, primary and secondary outcomes, choice of covariates, sensitivity analyses, and all other key aspects of the analysis. The primary analyses used intention-to-treat principles. To reduce bias, data from the trial were managed by a separate clinical trials unit and locked prior to analysis. The chief investigator (AW), trial statisticians and research assistants were kept unaware of patient treatment allocation throughout the programme and the analyses followed a prespecified plan. Cost-effectiveness analysis For Group-MCT only, a within-trial cost-effectiveness analysis with a 12-month time horizon compared the cost-effectiveness of MCT plus usual CR with that of CR alone, from a UK health and social care perspective. Key measures included health status (measured using the EuroQol-5 Dimensions, five-level) and self-reported health and social care use. Total costs and quality-adjusted life-years (QALYs) were calculated for the trial follow-up. Missing values were addressed using multiple imputation. The primary outcome was the incremental cost-effectiveness ratio. Regression analysis was used to estimate net costs and net QALYs, and 10,000 bootstrapped pairs of net costs and QALYs were generated to inform the probability of cost-effectiveness. For the home-based MCT pilot study, a simple between-group comparison of the available economic data (health status and NHS and social care costs), using summary statistics, was performed. Two stated preference studies (using discrete choice experiment designs), one focused on Group-MCT and the other on Home-MCT, were conducted to explore patient preferences for the delivery of psychological therapy in CR. Participants were asked to choose between two hypothetical interventions, described using five attributes. The cost to the NHS was used to estimate willingness to pay for aspects of intervention delivery. Results Group-MCT Fifty-two CR patients were consented to the pilot trial of Group-MCT + CR versus CR alone, of whom 23 were randomly allocated to Group-MCT + CR and 29 to CR. The trial recruited to target, and > 70% of participants completed the 4-month follow-up questionnaire. More than half of the patients in both arms attended at least six CR sessions, and 57% of Group-MCT participants completed an a priori defined minimal dose of the intervention likely to produce the benefit of at least four of the six MCT sessions. The addition of MCT to rehabilitation did not negatively impact on CR attendance, and we observed high therapist adherence to the protocol. The trial concluded that Group-MCT is an acceptable and feasible intervention to deliver in CR services. The Trial Steering Committee and NIHR as funder agreed to support the progression to a full-scale RCT of the Group-MCT intervention. No substantive changes were required to the trial procedures; therefore, the pilot and full RCT samples were pooled for final analysis. A total of 332 patients (including 52 from the pilot trial) consented to the full-scale RCT of Group-MCT + CR versus CR alone, with 163 randomly allocated to Group-MCT + CR and 169 randomly allocated to CR alone; 81% returned data at 4-month follow-up. The adjusted group difference on the primary outcome of HADS total score at 4 months significantly favoured Group-MCT + CR [–3.24, 95% confidence interval (CI) –4.67 to –1.81, p < 0.001; SMD 0.52], as did the difference at the 12-month secondary outcome point (–2.19, 95% CI –3.72 to –0.66, p < 0.01; SMD 0.33). Patients in the Group-MCT + CR arm also had lower mean HADS anxiety and depression subscale scores at 4 months (p < 0.001). Differences in anxiety remained statistically significant at 12 months (p < 0.01), but those in depression did not (p = 0.065). Most of the other secondary outcomes also favoured the MCT intervention. Attendance at CR sessions did not differ between trial arms. Over 60% of Group-MCT + CR participants attended four or more of the six MCT intervention sessions. However, Group-MCT did not appeal to some patients, with 40 (25%) of the 163 patients randomised to receive MCT attending no MCT intervention sessions. Home-MCT One hundred and eight CR patients consented to the pilot trial of Home-MCT, with 54 randomised to Home-MCT + CR and 54 randomised to CR alone. The trial recruited to target, with 96% of CR only and 83% of Home-MCT + CR participants completing 4-month follow-up measures. Forty-four per cent of patients in the MCT arm completed a minimally effective dose of more than four out of six modules. Exit questionnaire ratings were good. However, views about telephone support were mixed and the quality of calls was rated low. Home-MCT appeared to be acceptable and feasible to deliver in CR services. The Trial Steering Committee and NIHR as funder agreed to support the progression to a full-scale RCT of the Home-MCT intervention. We submitted a no-additional-cost variation to contract (VTC) on 29 January 2019 to progress WS3 to a full-scale RCT (WS3+). The VTC was awarded on 12 March 2019. No substantive changes were required to the trial procedures; therefore, the pilot sample was pooled with the sample from the full RCT in final analysis. A total of 240 patients (including 108 from the pilot trial) were consented to the full-scale RCT of Home-MCT, with 118 randomly allocated to Home-MCT + CR and 122 randomly allocated to CR alone; 89% returned 4-month follow-up data. The adjusted group difference on the primary outcome of HADS total score at 4 months significantly favoured the MCT + CR arm (−2.64, 95% CI −4.49 to −0.78, p = 0.005; SMD 0.38). Patients in the MCT + CR arm also reported significantly lower mean HADS anxiety and depression scores (p < 0.05). Most other secondary outcomes also favoured the MCT intervention. Attendance at CR sessions did not differ between the trial arms. Over 70% of participants in the Home-MCT arm completed more than four MCT modules, but the intervention did not appeal to some patients; 21 participants (18%) withdrew or were not contactable at 4 months, compared with only one in the CR-alone arm. An investigation of the impact of differential attrition on the findings using last-observation-carried-forward resulted in no changes in statistical significance for the primary outcome and most of the secondary outcomes. In the primary cost-effectiveness analysis, the Group-MCT intervention was dominant, that is cost saving (net cost −219, 95% CI −£1446 to £1007) and health increasing (net QALY 0.015, 95% CI −0.015 to 0.045). However, the CIs are wide and overlap zero, indicating a high level of variability in the data and uncertainty in the estimates. Stated preference research indicated a preference for the inclusion of psychological therapy as part of a programme of CR. Conclusions There is not currently a standardised approach for psychological interventions in CR, and interventions can vary. There is a preference for the inclusion of psychological therapy in rehabilitation. Group-based MCT and Home-MCT were associated with significantly better anxiety and depression outcomes when added to CR compared with CR alone. The implications for health care are (1) MCT could be provided as part of the menu of approaches used in CR and (2) patients could be given the option to choose between group-based or home-based treatment to increase access. The recommendations for future research are (1) implementation studies that assess barriers to and enablers of roll-out in the NHS, (2) studies of longer-term outcomes of home-based MCT and (3) an evaluation of MCT against alternative therapies. Trial registration Work stream 1/work stream 2: NCT02420431 and ISRCTN74643496; work stream 3: NCT03129282; work stream 3+: NCT03999359. The trial is registered with clinicaltrials.gov NCT03999359. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1211-20011) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information.

