Control Arm Research Articles

Interaction of base excision repair gene polymorphism and estrogen-DNA adducts in breast cancer risk among East Asian women.

In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.

A self-help mobile messaging intervention to improve subthreshold depressive symptoms among older adults in a socioeconomically deprived region of Brazil (PRODIGITAL): a pragmatic, two-arm randomised controlled trial

Subthreshold depression is a risk factor for major depression and is associated with increased morbidity and mortality, especially in older adults. There is emerging evidence that digital interventions, including self-help interventions, may reduce depressive symptoms. We aimed to evaluate the effectiveness of a mobile messaging intervention at reducing subthreshold depressive symptoms among older adults in Brazil. PRODIGITAL was a single blind, two-arm, individually randomised controlled trial conducted in 46 primary care clinics in the city of Guarulhos, Brazil. Individuals aged 60+ years were contacted by phone following a randomly ordered list for a screening assessment. Those who presented with anhedonia and/or depressed mood (Patient Health Questionnaire (PHQ)-2≥1), and who subsequently scored between 5 and 9 on the PHQ-9 were invited to participate. The intervention arm received the 'Viva Vida' digital self-help intervention consisting of automated multi-media messages sent via WhatsApp. Forty-eight audio and visual messages based on psychoeducation and behavioural activation were automatically delivered over six weeks. The control arm received a single message containing information about depression. The primary outcome was the difference in mean PHQ-9 scores between treatment arms at the three-month follow-up. All primary analyses were performed according to allocated arm with imputed data. The trial is registered with ReBEC, RBR-6c7ghfd. Participants were recruited between 8 September 2021 and 19 August 2022. Of the 454 participants enrolled, 223 were randomised to the intervention arm, 231 to the control arm. Participants' mean age was 65.3 years (SD 5.0) and 64.0% (n=292) were female. A total of 385 (84.8%) completed the three-month follow-up assessment; no difference in mean PHQ-9 scores between the treatment arms was observed (adjusted difference:-0.61; 95% CI:-1.75, 0.53; p=0.29). These results demonstrate that the Viva Vida digital self-help intervention did not help to improve subthreshold depressive symptoms amongst older adults. Further research is needed to understand why this self-help intervention was not effective in this population, and to explore how it might be adapted to achieve this goal. São Paulo Research Foundation and UK Joint Global Health Trials.

Fastidious adherence to 0/1-hour high-sensitivity troponin T testing reduces emergency department length of stay in patients presenting with suspected acute coronary syndromes

Abstract Background High-sensitivity cardiac troponins (hs-cTn) are key clinical biomarkers in patients presenting with suspected acute coronary syndromes (ACS) to Emergency Departments (EDs). They have facilitated rapid 0h/1h troponin testing protocols, leading to safe, effective, and efficient triage of patients. However, early distinction of myocardial infarction (MI), which has a reported frequency of less than 10% in most cohorts, from the apparently stable hs-cTn elevations of chronic myocardial injury (CMI) remains a challenge. Often CMI patients require confirmation by further testing and observation, prolonging patient length of stay. Further, reliably obtaining serial hs-cTn samples at 60-minutes in a busy ED setting may be difficult. A potential explanation for only 5-6% of Australian sites adopting 0h/1h hs-cTn testing. Methods and Results We undertook a case-control study between March and August 2023 among patients with suspected ACS presenting to Liverpool Hospital ED (Sydney, Australia). 185 patients (cases) underwent hs-cTnT sampling at 30- and 60-minutes (± 5 minutes) after baseline. Diagnosis of MI was made in 8.6%, 35.7% were placed into a further observation group and MI ruled-out in 55.7%. The latter two groups were matched to 169 patients (controls) who received ‘usual’ care, which was a 0h/1h hs-cTnT testing protocol. The case and control arms were matched by age, gender, time from symptom onset and main presenting symptom. Control patients had a median sampling interval of 118 [85 to 174] minutes, rather 60 minutes as the protocol directs. When comparing the paired differences between the case and control arms, there was a mean reduction in length of stay of 104 (95% CI: 41 to 186, P = 0.01) and 47 (95% CI: 11 to 84, P = 0.01) minutes, for the observation and rule-out MI groups respectively. The figure shows the distribution of lengths of stay by group. Among the rule-out group, Wilcoxon signed rank test indicated the control arm had a longer median length of stay of 6.3 [5.1 to 8.4] hours, compared to 5.0 [4.5 to 7.1] hours in the case arm (P=0.005). Similarly, in the further observation group, control patients also had a longer median length of stay of 9.2 [6.9 to 10.4] hours compared to case patients of 8.1 [5.1 to 10.3] hours (P = 0.009). At 30-days, ED representation rates were 10.7% in controls and 8.3% in cases, rehospitalisation 3.6% in controls and 5.3% in cases, cardiac death 0% in both arms and non-cardiac death 1% in both arms. There were no differences in event rates between each arm (P > 0.05). Conclusion Accurate 0h/1h hs-cTnT testing reduces patient length of stay in ED and offers more personalised prediction of MI risk. The importance of adherence to protocol-directed sampling times is clear, where further studies are required regarding routine implementation in a busy ED setting.Exact 60 min TnT and LOSOutcomes at 30 days

