Lung-Protective Ventilation for Pediatric Acute Respiratory Distress Syndrome: A Nonrandomized Controlled Trial.

OBJECTIVES: Despite the recommendation for lung-protective mechanical ventilation (LPMV) in pediatric acute respiratory distress syndrome (PARDS), there is a lack of robust supporting data and variable adherence in clinical practice. This study evaluates the impact of an LPMV protocol vs. standard care and adherence to LPMV elements on mortality. We hypothesized that LPMV strategies deployed as a pragmatic protocol reduces mortality in PARDS. DESIGN: Multicenter prospective before-and-after comparison design study. SETTING: Twenty-one PICUs. PATIENTS: Patients fulfilled the Pediatric Acute Lung Injury Consensus Conference 2015 definition of PARDS and were on invasive mechanical ventilation. INTERVENTIONS: The LPMV protocol included a limit on peak inspiratory pressure (PIP), delta/driving pressure (DP), tidal volume, positive end-expiratory pressure (PEEP) to Fio2 combinations of the low PEEP acute respiratory distress syndrome network table, permissive hypercarbia, and conservative oxygen targets. MEASUREMENTS AND MAIN RESULTS: There were 285 of 693 (41·1%) and 408 of 693 (58·9%) patients treated with and without the LPMV protocol, respectively. Median age and oxygenation index was 1.5 years (0.4-5.3 yr) and 10.9 years (7.0-18.6 yr), respectively. There was no difference in 60-day mortality between LPMV and non-LPMV protocol groups (65/285 [22.8%] vs. 115/406 [28.3%]; p = 0.104). However, total adherence score did improve in the LPMV compared to non-LPMV group (57.1 [40.0-66.7] vs. 47.6 [31.0-58.3]; p < 0·001). After adjusting for confounders, adherence to LPMV strategies (adjusted hazard ratio, 0.98; 95% CI, 0.97-0.99; p = 0.004) but not the LPMV protocol itself was associated with a reduced risk of 60-day mortality. Adherence to PIP, DP, and PEEP/Fio2 combinations were associated with reduced mortality. CONCLUSIONS: Adherence to LPMV elements over the first week of PARDS was associated with reduced mortality. Future work is needed to improve implementation of LPMV in order to improve adherence.

Feasibility of Weekly Integrated Palliative Care Outcome Scale (IPOS) Within a Stepped Care Model.

CONTEXT: Patients with advanced cancer may experience symptoms and concerns that are inadequately identified by the healthcare team, leading to calls for patient-reported symptom monitoring. OBJECTIVES: Assess the feasibility of administering weekly patient-reported online Integrated Palliative care Outcome Scale (IPOS) questionnaires within the context of a stepped care model in the outpatient care setting. METHODS: Analysis of intervention group data in a randomized controlled trial to assess the effectiveness of a stepped care model of palliative care for patients with advanced cancer. Patients in the intervention group were invited to complete the IPOS weekly for 16 weeks through a remotely-administered online questionnaire. At the end of the 16-week period, patients were invited to complete a feedback survey. Multivariable logistic regression was used to assess factors associated with more versus less than 70% completion of weekly questionnaires. RESULTS: Among 111 patients who survived more than 16 weeks, the mean number of questionnaires completed was 9.2/16 (58%). A total of 53 out of the 111 patients (48%) completed more than 70% of the questionnaires. Higher education level was found to be associated with higher completion of the questionnaires. A total of 79 out of 111 (71%) patients responded to the feedback survey, of which 67 (85%) felt comfortable with completing the online questionnaire and 11 (14%) felt it was troublesome to complete it on a weekly basis. CONCLUSION: In our study, there was suboptimal completion of patient-reported IPOS questionnaire. Further research is needed to improve the uptake of patient-reported outcomes in real-world clinical settings.

Guidance on mucositis assessment from the MASCC Mucositis Study Group and ISOO: an international Delphi study.

Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment. Methods: This study was conducted over two stages (January 2022-July 2023). The first phase involved a survey to MASCC-MSG members (January 2022-May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023-May 2023). Consensus was defined as agreement on a parameter by >80% of respondents. Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus). Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice. Funding: No funding was received.

Electron transport chain capacity expands yellow fever vaccine immunogenicity.

Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Timing along the cardiac cycle modulates neural signals of reward-based learning.

Natural fluctuations in cardiac activity modulate brain activity associated with sensory stimuli, as well as perceptual decisions about low magnitude, near-threshold stimuli. However, little is known about the relationship between fluctuations in heart activity and other internal representations. Here we investigate whether the cardiac cycle relates to learning-related internal representations - absolute and signed prediction errors. We combined machine learning techniques with electroencephalography with both simple, direct indices of task performance and computational model-derived indices of learning. Our results demonstrate that just as people are more sensitive to low magnitude, near-threshold sensory stimuli in certain cardiac phases, so are they more sensitive to low magnitude absolute prediction errors in the same cycles. However, this occurs even when the low magnitude prediction errors are associated with clearly suprathreshold sensory events. In addition, participants exhibiting stronger differences in their prediction error representations between cardiac cycles exhibited higher learning rates and greater task accuracy.