To obtain valid inference following stratified randomisation, treatment effects should be estimated with adjustment for stratification variables. Stratification sometimes requires categorisation of a continuous prognostic variable (eg, age), which raises the question: should adjustment be based on randomisation categories or underlying continuous values? In practice, adjustment for randomisation categories is more common. We reviewed trials published in general medical journals and found none of the 32 trials that stratified randomisation based on a continuous variable adjusted for continuous values in the primary analysis. Using data simulation, this article evaluates the performance of different adjustment strategies for continuous and binary outcomes where the covariate‐outcome relationship (via the link function) was either linear or non‐linear. Given the utility of covariate adjustment for addressing missing data, we also considered settings with complete or missing outcome data. Analysis methods included linear or logistic regression with no adjustment for the stratification variable, adjustment for randomisation categories, or adjustment for continuous values assuming a linear covariate‐outcome relationship or allowing for non‐linearity using fractional polynomials or restricted cubic splines. Unadjusted analysis performed poorly throughout. Adjustment approaches that misspecified the underlying covariate‐outcome relationship were less powerful and, alarmingly, biased in settings where the stratification variable predicted missing outcome data. Adjustment for randomisation categories tends to involve the highest degree of misspecification, and so should be avoided in practice. To guard against misspecification, we recommend use of flexible approaches such as fractional polynomials and restricted cubic splines when adjusting for continuous stratification variables in randomised trials. [ABSTRACT FROM AUTHOR]

• RSVpreF immunogenicity, safety, and tolerability were evaluated in healthy adults. • Equivalence in immunogenicity was assessed across 3 RSVpreF lots. • All 3 RSVpreF lots elicited strong immune responses 1 month after vaccination. • Lot-pair comparisons met the 1.5-fold equivalence criterion for both RSV A and RSV B. • RSVpreF single doses were safe and well tolerated, with safety similar across lots. Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots. This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18–49-year-old adults. Participants received a single 120-µg injection of 1 of 3 RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667–1.5 interval). Safety and tolerability were assessed. Of 992 participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671–1795; RSV B 1358–1429) to 1 month after RSVpreF vaccination (RSV A, 24,131–25,238; RSV B, 19,238–21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots. These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208). [ABSTRACT FROM AUTHOR]

Background: We compared analgesia with an ultrasound (US)‐guided serratus anterior plane block (SAPB) to thoracic epidural analgesia (EA) with continuous local anaesthetic infusion in patients with unilateral multiple traumatic rib fractures. EA often carries contraindications in patients with multiple rib fractures (MRFs), whereby having alternative effective methods to treat rib fracture pain remains important to patient care. Thus, we hypothesised that both regional anaesthetic techniques would provide effective pain relief. Methods: In this study, we included 59 patients with unilateral MRFs and a numerical rating scale (NRS) pain score ≥4 at rest or upon movement. Patients were randomised to receive a US‐guided SAPB or continuous infusion EA with 2 mg/mL ropivacaine. Patients were given a patient‐controlled analgesia (PCA) device with intravenous oxycodone boluses for rescue medication. The primary outcome was a change in the NRS score at rest and upon movement from baseline to Day 2 following the block. We also measured the forced expiratory volume in 1 s of expiration (FEV1) and FEV1% at the same time points when NRS was measured. The total consumption of oxycodone with PCA was measured at 24 and 48 h after the block. Results: We detected a significant reduction (≥2) in NRS for both groups; however, EA associated with a greater reduction in NRS upon movement after block initiation. The mean reduction in NRS upon movement within 1 h was 3 (1.8, p <.01) in the SAPB group versus 4.7 (2.4, p <.01) in the EA group. We found no significant difference between groups in pain scores on Days 1 and 2 following the block. In the EA group, FEV1% increase in the first 12 h from baseline. Finally, PCA oxycodone consumption did not differ between groups. Conclusions: SAPB with continuous local anaesthetic infusion is an effective alternative to treat rib fracture pain when EA is contraindicated. We found that SABP significantly reduces pain in patients with unilateral MRFs, although EA achieves better analgesia over the first 12 h following the block. [ABSTRACT FROM AUTHOR]