Implementation of digital patient decision support tools for Atrial Fibrillation treatment: systematic review

Abstract Background/ Introduction Treating atrial fibrillation (AF) involves complex decisions. Digital patient decision-support tools can facilitate shared decision making by significantly reducing decisional conflict and improving patient knowledge [1,2]. Yet, implementation in clinical practice is lagging [3]. Purpose To systematically review trials of digital patient decision-support tools for AF treatment decisions, focusing on factors influencing their implementation in clinical practice. Methods We conducted a systematic review following Cochrane methods. EMBASE, MEDLINE and Scopus were searched from 2005 to 2023. Eligible randomised controlled trials and quasi-experimental trials that evaluated digital patient decision-support tools for AF treatment decisions were included. Two independent reviewers screened title and abstract, extracted data and assessed risk of bias. The implementation outcomes included a description of when and how the tool was used, as well as its characteristics and user satisfaction. Results Thirteen articles reporting on eleven studies (5 RCTs and 6 quasi-experimental trials) met the inclusion criteria (2,714 participants; mean age 71±4.2 years; 26% women; 92% with non-valvular AF, remaining not reported). Risk of bias was low for 2 studies, moderate for one and high for seven studies. All tools (n=11) focused on anticoagulation choice (1: warfarin vs no warfarin; 1: aspirin vs warfarin; 7: Direct Oral Anticoagulants (DOAC) vs antiplatelet or warfarin; 2: unspecified choice). The tools were used either pre-visit (at home or in the waiting room) or during the consultation (n=5). Tools were delivered using a mobile application (n=4), web-based application (n=5), or a desktop (n=2). Of the eleven tools, 2 could automatically calculate individualized stroke risk using data from electronic health records. Most articles reported favourable user feedback regarding use of the digital patient decision-support tools, such as high perceived usefulness, user-friendliness, and overall satisfaction. No significant difference was found in encounter times between intervention and control arms (2 RCTs). Four tools were publicly available and 3 were implemented in healthcare delivery beyond research. Conclusion Despite demonstrated efficacy in reducing decisional conflict and improving patient knowledge, as well as positive clinician and patient experience, only 3 tools were implemented in clinical practice beyond their trial. Future tools could better leverage digital capabilities to integrate with Electronic Health Records, automate stroke and bleeding risk calculations, and personalise content based on patient values and preferences. Additional robust trials and implementation studies are warranted to understand barriers and enablers to the use of these tools.

Community Paramedicine Program in Social Housing and Health Service Utilization: A Cluster Randomized Clinical Trial.

Community Paramedicine at Clinic (CP@clinic) is a chronic disease prevention program that decreases 911 calls for emergency medical services, but its wider system effects are unknown. To evaluate the effects of CP@clinic vs usual care on individual-level health service utilization outcomes. This open-label, pragmatic cluster randomized clinical trial evaluated all residents 55 years or older in 30 social housing buildings in Ontario, Canada, that had (1) a unique postal code, (2) at least 50 apartments, (3) 60% or more residents 55 years or older, and (4) a similar building for pairing (15 intervention and 15 control buildings, pair-matched randomization). The 12-month intervention had a staggered start date from January 1, 2015, to December 1, 2015, and ended between December 31, 2015, and November 30, 2016. Administrative health data analysis was conducted in May 2022. CP@clinic was a health promotion and disease prevention program led by specially trained community paramedics who held weekly drop-in sessions in social housing buildings. These paramedics conducted 1-on-1 risk assessments, provided health education and referrals to relevant community resources, and, with consent, sent assessments to family physicians. Control buildings received usual care (universal health care, including free primary and specialty medical care). Individual-level health service utilization was measured from administrative health data, with ED visits via ambulance as the primary outcome; secondary outcomes included ED visits for any reason, primary care visits, hospitalizations, length of hospital stay, laboratory tests, receipt of home care, transfer to long-term care, and medication initiation. Generalized estimating equations were used to estimate intervention effects on individual-level health service utilization, accounting for trial design and individual-level baselines. The 30 social housing buildings had 3695 residents (1846 control and 1849 intervention participants; mean [SD] age, 72.8 [9.1] years; 2400 [65.0%] female). Intention-to-treat analysis found no significant difference in ED visits by ambulance (445 of 1849 [24.1%] vs 463 of 1846 [25.1%]; adjusted odds ratio [AOR], 0.97; 95% CI, 0.89-1.05) but found higher antihypertensive medication initiation (74 of 500 [14.8%] vs 47 of 552 [8.5%]; AOR, 1.74; 95% CI, 1.19-2.53) and lower anticoagulant initiation (48 of 1481 [3.2%] vs 69 of 1442 [4.8%]; AOR, 0.68; 95% CI, 0.53-0.86) in the intervention arm vs the control arm. CP@clinic attendance was associated with higher incidence of primary care visits (adjusted incidence rate ratio, 1.10; 95% CI, 1.03-1.17), higher odds of receiving home care (AOR, 1.07; 95% CI, 1.01-1.13), and lower odds of long-term care transfers (AOR, 0.32; 95% CI, 0.13-0.81). In this cluster randomized clinical trial of CP@clinic, the intervention did not affect the rate of ED visits by ambulance; however, there were increased primary care visits and connections to home care services, which may have increased antihypertensive medication initiation and reduced long-term care transfers from social housing. Health policymakers should consider CP@clinic's impact as an upstream approach to improve care for older adults with low income. ClinicalTrials.gov Identifier: NCT02152891.