The use of potentially interacting supplement-drug pairs in adults with type 2 diabetes: A large population-based cohort study in the UK Biobank.

AIMS: To examine the patterns of use of potentially interacting supplement-drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement-drug pairs on downstream outcomes. METHODS: Potentially interacting supplement-drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. RESULTS: 26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement-drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement-drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10-1.44, P < 0.001). CONCLUSIONS: Real-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement-drug interactions in clinical settings.

Care Models and Barriers to Long-Term Follow-Up Care Among Childhood Cancer Survivors and Health Care Providers in Asia: A Literature Review.

Most available data evaluating childhood cancer survivorship care focus on the experiences of high-income Western countries, whereas data from Asian countries are limited. To address this knowledge deficit, we aimed to characterize survivorship care models and barriers to participation in long-term follow-up (LTFU) care among childhood cancer survivors (CCSs) and health care providers in Asian countries. Twenty-four studies were identified. Most institutions in China and Turkey adopt the oncology specialist care model, whereas in Japan, India, Singapore, and South Korea, after completion of therapy LTFU programs are available in some institutions. In terms of survivor barriers, findings highlight the need for comprehensive age-appropriate education and support and personalized approaches in addressing individual preferences and challenges during survivorship. Health care professionals need education about potential late effects of cancer treatment, recommended guidance for health surveillance and follow-up care, and their role in facilitating the transition from pediatric to adult-focused care. To optimize the delivery of cancer survivorship care, efforts are needed to increase patient and family awareness about the purpose and potential benefits of LTFU care, improve provider education and training, and promote policy change to ensure that CCSs have access to essential services and resources to optimize quality of survival.

Estimation and reduction of bias in self-controlled case series with non-rare event dependent outcomes and heterogeneous populations.

The self-controlled case series (SCCS) is a commonly adopted study design in the assessment of vaccine and drug safety. Recurrent event data collected from SCCS studies are typically analyzed using the conditional Poisson model which assumes event times are independent within-cases. This assumption is violated in the presence of event dependence, where the occurrence of an event influences the probability and timing of subsequent events. When event dependence is suspected in an SCCS study, the standard recommendation is to include only the first event from each case in the analysis. However, first event analysis can still yield biased estimates of the exposure relative incidence if the outcome event is not rare. We first demonstrate that the bias in first event analysis can be even higher than previously assumed when subpopulations with different baseline incidence rates are present and describe an improved method for estimating this bias. Subsequently, we propose a novel partitioned analysis method and demonstrate how it can reduce this bias. We provide a recommendation to guide the number of partitions to use with the partitioned analysis, illustrate this recommendation with an example SCCS study of the association between beta-blockers and acute myocardial infarction, and compare the partitioned analysis against other SCCS analysis methods by simulation.

Perceived Barriers Toward Patient-Reported Outcome Implementation in Cancer Care: An International Scoping Survey.

PURPOSE: Implementation of patient-reported outcomes (PROs) collection is an important priority in cancer care. We examined perceived barriers toward implementing PRO collection between centers with and without PRO infrastructure and administrators and nonadministrators. PATIENTS AND METHODS: We performed a multinational survey of oncology practitioners on their perceived barriers to PRO implementations. Multivariable regression models evaluated for differences in perceived barriers to PRO implementation between groups, adjusted for demographic and institutional variables. RESULTS: Among 358 oncology practitioners representing six geographic regions, 31% worked at centers that did not have PRO infrastructure and 26% self-reported as administrators. Administrators were more likely to perceive concerns with liability issues (aOR, 2.00 [95% CI, 1.12 to 3.57]; P = .02) while having nonsignificant trend toward less likely perceiving concerns with disruption of workflow (aOR, 0.58 [95% CI, 0.32 to 1.03]; P = .06) and nonadherence of PRO reporting (aOR, 0.53 [95% CI, 0.26 to 1.08]; P = .08) as barriers. Respondents from centers without PRO infrastructure were more likely to perceive that not having access to a local PRO expert (aOR, 6.59 [95% CI, 3.81 to 11.42]; P < .001), being unsure how to apply PROs in clinical decisions (aOR, 4.20 [95% CI, 2.32 to 7.63]; P < .001), and being unsure about selecting PRO measures (aOR, 3.36 [95% CI, 2.00 to 5.66]; P < .001) as barriers. Heat map analyses identified the largest differences between participants from centers with and without PRO infrastructure in agreed-upon barriers were (1) not having a local PRO expert, (2) being unsure about selecting PRO measures, and (3) not recognizing the role of PROs at the institutional level. CONCLUSION: Perceived barriers toward PRO implementation differ between administrators and nonadministrators and practitioners at centers with and without PRO infrastructure. PRO implementation teams should consider as part of a comprehensive strategy including frontline clinicians and administrators and members with PRO experience within teams.