Abstract Background The global research response to the COVID-19 pandemic was impressive, but also led to an infodemic and considerable research waste. Registered, but unpublished trials added to this noise. We aimed to determine the proportion of registered randomised trials of common COVID-19 treatments that were published and to describe the characteristics of these trials to examine the association between trial characteristics, publication status and research waste. Methods This meta-epidemiological cohort study used a sample of randomised trials of corticosteroids, hydroxychloroquine or vitamin D as treatments for COVID-19, registered between 1 November 2019 and 31 December 2021 and available via the WHO ICTRP portal. We searched for the trials’ published results up to 20 October 2022. We extracted the trial characteristics, analysing with descriptive statistics. We performed univariate logistic regression to examine the association between trials’ characteristics and publication status, followed by multiple logistic regression using significant characteristics to assess the association between trial characteristics and publication status. Results We identified 357 eligible trials on ICTRP. Of these, 107 (30%) had published or made their results available publicly by 20 October 2022, while 250 (70%) had not been published or shared their results publicly. Multiple logistic regression analysis showed that a larger target sample size was a significant positive predictor of publication with target sample sizes above 300 almost tripling the odds of publication (aOR: 2.75, 95% CI: 1.35 to 5.62). Conclusions Less than one third of registered trials made their results public and our findings identified that many trialists had not updated their trial registry entry with the trial status, results or both. Failure to share trial results publicly is a disservice to patients, clinicians and policy makers and adds to research waste.

Abstract Background Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. Methods Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. Results At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] − 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the “normal” weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). Conclusions Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. Trial registration ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171–8056). Registered on 16 July 2015.

Background: Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. Methods: Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. Results: At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] − 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the "normal" weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). Conclusions: Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. Trial registration: ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171–8056). Registered on 16 July 2015. [ABSTRACT FROM AUTHOR]

Background: The global research response to the COVID-19 pandemic was impressive, but also led to an infodemic and considerable research waste. Registered, but unpublished trials added to this noise. We aimed to determine the proportion of registered randomised trials of common COVID-19 treatments that were published and to describe the characteristics of these trials to examine the association between trial characteristics, publication status and research waste. Methods: This meta-epidemiological cohort study used a sample of randomised trials of corticosteroids, hydroxychloroquine or vitamin D as treatments for COVID-19, registered between 1 November 2019 and 31 December 2021 and available via the WHO ICTRP portal. We searched for the trials' published results up to 20 October 2022. We extracted the trial characteristics, analysing with descriptive statistics. We performed univariate logistic regression to examine the association between trials' characteristics and publication status, followed by multiple logistic regression using significant characteristics to assess the association between trial characteristics and publication status. Results: We identified 357 eligible trials on ICTRP. Of these, 107 (30%) had published or made their results available publicly by 20 October 2022, while 250 (70%) had not been published or shared their results publicly. Multiple logistic regression analysis showed that a larger target sample size was a significant positive predictor of publication with target sample sizes above 300 almost tripling the odds of publication (aOR: 2.75, 95% CI: 1.35 to 5.62). Conclusions: Less than one third of registered trials made their results public and our findings identified that many trialists had not updated their trial registry entry with the trial status, results or both. Failure to share trial results publicly is a disservice to patients, clinicians and policy makers and adds to research waste. [ABSTRACT FROM AUTHOR]

Despite the known beneficial effects of exercise, most pregnant women do not exercise regularly. Most studies on exercise have been conducted on supervised exercise and there is limited evidence regarding the adherence and effect of other exercise programs on pregnancy outcomes. Therefore, we aimed to investigate adherence to a face-to-face plus monitored home exercise program versus a monitored home-based exercise program on its own during pregnancy. In addition, effects of these two exercise programs on women's mental health during pregnancy and postpartum (primary outcomes) and on some other maternal and neonatal outcomes (secondary outcomes) will be assessed. In this superiority trial with three parallel arms, 150 women at 12–18 weeks of gestation will be randomised equally into three groups (face-to-face plus monitored home exercise, only monitored home-based exercise, and control). The exercise programs will be performed up to the 38th week of gestation during which participants will be assessed at specific intervals during the pregnancy, and post-partum and followed up until six months after childbirth. The exercise diary will be used to assess the adherence. The Edinburgh Depression Scale and the Positive and Negative Affect Schedule will be used to assess prenatal and postnatal depression and affect, respectively. This study reflects the feasibility and acceptance of two exercise programs for pregnant women and their effects on important outcomes. If these programs are followed properly and effectively, pregnant women's health can be improved using these methods at a lower cost compared to the conventional supervised exercise program. [ABSTRACT FROM AUTHOR]