Leveraging real-world data to conduct externally controlled trial for rare diseases with count-type endpoints: utilizing multiple entries – a simulation study

ABSTRACT Conducting randomized controlled trials for medications targeting rare diseases presents significant challenges, due to the scarcity of participants and ethical considerations. Under such circumstances, leveraging real-world data (RWD) to generate supporting evidence may be accepted by the regulatory agency. Constructing an external control arm (ECA) from RWD for a single-arm trial has been conducted occasionally. A complication in this design is that patients from RWD may be eligible at multiple time points. Most studies approach this by selecting one time point as the index date for ECA patients. Here, we propose a novel design for externally controlled trials that permits the inclusion of ECA patients at various entry points. Accompanying this design, we make recommendations for statistical methods to account for measured confounders, limited sample size, within-subject correlation, and potential overdispersion inherent in count data. Furthermore, we present an idea for the blinding process for this type of study. We have conducted a series of simulations to assess the performance of the design and statistical methods in terms of bias, type I error, and efficiency, as compared to the approach of selecting only one entry per ECA patient. The study and parameter setup were based on a hypothetical case inspired by a rare disease study. The results indicate that allowing multiple entries for ECA patients can lead to enhanced performance in many aspects. It provides a controlled type I error, robustness against certain model misspecifications, and a moderate power improvement compared with selecting a single entry per ECA patient.

Effect of primary pci in asymptomatic stemi patients presenting 12 to 48 hours of symptom onset, on myocardial viability assessed by spect tc 99m sestamibi scan epitome99

Abstract Background Guidelines on revascularization of asymptomatic stable STEMI patients presenting 12-48 hours of symptom onset are limited. We utilized TC-99mSestaMIBI scan to study the impact of primary PCI on myocardial viability by deriving myocardial salvage index (MSI) from area at risk (AAR), prior to revascularization and final infarct size (FIS) at follow up, in asymptomatic stable STEMI patients presenting between 12-48 hours of symptom onset to PCI. Purpose Evidence contributing lack of symptoms to a non-viable myocardium is lacking and it would be unethical to randomize patients with myocardial infarction (< 48 hours old) to a control arm or a non-intervention arm without evaluating the possibility of salvageable myocardium. Our study aims to inculcate evidence based management of late presenting stable asymptomatic STEMI patients. Methods We enrolled 141 patients presenting with STEMI (12-48 hours), from January 2021 to December 2023, who then underwent TC-99mSestaMIBI scan, followed by revascularization of IRA with 138 patients completing the designed study with follow-up scan at 3 months. Subjects were subcategorised into cohort A(12-24 hrs.), B(25-36 hrs.), and C(37-48 hrs.) according to the duration of symptom onset. Results A substantial MSI of > 0.50 was achieved by 36 %, 8% and 5 % of patients from cohort A, cohort B, and cohort C respectively. Although the AAR was comparable throughout cohorts, on post HOC analysis a statistically significant reduction in the final infarct size was seen among patients in cohort A vs C [Q = 4.72 (p = .00309)], while a reduction of FIS in cohort B and cohort C were obvious but statistically insignificant. Myocardial salvage index was smaller in late presenters, with no statistically significant difference among cohort B & cohort C [Q = 0.96 (p = .77697)]. Delaying the timing of Primary PCI from symptom onset was associated with larger AAR (R= - 0.01) & FIS (R= 0.35) although with a lower correlation coefficient. While evaluating MSI against timing of Primary PCI, a moderately negative (R= - 0.41) relation exists, indicating a linear correlation to reduced myocardial salvage Index with delay in the timing of primary PCI to symptom onset. Conclusion Asymptomatic stable STEMI patients presenting 12-24 hours of symptom onset to PCI, benefited from primary PCI with lesser final infarct size and larger MSI. Despite a comparable AAR across cohorts, MSI fell sharply among patients undergoing primary PCI 24-48 hours of symptom onset with a larger final infarct size, warranting viability guided revascularization. Although primary PCI improved final LVEF and MSI in patients with ischemic heart failure, parameter gain alone was insufficient in endeavoring a positive clinical impact.

Cost-effectiveness of semaglutide for secondary prevention of cardiovascular disease in the United States

Abstract Background In the SELECT trial, semaglutide produced a 20% reduction in the composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke in individuals with overweight or obesity who did not have diabetes but had established pre-existing cardiovascular disease (CVD). Cost is an important barrier to widespread uptake of semaglutide, particularly in the US, and the cost-effectiveness for the secondary prevention of CVD is uncertain. Purpose To evaluate the cost-effectiveness of semaglutide vs. no obesity treatment for the secondary prevention of CVD from a US healthcare sector perspective. Methods The CVD Policy Model is an established, validated simulation model of fatal and non-fatal CVD outcomes and costs in the US population. Using data from the National Health and Nutrition Examination Survey, we created a nationally representative cohort of SELECT-eligible individuals (age ≥45, BMI ≥27kg/m2, no diabetes, pre-existing CVD). Healthcare costs associated with acute and chronic CVD were estimated from national survey and claims data and inflated to 2023 US dollars. The simulated control arm received usual care; the intervention arm received weekly semaglutide 2.4mg injections (assuming 8% discontinuation, which occurs year one). We reproduced the effectiveness of semaglutide based on results of the SELECT trial primary cardiovascular composite endpoint (non-fatal MI, non-fatal strokes and CVD death). The base case assumed 7% of patients receiving semaglutide developed injection-site reactions. Monthly cost of semaglutide was assumed to be $717 (US price net of rebates and discounts), but this was varied in sensitivity analyses. The analysis adopted a health system perspective over lifetime horizon. Results Approximately 4.7 million US adults would meet SELECT trial eligibility criteria. Over a lifetime horizon, semaglutide is projected to avert 538,000 major adverse cardiovascular events (241,000 nonfatal MIs; 80,000 nonfatal stokes, and 217,000 cardiovascular deaths) at an incremental cost of $613 billion. The incremental cost effectiveness ratio for semaglutide was $443,000 per quality-adjusted life year (QALY) gained. In order to meet cost-effectiveness thresholds of $50,000/QALY, $100,000/QALY, $150,000/QALY, drug costs would have to decline 90%, 79%, and 69% respectively. In sensitivity analyses, lowering drug cost to the current UK price (~ $220 per patient per month) would improve the incremental cost-effectiveness of semaglutide to <$150,000 per QALY gained, a potential upper threshold for cost-effectiveness in the US. Conclusion Widespread uptake of semaglutide in the SELECT-eligible U.S. population would prevent a large number of cardiovascular events, but its use would be low economic value at current US prices. Lowering prices in line with those in Europe (e.g., monthly price from $717 to $223) would make the therapy cost-effective at a threshold of $150,000 per QALY gained.

The change of paradigm: high HDL-c levels could not mean a long lifespan

Abstract Background It is known that a low HDL-c level is associated with a high risk of overall mortality. Consequently, it was presumed that achieving higher levels of high-density lipoprotein cholesterol (HDL-c) would reduce the risk or even extend the lifespan. However, clinical trials with medical intervention failed to find clinical benefits. Aim We aimed to investigate the association between (HDL-c) levels and overall mortality using a prospective cohort from Portugal. Methods A prospective sub-study (2001-2022) was performed in a cohort of 1718 participants without coronary artery disease (CAD) of the control arm of the ongoing GENEMACOR study. The participants <65 years were followed during a mean follow-up of 7.0±5.7 years. All demographic, biochemical, and clinical data were collected. Participants were stratified into six levels of HDL-c. Kaplan-Meier estimated differences in the survival probability of each HDL-c level. Cox proportional analysis models (unadjusted and adjusted) were used to assess the association between HDL-c levels and overall mortality. Results The HDL-c levels with the lowest overall mortality rate were 60 to 70 mg/dl, set as the reference level. Total HDL-c strata were associated with overall mortality with a U-shaped relationship: in the control group, the first level (<40 mg/dl) was independently associated with increased risk of overall mortality (HR of 3.533; 95% CI: 1.738-7.178; p<0.0001). This risk drops and falls to the reference level (the lower risk) and rises again to an HR of 3.875 (95% CI: 1.472-10.201; p=0.006) in the very high HDL-c levels (≥80 mg/dl). Conclusions Our results, based on a large Portuguese cohort, suggest that very high HDL-c levels in the normal population may not represent a good prognosis, especially in women. Future research may confirm these findings and investigate the underlying mechanisms.

Initial experience with a 5G cellular network and robotic arm-based remote echocardiographic system in an all-comers setting

Abstract Background Echocardiography is the test-of-choice for the initial evaluation of many cardiac diseases and requires expertise that is often limited in rural area. Robotic arm-assisted remote echocardigram has been attampted for teleconsultation but was limited to heart failure patients(ref), primarily due to the network delay in telecommunication and the subsequent incoordination in robotic arm control. Purpose We aim to assess the feasibility and diagnostic accuracy of a 5G cellular network and robotic arm-based remote echocardiographic system in an all-comers setting. Methods 51 pts were enrolled from the outpatient cardiology clinic of our institute. All pts underwent standard comprehensive echocardiography on a 5G cellular network and robotic arm-based remote echocardiographic system (the robotic part was deployed at our hospital and the control part was located at another campus 20 kilometers away) (Figure 1)and a conventional echocardiographic platform (at our hospital) successively. The order in which patients were examined on the remote and conventional instruments was randomly determined. There was no interval between the two examinations, and examinations of the same patient were performed by experienced but different cardiologists, who were blinded to each other’s diagnosis. The doctor who used the remote system was also randomly allocated and had not been previously specifically trained. The exams were real-time and diagnoses were made right after the exams. Results Of the 51 pts, the image quality was sufficient for diagnosis in 50 patients (48% female, 40±18 years). 1 pt was excluded because some key views could not be obtained using the remote system (98% of exams successful). 17 pts had positive findings, including 10 with a primary diagnosis of valvulopathy (1 Barlow's syndrome, 1 bicuspid aortic valve and 8 less-than-moderate regurgitation), 2 cardiac surgery follow-ups (1 case of aortic valve replacement and septal myectomy, and 1 case of mitral valve replacement and tricuspid annuloplasty), and 2 hypertrophic cardiomyopathy (including 1 case of obstruction at papillary muscle level), 2 with abnormal left ventricular wall motion(including 1 case of apical mural thrombus) (Figure 2), and 1 with congenital heart disease (secumdum atrial septal defect). The main diagnosis was consistent in 98% of cases (papillary muscle level obstruction was missed in one case), using conventional echocardiographic findings as the standard. Time for image acquision using remote echocardiography was significantly longer than conventional one (24 minutes 36 seconds ± 4 minutes 52 seconds vs. 16 minutes 15 seconds ± 1 minute 54 seconds, p<0.0001, paired t-test). Conclusions Comprehensive echocardiographic exam with a 5G cellular network and robotic arm-based remote system is feasible with relatively good diagnostic accuracy.Figure 1Figure 2