• Mandala coloring is helping reduce pregnancy-related anxiety. • Mandala coloring is a safe, inexpensive methods. • Mandala coloring is accessible alternative treatment option for reducing anxiety. In the literature, the efficacy of mandala coloring on pregnancy-related anxiety has been investigated, and no study has been found on its effect on anxiety. This randomized controlled trial was designed to assess the efficacy of mandala coloring application on pregnancy-related anxiety. The study included 77 primiparous pregnant women: 39 in the control group and 38 in the experimental group, and was carried out in an education-research hospital's obstetric clinic. Data for the study were gathered using Information Form, the Pregnancy-related Anxiety Scale, and the State Anxiety Inventory. While the experimental group did mandala coloring during a month twice in a week, and the control group was not do anything. The "Pregnancy-related Anxiety Scale" and "The State Anxiety Inventor" were used to assess anxiety in all groups before and after application. In the statistical analysis of the data, the SPSS 23.0 package program was used. In all tests, p < 0.005 was considered statistically significant. Immediately post-intervention, the women in the experimental group had a significantly higher reduce pregnancy-related anxiety (p < 0.05). Especially in the mandala group within according to control group were found to have significantly reduced anxiety the application (PrAS-1 82,50 ± 2,47 vs. 84,41 ± 4,12; PrAS-2 77,92 ± 2,16 vs. 83,89 ± 3,80; PrAS-3 72,05 ± 3,97 vs. 84,10 ± 4,35; PrAS-Total 77,49 ± 5,21 vs. 84,13 ± 4,07; STAI-1 52,39 ± 2,50 vs. 51,17 ± 1,16; STAI-2 49,73 ± 0,75 vs. 49,05 ± 1,27; STAI-3 48,84 ± 3,17 vs. 49,02 ± 1,22; STAI-Total 50,32 ± 2,8 vs. 49,75 ± 1,58). Mandala coloring is effective in reducing pregnancy-related anxiety. Clinical trial number: (NCT05534867) [ABSTRACT FROM AUTHOR]

Background: Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment. Methods: Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists. Results: The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023. Discussion: PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development. Trial registration: PROSPERO CRD42023446809. Registered on 08 February 2023. [ABSTRACT FROM AUTHOR]

Abstract Background Acquired brain injury (ABI) is linked to increased depression risk. Existing therapies for depression in ABI (e.g., cognitive behavioural therapy) have mixed efficacy. Behavioural activation (BA), an intervention that encourages engaging in positively reinforcing activities, shows promise. The primary aims were to assess feasibility, acceptability, and potential efficacy of two 8-week BA groups. Methods Adults (≥ 18 years) recruited from local ABI services, charities, and self-referral via social media were randomised to condition. The Activity Planning group (AP; “traditional” BA) trained participants to plan reinforcing activities over 8 weeks. The Activity Engagement group (AE; “experiential” BA) encouraged engagement in positive activities within session only. Both BA groups were compared to an 8-week Waitlist group (WL). The primary outcomes, feasibility and acceptability, were assessed via recruitment, retention, attendance, and qualitative feedback on groups. The secondary outcome, potential efficacy, was assessed via blinded assessments of self-reported activity levels, depression, and anxiety (at pre- and post-intervention and 1 month follow-up) and were compared across trial arms. Data were collected in-person and remotely due to COVID-19. Results N = 60 participants were randomised to AP (randomised n = 22; total n = 29), AE (randomised n = 22; total n = 28), or re-randomised following WL (total n = 16). Whether in-person or remote, AP and AE were rated as similarly enjoyable and helpful. In exploring efficacy, 58.33% of AP members had clinically meaningful activity level improvements, relative to 50% AE and 38.5% WL. Both AP and AE groups had depression reductions relative to WL, but only AP participants demonstrated anxiety reductions relative to AE and WL. AP participants noted benefits of learning strategies to increase activities and learning from other group members. AE participants valued social discussion and choice in selecting in-session activities. Conclusions Both in-person and remote group BA were feasible and acceptable in ABI. Though both traditional and experiential BA may be effective, these may have different mechanisms. Trial registration Clinicaltrials.gov, NCT03874650. Protocol version 2.3, May 26 2020.