Cost-utility analysis of adapted problem adaptation therapy for depression in mild-to-moderate dementia caused by Alzheimer's disease: PATHFINDER randomised controlled trial.

Depression is common in people with dementia, and negatively affects quality of life. This paper aims to evaluate the cost-effectiveness of an intervention for depression in mild and moderate dementia caused by Alzheimer's disease over 12 months (PATHFINDER trial), from both the health and social care and societal perspectives. A total of 336 participants were randomised to receive the adapted PATH intervention in addition to treatment as usual (TAU) (n = 168) or TAU alone (n = 168). Health and social care resource use were collected with the Client Service Receipt Inventory and health-related quality-of-life data with the EQ-5D-5L instrument at baseline and 3-, 6- and 12-month follow-up points. Principal analysis comprised quality-adjusted life-years (QALYs) calculated from the participant responses to the EQ-5D-5L instrument. The mean cost of the adapted PATH intervention was estimated at £1141 per PATHFINDER participant. From a health and social care perspective, the mean difference in costs between the adapted PATH and control arm at 12 months was -£74 (95% CI -£1942 to £1793), and from the societal perspective was -£671 (95% CI -£9144 to £7801). The mean difference in QALYs was 0.027 (95% CI -0.004 to 0.059). At £20 000 per QALY gained threshold, there were 74 and 68% probabilities of adapted PATH being cost-effective from the health and social care and societal perspective, respectively. The addition of the adapted PATH intervention to TAU for people with dementia and depression generated cost savings alongside a higher quality of life compared with TAU alone; however, the improvements in costs and QALYs were not statistically significant.

Effects of an online program about intimate and romantic relationships for people with mental disorders (AIRIKI): a study protocol for a randomized controlled trial

BackgroundThe concept of recovery has become internationally widespread. To promote personal recovery of individuals with mental disorders, it is important that they live life on their own terms. Many people with mental disorders wish to build intimate relationships and marry. However, people with mental disorders face obstacles in building such relationships and communicating with their partners. The program AIRIKI, which means “power to love,” was developed to help people with mental disorders gain confidence in building intimate relationships. The AIRIKI pilot study with one-group pre post test showed positive effects on self-esteem, hope, and communication. Therefore, the purpose of the proposed randomized controlled trial (RCT) is to determine the effects of the videoconferencing program on self-esteem, hope, and self-confidence in communication among un-married people with mental disorders.MethodsThe proposed randomized controlled trial has two arms (intervention group and control group). After baseline questionnaire assessment, participants will be allocated randomly. Within two months of allocation, the intervention group will participate in videoconferences about intimate relationships and marriage with 2–5 participants and 3 facilitators, which will last 3 h, for two days. Three facilitators will support participants in each session. The intervention group will complete a questionnaire for outcome assessment at termination and one month after the program. The control group will complete the outcome questionnaire at one month after baseline and two months after baseline. The questionnaire will include the Rosenberg Self-Esteem Scale (RSES), Herth Hope Index (HHI), and Self-confidence in Communication Scale (SCS). Control group members can participate in a videoconference program, which will be held separately from the intervention group, after completing their outcome assessments.DiscussionThis trial is the first randomized controlled trial of which we are aware to test the effects of an online program for un-married people with mental disorders to consider and discuss their romantic relationship and marriage. The results will provide information on the effectiveness of an online program for people with mental disorders to imagine their romantic relationships and marriages.Trial registrationThis trial has been registered with the UNIN Clinical Trials Registry (UMIN000052027; 2023/08/28).

Patient trust in the use of machine learning-based clinical decision support systems in psychiatric services: A randomized survey experiment.