This randomised double-blind placebo-controlled trial evaluated the efficacy and safety of fermented gold kiwi (FGK) in improving gastrointestinal health. A total of 100 participants were enrolled and randomly assigned to treatment or placebo groups. Over 8 weeks, the participants consumed an FGK or placebo preparation daily. Primary outcomes included changes in gastrointestinal symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS) and the Korean version of the Nepean Dyspepsia Index (NDI-K), as well as quality of life assessed using the Functional Dyspepsia-related Quality of Life questionnaire. The FGK group showed significant improvements in GSRS and NDI-K total and subdomain scores compared with the placebo group. Moreover, the quality of life scores were significantly better in the FGK group than in the placebo group. Safety evaluations revealed no significant adverse events or clinically meaningful changes upon assessing laboratory test results. This study demonstrated that FGK is a safe and effective dietary supplement for improving gastrointestinal health in adults with gastrointestinal symptoms.

Abstract Background Delphi surveys are commonly used to prioritise critical outcomes in core outcome set (COS) development. This trial aims to compare a three-round (Multi-Round) Delphi (MRD) with a Real-Time Delphi (RTD) in the prioritisation of outcomes for inclusion in a COS for neonatal encephalopathy treatments and explore whether ‘feedback’, ‘iteration’, and ‘initial condition’ effects may occur in the two survey methods. Methods We recruited 269 participants (parents/caregivers, healthcare providers and researchers/academics) of which 222 were randomised to either the MRD or the RTD. We investigated the outcomes prioritised in each survey and the ‘feedback’, ‘iteration’, and ‘initial condition’ effects to identify differences between the two survey methods. Results In the RTD, n = 92 participants (83%) fully completed the survey. In the MRD, n = 60 participants (54%) completed all three rounds. Of the 92 outcomes presented, 26 (28%) were prioritised differently between the RTD and MRD. Significantly fewer participants amended their scores when shown stakeholder responses in the RTD compared to the MRD (‘feedback effect’). The ‘iteration effect’ analysis found most experts appeared satisfied with their initial ratings in the RTD and did not amend their scores following stakeholder response feedback. Where they did amend their scores, ratings were amended substantially, suggesting greater convergence. Variance in scores reduced with subsequent rounds of the MRD (‘iteration effect’). Whilst most participants did not change their initial scores in the RTD, of those that did, later recruits tended to align their final score more closely to the group mean final score than earlier recruits (an ‘initial condition’ effect). Conclusion The feedback effect differed between the two Delphi methods but the magnitude of this difference was small and likely due to the large number of observations rather than because of a meaningfully large difference. It did not appear to be advantageous to require participants to engage in three rounds of a survey due to the low change in scores. Larger drop-out through successive rounds in the MRD, together with a lesser convergence of scores and longer time to completion, indicate considerable benefits of the RTD approach. Trial registration NCT04471103. Registered on 14 July 2020.

Background: Recurrence of non–muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumour (TURBT). Photodynamic diagnosis (PDD) may reduce recurrence. PDD uses a photosensitiser in the bladder that causes the tumour to fluoresce to guide resection. PDD provides better diagnostic accuracy and allows more complete tumour resection. Objective: To estimate the economic efficiency of PDD-guided TURBT (PDD-TURBT) in comparison to white light–guided TURNT (WL-TURBT) in individuals with a suspected first diagnosis of NMIBC at intermediate or high risk of recurrence on the basis of routine visual assessment before being scheduled for TURBT. Design, setting, and participants: This is a health economic evaluation alongside a pragmatic, open-label, parallel-group randomised trial from a societal perspective. A total of 493 participants (aged ≥16 yr) were randomly allocated to PDD-TURBT (n = 244) or WL-TURBT (n = 249) in 22 UK National Health Service hospitals. Outcome measurements and statistical analysis: Cost effectiveness ratios were based on the use of health care resources associated with PDD-TURBT and WL-TURBT and quality-adjusted life years (QALYs) gained within the trial. Uncertainties in key parameters were assessed using sensitivity analyses. Results and limitations: On the basis of the use of resources driven by the trial protocol, the incremental cost effectiveness of PDD-TURBT in comparison to WL-TURBT was not cost saving. At 3 yr, the total cost was £12 881 for PDD-TURBT and £12 005 for WL-TURBT. QALYs at three years were 2.087 for PDD-TURBT and 2.094 for WL-TURBT. The probability that PDD-TURBT is cost effective was never >30% above the range of societal cost-effectiveness thresholds. Conclusions: There was no evidence of a difference in either costs or QALYs over 3-yr follow-up between PDD-TURBT and WL-TURBT in individuals with suspected intermediate- or high-risk NMIBC. PDD-TURBT is not supported for the management of primary intermediate- or high-risk NMIBC. Patient summary: We assessed overall costs for two approaches for removal of bladder tumours in noninvasive cancer and measured quality-adjusted life years gained for each. We found that use of a photosensitiser in the bladder was not more cost effective than use of white light only during tumour removal.

Background: Acquired brain injury (ABI) is linked to increased depression risk. Existing therapies for depression in ABI (e.g., cognitive behavioural therapy) have mixed efficacy. Behavioural activation (BA), an intervention that encourages engaging in positively reinforcing activities, shows promise. The primary aims were to assess feasibility, acceptability, and potential efficacy of two 8-week BA groups. Methods: Adults (≥ 18 years) recruited from local ABI services, charities, and self-referral via social media were randomised to condition. The Activity Planning group (AP; "traditional" BA) trained participants to plan reinforcing activities over 8 weeks. The Activity Engagement group (AE; "experiential" BA) encouraged engagement in positive activities within session only. Both BA groups were compared to an 8-week Waitlist group (WL). The primary outcomes, feasibility and acceptability, were assessed via recruitment, retention, attendance, and qualitative feedback on groups. The secondary outcome, potential efficacy, was assessed via blinded assessments of self-reported activity levels, depression, and anxiety (at pre- and post-intervention and 1 month follow-up) and were compared across trial arms. Data were collected in-person and remotely due to COVID-19. Results: N = 60 participants were randomised to AP (randomised n = 22; total n = 29), AE (randomised n = 22; total n = 28), or re-randomised following WL (total n = 16). Whether in-person or remote, AP and AE were rated as similarly enjoyable and helpful. In exploring efficacy, 58.33% of AP members had clinically meaningful activity level improvements, relative to 50% AE and 38.5% WL. Both AP and AE groups had depression reductions relative to WL, but only AP participants demonstrated anxiety reductions relative to AE and WL. AP participants noted benefits of learning strategies to increase activities and learning from other group members. AE participants valued social discussion and choice in selecting in-session activities. Conclusions: Both in-person and remote group BA were feasible and acceptable in ABI. Though both traditional and experiential BA may be effective, these may have different mechanisms. Trial registration: Clinicaltrials.gov, NCT03874650. Protocol version 2.3, May 26 2020. [ABSTRACT FROM AUTHOR]

Aim: Non‐surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short‐term intensive glucose‐lowering therapy. Methods: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time‐to‐event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. Results: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40‐0.81; p =.002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14‐3.24) and 1.83 (1.03‐3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00‐3.53) at 48 weeks and 2.05 (0.98‐4.29) at 64 weeks. Conclusions: A 12‐week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effectiveness of an intervention combining Integrative Nursing and Omaha System on physical, mental, social, spiritual health of older women living with high level of loneliness. The second aim was to determine the effect of Omaha System interventions on knowledge, behaviour and status scores. Methods: A randomised controlled trial was conducted with 69 older women feeling loneliness (INOSEL n = 36, control n = 33 groups). INOSEL group received group-based and person-centered intervention and control group received routine care. Results: INOSEL and control groups showed an improvement in loneliness score. The decrease in loneliness score and level was higher in the INOSEL group. The physical activity, health status perception, social support, social inclusion, well-being, and spirituality scores increased in the INOSEL group. INOSEL group experienced an increase in the knowledge, behaviour and status. Discussion: INOSEL program, a theoretical structure, reduced loneliness and positively affected women's health. Implications for practice: Health professionals can use this program based on Integrative Nursing and Omaha System in nursing caring. Clinical trial registration: NCT03695133. [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

Aims and Objectives: The aim of the study was to investigate the effect of supporting family members to partner with health professionals on nutrition intakes and decision‐making and to evaluate intervention and study feasibility. Background: Family partnerships can improve outcomes for critically ill patients and family members. Interventions that support families to engage with health professionals require evaluation. Design: A multi‐centre, randomised, parallel group superiority Phase II randomised controlled trial. Methods: In nine intensive care units (ICUs) across three countries, critically ill patients ≥60 years, or those 55–59 years with advanced chronic diseases and expected ICU length of stay >72 h and their family member were enrolled between 9 May 2017 and 31 March 2020. Participants were randomised (1:1:1) to either a decision support or nutrition optimisation family‐centred intervention, or usual care. Primary outcomes included protein and energy intake during ICU and hospital stay (nutrition intervention) and family satisfaction (decision support). Study feasibility was assessed as a composite of consent rate, intervention adherence, contamination and physician awareness of intervention assignment. Results: We randomised 135 patients/family members (consent rate 51.7%). The average rate of randomisation was 0.5 (0.13–1.53) per month. Unavailability (staff/family) was the major contributor to families not being approached for consent. Declined consent was attributed to families feeling overwhelmed (58/126, 46%). Pandemic visitor restrictions contributed to early study cessation. Intervention adherence for the decision support intervention was 76.9%–100.0% and for the nutrition intervention was 44.8%–100.0%. Nutritional adequacy, decisional conflict, satisfaction with decision‐making and overall family satisfaction with ICU were similar for all groups. Conclusions: Active partnerships between family members and health professionals are important but can be challenging to achieve in critical care contexts. We were unable to demonstrate the efficacy of either intervention. Feasibility outcomes suggest further refinement of interventions and study protocol may be warranted. Relevance to Clinical Practice: Interventions to promote family partnerships in critical illness are needed but require a greater understanding of the extent to which families want and are able to engage and the activities in which they have most impact. Reporting Method: This study has been reported following the Consolidated Standards of Reporting Trials (CONSORT) and the Template for Intervention Description and Replication (TIDieR) guidelines. Patient or Public Contribution: Patients and caregivers were engaged in and contributed to the development and subsequent iterations of the two family‐centred interventions use in this study. Clinical Trial Registration Number: Trial registration. Clinicaltrials.gov, ID: NCT02920086. Registered on 30 September 2016. First patient enrolled on 9 May 2017 https://clinicaltrials.gov/ct2/results?cond=&term=NCT02920086&cntry=&state=&city=&dist=. [ABSTRACT FROM AUTHOR]