Clinical decision support systems (CDSS) based on machine-learning (ML) models are emerging within psychiatry. If patients do not trust this technology, its implementation may disrupt the patient-clinician relationship. Therefore, the aim was to examine whether receiving basic information about ML-based CDSS increased trust in them. We conducted an online randomized survey experiment in the Psychiatric Services of the Central Denmark Region. The participating patients were randomized into one of three arms: Intervention=information on clinical decision-making supported by an ML model; Active control=information on a standard clinical decision process, and Blank control=no information. The participants were unaware of the experiment. Subsequently, participants were asked about different aspects of trust and distrust regarding ML-based CDSS. The effect of the intervention was assessed by comparing scores of trust and distrust between the allocation arms. Out of 5800 invitees, 992 completed the survey experiment. The intervention increased trust in ML-based CDSS when compared to the active control (mean increase in trust: 5% [95% CI: 1%; 9%], p=0.0096) and the blank control arm (mean increase in trust: 4% [1%; 8%], p=0.015). Similarly, the intervention reduced distrust in ML-based CDSS when compared to the active control (mean decrease in distrust: -3%[-1%; -5%], p=0.021) and the blank control arm (mean decrease in distrust: -4% [-1%; -8%], p=0.022).No statistically significant differences were observed between the active and the blank control arms. Receiving basic information on ML-based CDSS in hospital psychiatry may increase patient trust in such systems.

Hyperbaric Oxygen Therapy (HBOT) in Moderate Traumatic Brain Injury (TBI): A Randomized Controlled Trial

Abstract Introduction Hyperbaric oxygen therapy (HBOT) is a novel technique recently under investigation with intention to improve outcomes in traumatic brain injury (TBI). It increases the partial pressure of oxygen in the blood and tissues by inhaling pure oxygen in an environment pressurized to at least 1.4 times normal atmospheric pressure (ATM) at sea level. The rationale behind the use of HBOT in TBI is its potential to mitigate the secondary brain injury cascade initiated by the primary mechanical trauma. Tissue damage and neuroinflammation secondary to intricate and complex cellular biochemical processes are expected to be counteracted by increased oxygen availability during HBOT, which reduces oxidative stress and improves neuroplasticity. Materials and Methods All patients, except whose legal guardians denied informed consent, with moderate TBI presenting to the neurotrauma center, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India, were included within the study period of June 2022 to July 2023. Patient allocation was randomized into two arms: namely, treatment and control arm. Simple randomization was done using randomization mobile app, RRApp. Each patient received standard of care per the Brain Trauma Foundation guidelines. Patients randomized under the treatment arm additionally received adjuvant HBOT sessions. One session daily for 10 consecutive days. Session duration was for 60 minutes each at 1.4 ATM. The primary objective of the study was to compare the Glasgow Coma Score (GCS) at discharge and 3-month post-TBI Glasgow Outcome Scale-Extended (GOS-E) among patients in the treatment arm (those who received adjuvant HBOT) with those in the control arm (those who received only standard of care). Results The mean GCS (±standard deviation [SD]) at discharge in the treatment arm was 14.37 (±00.51) with a median of 14 and a range of 14 to 15. Comparatively, the mean GCS (±SD) at discharge in the control arm was 13.40 (±00.84) with a median of 13 and a range of 12 to 15. The difference between the two arms was statistically significant (p < 0.001). GOS-E at 3 months postinjury for the treatment arm was 7.62 ± 00.51 (mean ± SD) with a median of 8 (range: 7–8). For the control arm, GOS-E at 3 months postinjury was 6.40 ± 1.50 (mean ± SD) with a median of 7 (range: 4–8). The difference between the two arms was statistically significant (p < 0.001). Conclusion The current study concludes that early adjuvant HBOT using 1.4 ATM with one session of one-hour daily for 10 days among adults sustaining moderate TBI significantly improves GCS at 10 days. Early adjuvant HBOT is also associated with significantly improved GOS-E at 3 months postinjury compared to standard of care alone.

Effectiveness of a Bullying Intervention (Be-Prox) in Norwegian Early Childhood and Education Care Centers: Protocol for a Cluster Randomized Controlled Trial.

A new and growing body of research has studied bullying among children in early childhood education and care centers (ECECs). The Bernese Program (Be-Prox) is designed to systematically prevent and handle bullying between children in Swiss ECECs. However, the effectiveness of the Be-Prox intervention has not yet been explored in a Norwegian ECEC setting. This study aims to evaluate the effectiveness of Be-Prox in preventing and handling bullying among peers in Norwegian ECECs. ECECs from 2 Norwegian municipalities were invited to participate in a cluster randomized controlled trial (RCT) to evaluate the effectiveness of the Be-Prox intervention on peer bullying in Norwegian ECECs. After baseline measures were taken, project ECECs were randomized to either an intervention or a control arm. The Be-Prox intervention was introduced to ECECs in the intervention arm through 6 modules over a 9-month period immediately after the randomization. ECECs in the control arm participated in the data collection and were offered the Be-Prox intervention the following year. The primary outcome of the effect evaluation is the mean sum of negative behavior between peers after the Be-Prox training is completed in the intervention arm. Secondary outcomes include child bystander behavior, teacher self-efficacy, and ECEC's authoritative climate. An extensive implementation and process evaluation, as well as cost-effectiveness analyses, will be conducted alongside the RCT. Baseline data collection was conducted in September 2023, and the postintervention data collection started in May 2024. At baseline, we collected data on 708 children and 413 personnel from 38 project ECECs in the 2 Norwegian municipalities. The results from the study will be available in late 2024 at the earliest. The proposed project includes a comprehensive evaluation of the effectiveness of Be-Prox in Norwegian ECECs directly targeting the prevention and handling of bullying, including implementation and cost-effectiveness evaluations. The results from the project have the potential to fill in identified knowledge gaps in the understanding of negative behavior and bullying between peers in ECECs, and how these may be prevented. If proven efficient, our ambition is to offer Be-Prox to Norwegian ECECs as an evidence-based practice to prevent and handle bullying among preschool children. ClinicalTrials.gov NCT06040437; https://clinicaltrials.gov/study/NCT06040437. DERR1-10.2196/60626.