Abstract Background Proximal humerus fractures (PHF) are common and painful injuries, with the majority resulting from falls from a standing height. As with other fragility fractures, its age-specific incidence is increasing. Surgical treatment with hemiarthroplasty (HA) and reverse shoulder arthroplasty (RSA) have been increasingly used for displaced 3- and 4-part fractures despite a lack of good quality evidence as to whether one type of arthroplasty is superior to the other, and whether surgery is better than non-surgical management. The PROFHER-2 trial has been designed as a pragmatic, multicentre randomised trial to compare the clinical and cost-effectiveness of RSA vs HA vs Non-Surgical (NS) treatment in patients with 3- and 4-part PHF. Methods Adults over 65 years of age presenting with acute radiographically confirmed 3- or 4-part fractures, with or without associated glenohumeral joint dislocation, who consent for trial participation will be recruited from around 40 National Health Service (NHS) Hospitals in the UK. Patients with polytrauma, open fractures, presence of axillary nerve palsy, pathological (other than osteoporotic) fractures, and those who are unable to adhere to trial procedures will be excluded. We will aim to recruit 380 participants (152 RSA, 152 HA, 76 NS) using 2:2:1 (HA:RSA:NS) randomisation for 3- or 4-part fractures without joint dislocation, and 1:1 (HA:RSA) randomisation for 3- or 4-part fracture dislocations. The primary outcome is the Oxford Shoulder Score at 24 months. Secondary outcomes include quality of life (EQ-5D-5L), pain, range of shoulder motion, fracture healing and implant position on X-rays, further procedures, and complications. Independent Trial Steering Committee and Data Monitoring Committee will oversee the trial conduct, including the reporting of adverse events and harms. Discussion The PROFHER-2 trial is designed to provide a robust answer to guide the treatment of patients aged 65 years or over who sustain 3- and 4-part proximal humeral fractures. The pragmatic design and recruitment from around 40 UK NHS hospitals will ensure immediate applicability and generalisability of the trial findings. The full trial results will be made available in a relevant open-access peer-reviewed journal. Trial registration ISRCTN76296703. Prospectively registered on 5th April 2018

Abstract Background As highly effective therapy against hepatitis C virus (HCV) infection is available with rapid uptake, there is newfound optimism for HCV elimination. Nevertheless, certain key populations have a high risk of HCV reinfection, in particular men who have sex with men (MSM) in Western European countries. Modelling data indicate that HCV elimination will not be feasible without reduction in risk behaviour, thus supporting the need for effective interventions aimed at reducing risk behaviour and preventing reinfections in MSM. Methods The ICECREAM study is an international, multi-centred, phase 2, 3-arm randomised trial comparing run-in and intervention periods enrolling MSM with a history of a cured or spontaneously cleared HCV infection. Individuals are followed in routine care for 6 months (i.e. run-in period) and then randomly allocated (1:1:1) to one of the following: a tailored, interactive online risk-reduction behavioural intervention, a validated home-based HCV-RNA self-sampling test service using dried blood spots, or a combination of both. After randomisation, individuals are followed every 6 months until 18 months (i.e. intervention period). Interventions are delivered in addition to standard of care. Online questionnaire measuring risk behaviour over the past 6 months is administered at every visit. The primary outcome is the proportion at risk of HCV infection during run-in versus intervention periods assessed by using the HCV-MOSAIC risk score. The risk score consists of six self-reported HCV-related risk behaviours. Secondary outcomes include incidence of HCV reinfection, changes in the individual risk behaviour items and changes in sexual well-being since changes in sexual behaviour may have an impact on sexual experience. Two hundred forty-six MSM aged 18 years or older will be invited to participate. Discussion The ICECREAM study is a trial aimed at establishing interventions that could effectively decrease the incidence of HCV re-infection in MSM with a previous HCV infection. By offering an online behavioural risk-reduction intervention and HCV-RNA self-sampling, both of which are aimed to influence risk behaviour, we are able to provide products to at-risk MSM that could further reduce population-level HCV incidence and ultimately help reach HCV micro-elimination. Trial registration ClinicalTrials.gov NCT04156945. Registered on November 8, 2019