Supporting African communities to increase resilience and mental health of kids with developmental disabilities and their caregivers using the World Health Organization’s Caregiver Skills Training Programme (SPARK trial): study protocol for a cluster randomised clinical controlled trial

BackgroundMost children with developmental disabilities (DD) live in low- and middle-income countries, but access to services is limited, impacting their ability to thrive. Pilot study findings of the World Health Organization’s Caregiver Skills Training (WHO CST) intervention, which equips caregivers with strategies to facilitate learning and adaptive behaviours in children with DD, are promising but evidence from an appropriately powered trial delivered by non-specialist facilitators is lacking. This study will investigate the effectiveness and the resource impacts and costs and consequences of the WHO CST intervention in four sites in rural and urban Kenya and Ethiopia.MethodsThis is a 2-arm multi-site hybrid type-1 effectiveness implementation cluster randomised controlled superiority trial. After baseline assessments (T0) are completed by participants in clusters comprising 7 to 10 caregiver-child dyads, the clusters will be randomised to either the WHO CST intervention arm or a waitlist enhanced care as usual control arm. Further assessments will be completed at endpoint (T1, 18 ± 2 weeks after randomisation) and follow-up (T2, 44 ± 2 weeks after randomisation). The intervention comprises three individualised home visits and nine group sessions with trained non-specialist facilitators. Participants in the control arm will receive the intervention after completing follow-up assessments. We aim to recruit 544 child-caregiver dyads, evenly distributed across the two arms and countries. The co-primary outcomes are the child-focused Child Behavior Checklist (assessing emotional and behavioural problems) and the caregiver-focused Pediatric Quality of Life Inventory (assessing caregiver quality of life), both assessed at endpoint. Secondary outcome measures comprise the two co-primary outcomes at follow-up and ten additional outcome measures at endpoint, assessing stigma-based experiences, depressive symptoms, household food insecurity, child disciplinary strategies and beliefs, CST knowledge and skill competencies, caregiver and child quality of life, social support, and children’s communication modes and functions. After quantitative follow-up assessments are completed, a mixed-methods evaluation approach will be used to investigate implementation processes and acceptability, feasibility, and potential sustainability of the intervention.DiscussionThe study’s findings will provide evidence of the effectiveness and resource impacts and costs and consequences of a non-specialist-delivered intervention in under-resourced contexts in one low-income and one middle-income country in East Africa. Findings will inform future research, intervention, and policy efforts to support children with DD and their families in under-resourced majority world contexts.Trial registrationPan African Clinical Trial Registry PACTR202310908063134. Registered on October 16, 2023.

Evaluating the Value of Eye-Tracking Augmented Debriefing in Medical Simulation-A Pilot Randomized Controlled Trial.

Debriefing after simulation facilitates reflective thinking and learning. Eye-tracking augmented debriefing (ETAD) may provide advantages over traditional debriefing (TD) by leveraging video replay with first-person perspective. This multisite randomized controlled trial compared the impact of ETAD with TD (without eye-tracking and without video) after simulation on 4 outcomes: (1) resident metacognitive awareness (the primary outcome), (2) cognitive load (CL) of residents and debriefers, (3) alignment of resident self-assessment and debriefer assessment scores, and (4) resident and debriefer perceptions of the debriefing experience. Fifty-four emergency medicine residents from 2 institutions were randomized to the experimental (ETAD) or the control (TD) arm. Residents completed 2 simulation stations followed by debriefing. Before station 1 and after station 2, residents completed a Metacognition Awareness Inventory (MAI). After each station, debriefers and residents rated their CL and completed an assessment of performance. After the stations, residents were interviewed and debriefers participated in a focus group. There were no statistically significant differences in mean MAI change, resident CL, or assessment alignment between residents and debriefers. Debriefer CL was lower in the experimental arm. Interviews identified 4 themes: (1) reflections related to debriefing approach, (2) eye-tracking as a metacognitive sensitizer, (3) translation of metacognition to practice, and (4) ETAD as a strategy to manage CL. Residents reported that eye tracking improved the specificity of feedback. Debriefers relied less on notes, leveraged video timestamps, appreciated the structure of the eye-tracking video, and found the video useful when debriefing poor performers. There were no significant quantitative differences in MAI or resident CL scores; qualitative findings suggest that residents appreciated the benefits of the eye-tracking video review. Debriefers expended less CL and reported less perceived mental effort with the new technology. Future research should leverage longitudinal experimental designs to further understand the impact of eye-tracking facilitated debriefing.

Feasibility and Acceptability of a Palliative Care Intervention Among Older or Adults with Advanced CKD and their Caregivers.

In non-nephrology settings, specialty Palliative Care (PC) improves decision-making, patient's quality of life (QoL), advance care planning (ACP), and certain indicators of the quality of end-of-life (EoL) care. This pilot RCT explored the feasibility and acceptability of a PC intervention, CKD-EDU, for older adults ≥75 years with eGFR ≤25 ml/min and their caregivers. Participants randomized to the control group received standard nephrology care and routine kidney therapy (KT) education, while those randomized to CKD-EDU received a decision aid and met with a PC clinician up to three times to discuss KT decisions and EoL planning. Patients were assessed at baseline, 4-6, 12-14, and 24-26 weeks. Main outcomes included intervention feasibility and acceptability, decision-conflict, and patient QoL. The mediating effects of reduced decision conflict on improved QOL were explored, as were the effects of CKD-EDU on ACP, EoL treatment intensity and 6-month-hospitalization. Statistical analyses encompassed descriptive analyses, adjusted repeated-measure-models, mediation analyses and logistic-regression models. Among the 127 eligible patients screened, 58 (44%) consented: 30 were randomized to CKD-EUD and 28 to the control arm. All patients completed baseline assessments, and 89% completed at least one intervention session (n=26/29), underscoring intervention adherence and feasibility. Similarly, assessments completion rates at 4 (83%, n=45/54) ), 12 (93%, n=42/45), and 24 (95%, n=40/42) weeks were high. The intervention received over 85% acceptability ratings for all questions. Patients exposed to CKD-EDU exhibited significant improvement in decisional conflict scale scores (P = 0.003) at 4-6 weeks and improvements in QoL at 24-26 weeks (P=0.02). Exploratory analyses were not statistically significant in this pilot, but all effect sizes were in the predicted direction. This study demonstrates the feasibility and acceptability of CKD-EDU. A larger scale trial is warranted to assess its effectiveness in improving key outcomes important to patients and families.

Study protocol for a randomized controlled trial of Adapt 2 Asthma (A2A), a culturally relevant coping skills and asthma management intervention for Latinx Families

BackgroundLatinx children in the United States experience disparities in asthma control and asthma-related functional outcomes compared to non-Latinx White children, including more school absences, emergency department visits, and hospitalizations for asthma. Stress appears to play a role in asthma control, but interventions designed to address the role of stress in asthma control for Latinx children are limited.MethodThe current randomized controlled trial tests the effects of Adapt 2 Asthma (A2A), a family-based coping skills and asthma management intervention tailored to the stressors, strengths, and cultural beliefs of Latinx families, compared to an asthma self-management control arm (the Asthma Plan for Kids; APK). Latinx families of children ages 8 to 14 years old with asthma (target N = 280) are identified and enrolled from primary care clinics and randomly assigned to either A2A or APK. The intervention is delivered by lay health workers trained and receiving ongoing consultation from the study team. The primary outcome is child- and parent-reported asthma control, while secondary outcomes are child’s quality of life, lung function, school absences, and emergency department visits, and child and parent coping and family asthma management behaviors. Participants will be assessed at baseline, post-intervention, and at 6- and 12-month follow-up timepoints.DiscussionThis study has the potential to provide new evidence regarding the effects of culturally relevant coping and asthma management intervention strategies for Latinx children with asthma.Trial RegistrationClinicaltrials.gov NCT05118282. Registered on 11 November 2021.

Exploring the effect of exercise training on breast cancer's pathologic response and tumor immune microenvironment after neoadjuvant chemotherapy.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) and the percentage of tumor-infiltrating lymphocytes (TILs) are established prognostic biomarkers in early breast cancer (BC). While exercise training is effective as supportive care throughout the BC journey, its impact on the efficacy of NAC is unknown. This study aims to investigate the influence of a supervised exercise training program (SETP) on pCR and TILs in BC women undergoing NAC. Retrospective exploratory analysis of the subgroup of BC patients treated with NAC included in a clinical trial randomizing to STEP and control arm. Endpoints were pCR, biopsy, and stromal TILs. Sixty-four participants were included, with a mean age of 50.3 ± 10.1years, predominantly stage II and III disease (n = 58, 90.6%), HER2 + (n = 23, 35.9%), or triple-negative (n = 19, 29.7%) tumors. pCR was achieved in 56.7% and 55.9% in the STEP and control arm (p = 0.950). In the STEP arm, median TILs were 5.0 (0.0-80.0) and 5.0 (5.0-30.0), while in the control arm, 5.0 (0.0-90.0) and 0.0 (0.0-30.0) for biopsy and tumor site, respectively. The difference in TILs between arms was 0.04 (confidence interval (CI 95%) - 13.6, 13.7; p = 0.995) and - 4.3 (CI 95% - 11.5, 2.9; (p = 0.233) for biopsy and tumor site, respectively. No statistically significant difference was discerned between the groups concerning TILs of the biopsy. However, a marginally higher TIL level at the tumor site was associated with the SETP arm. No differences were discerned within and between groups on both pCR and TILs, in possible relation to the exploratory nature of the analysis. Future adequately powered research is warranted.