IntroductionKaplan-Meier survival analysis, the cornerstone of evaluating efficacy of oncology drugs in randomised controlled trials (RCTs), assumes censored patients are neither healthier nor sicker than those followed. We sought to examine whether censoring patterns differ between the control and experimental arms in one oncology journal that mandates the reporting of the number of patients censored.MethodsIn this retrospective review, proportion of censoring and study design data were gathered from RCTs published in The Lancet Oncology that reported Kaplan-Meier curves between May 2018 and August 2019. Differential censoring rates were analysed at the 1st, 3rd, 6th, and overall time points in each study. Analysis was stratified by curves reporting progression-free survival (PFS) or overall survival (OS) end-points.ResultsOf the 160 articles reviewed, 29 studies with 51 Kaplan-Meier curves were eligible. In both OS (N = 25) and PFS curves (N = 26), the absolute weighted difference in censoring between the control and experimental arms was initially positive, indicating more censoring in the control arm (first time point OS: 0.32%; PFS: 2.00%). The absolute difference then became negative, indicating more censoring in the experimental arm as time progressed (end-of-study OS: -7.54%; PFS: -9.09%).ConclusionDifferences in censoring between control and experimental arms of cancer RCTs suggest that there could be systematic bias present at various study time points that may influence key results. Further investigation is needed, as possible reasons include study assignment disappointment, inappropriate follow-up length, lack of efficacy, or intolerable toxicity, each predominant at specific time points after randomisation.

Background Despite methodological improvements in clinical trial design and conduct more generally, methodological limitations persist in trials concerning mental health care. A qualitative Study Within A Trial (Qual-SWAT), embedded in the KARMA-Dep-2 host trial, will be undertaken to explore and gain an understanding of two methodological questions in randomised trials specific to mental health care: (1) what are the key barriers and enablers of participation in randomised trials in mental health; and (2) how can randomised trials become part of routine mental health care. These issues will be examined from patient-participant and clinician- / researcher-participant perspectives, in alignment with PRioRiTy research themes. Methods A descriptive qualitative study design will be used. Data will be collected via one-to-one semi-structured interviews, conducted via Microsoft Teams. The interview data will be analysed using Braun and Clarke’s Thematic Analysis approach. One-to-one interviews will be conducted with three participant groups (N = 30): 1) host trial patient-participants (n = 10); 2) potentially eligible host trial patient-participants who refused enrolment in the host trial (n = 10); and 3) clinician- / researcher-participants who are associated with work on the host trial (n = 10). Ethics and dissemination Ethical approval has been granted by St. Patrick’s Mental Health Services Research Ethics Committee, Ireland (Ref: Protocol 09/20). When the study is completed, a report will be prepared and submitted to the Health Research Board (HRB). Findings will be shared with the host trial team and study participants, and submitted for publication. Host trial registration ClinicalTrials.gov (NCT04939649); EudraCT (2019-003109-92). Official title: Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)].

Background Modern psychometric methods make it possible to eliminate nonperforming items and reduce measurement error. Application of these methods to existing outcome measures can reduce variability in scores, and may increase treatment effect sizes in depression treatment trials. Aims We aim to determine whether using confirmatory factor analysis techniques can provide better estimates of the true effects of treatments, by conducting secondary analyses of individual patient data from randomised trials of antidepressant therapies. Method We will access individual patient data from antidepressant treatment trials through Clinicalstudydatarequest.com and Vivli.org, specifically targeting studies that used the Hamilton Rating Scale for Depression (HRSD) as the outcome measure. Exploratory and confirmatory factor analytic approaches will be used to determine pre-treatment (baseline) and post-treatment models of depression, in terms of the number of factors and weighted scores of each item. Differences in the derived factor scores between baseline and outcome measurements will yield an effect size for factor-informed depression change. The difference between the factor-informed effect size and each original trial effect size, calculated with total HRSD-17 scores, will be determined, and the differences modelled with meta-analytic approaches. Risk differences for proportions of patients who achieved remission will also be evaluated. Furthermore, measurement invariance methods will be used to assess potential gender differences. Conclusions Our approach will determine whether adopting advanced psychometric analyses can improve precision and better estimate effect sizes in antidepressant treatment trials. The proposed methods could have implications for future trials and other types of studies that use patient-reported outcome measures.

Objective: During cardiac arrest, current guidelines recommend attempting intravenous access first and to consider intraosseous access if intravenous access is unsuccessful or impossible. However, these recommendations are only based on very low-certainty evidence. Therefore, the “Intravenous vs Intraosseous Vascular Access During Out-of-Hospital Cardiac Arrest“ (IVIO) trial aims to determine whether there is a difference in patient outcomes depending on the type of vascular access attempted during out-of-hospital cardiac arrest. This current article describes the clinical IVIO trial. Methods: The IVIO trial is an investigator-initiated, randomised trial of intravenous vs. intraosseous vascular access during adult non-traumatic out-of-hospital cardiac arrest in Denmark. The intervention will consist of minimum two attempts (if unsuccessful on the first attempt) to successfully establish intravenous or intraosseous vascular access during cardiac arrest. The intraosseous group will be further randomised to the humeral or tibial site. The primary outcome is sustained return of spontaneous circulation and key secondary outcomes include survival and survival with a favourable neurological outcome at 30 days. A total of 1,470 patients will be included. Results: The trial started in March 2022 and the last patient is anticipated to be included in the spring of 2024. The primary results will be reported after 90-day follow-up and are anticipated in mid-2024. Conclusion: The current article describes the design of the Danish IVIO trial. The findings of this trial will help inform future guidelines for selecting the optimal vascular access route during out-of-hospital cardiac arrest.