Effects of immersive virtual reality for alleviating anxiety, nausea and vomiting among patients with paediatric cancer receiving their first chemotherapy: protocol for a randomised controlled trial.

INTRODUCTION: Anxiety, nausea and vomiting are common side effects suffered by paediatric patients receiving chemotherapy. Emerging evidence supports the efficacy of immersive virtual reality (IVR) on improving anxiety and distress symptoms including nausea and vomiting in this vulnerable group. This trial aims to evaluate the effects of IVR intervention on anxiety, chemotherapy-induced nausea and vomiting and anticipatory nausea and vomiting in patients with paediatric cancer receiving first chemotherapy. METHOD AND ANALYSIS: An assessor-blinded, randomised controlled trial with a mixed methods evaluation approach. On the basis of our pilot results, 128 chemotherapy-naive patients with paediatric cancer scheduled to receive their first intravenous chemotherapy will be recruited from a public hospital and randomly allocated to intervention (n=64) or control groups (n=64). The intervention group will receive the IVR intervention for three sessions: 2 hours before the first chemotherapy, 5 min before and during their first chemotherapy and 5 min before and during their second chemotherapy, respectively. The control group will receive standard care only. A subsample of 30 participants in the intervention group will be invited for a qualitative interview. Study instruments are: (1) short form of the Chinese version of the State Anxiety Scale for Children, (2) visual analogue scale for anticipatory nausea and vomiting, (3) Chinese version of the Multinational Association of Supportive Care in Cancer Antiemesis Tool and (4) individual face-to-face semistructured interviews to explore intervention participants' perceptions of the IVR intervention. ETHICS AND DISSEMINATION: This study has been approved by the Hong Kong Children's Hospital Research Ethics Committee (HKCH-REC-2021-009). The findings will be disseminated in peer-reviewed journals and through local or interventional conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2100048732.

Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times.

In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one-off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non-linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen-Gill model for analysis of recurrent event time data and compare it with alternative parametric and non-parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti-malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out-performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

Association of healthy lifestyle behaviours with incident irritable bowel syndrome: a large population-based prospective cohort study.

OBJECTIVES: To evaluate the association between healthy lifestyle behaviours and the incidence of irritable bowel syndrome (IBS). DESIGN: Population-based prospective cohort study. SETTING: The UK Biobank. PARTICIPANTS: 64 268 adults aged 37 to 73 years who had no IBS diagnosis at baseline were enrolled between 2006 and 2010 and followed up to 2022. MAIN EXPOSURE: The five healthy lifestyle behaviours studied were never smoking, optimal sleep, high level of vigorous physical activity, high dietary quality and moderate alcohol intake. MAIN OUTCOME MEASURE: The incidence of IBS. RESULTS: During a mean follow-up of 12.6 years, 961 (1.5%) incident IBS cases were recorded. Among the 64 268 participants (mean age 55.9 years, 35 342 (55.0%) female, 7604 (11.8%) reported none of the five healthy lifestyle behaviours, 20 662 (32.1%) reported 1 behaviour, 21 901 (34.1%) reported 2 behaviours and 14 101 (21.9%) reported 3 to 5 behaviours at baseline. The multivariable adjusted hazard ratios associated with having 1, 2 and 3 to 5 behaviours for IBS incidence were 0.79 (95% confidence intervals 0.65 to 0.96), 0.64 (0.53 to 0.78) and 0.58 (0.46 to 0.72), respectively (P for trend <0.001). Never smoking (0.86, 0.76 to 0.98, P=0.02), high level of vigorous physical activity (0.83, 0.73 to 0.95, P=0.006) and optimal sleep (0.73, 0.60 to 0.88, P=0.001) demonstrated significant independent inverse associations with IBS incidence. No significant interactions were observed between these associations and age, sex, employment status, geographic location, gastrointestinal infection, endometriosis, family history of IBS or lifestyle behaviours. CONCLUSIONS: Adhering to a higher number of healthy lifestyle behaviours is significantly associated with a lower incidence of IBS in the general population. Our findings suggest the potential of lifestyle modifications as a primary prevention strategy for IBS.

Patterns and factors associated with the prescription of psychotropic medications after diagnosis of cancer in Chinese patients: A population-based cohort study.

PURPOSE: Patients with cancer may be prescribed psychotropic medications to address their psychiatric symptoms and disorders. This study examined the patterns and factors associated with the prescription of psychotropics after cancer diagnosis using a population-based database in Hong Kong. METHODS: Patients who were diagnosed with malignant cancer and had no documented psychiatric diagnosis or psychotropic medications prior to cancer diagnosis, were included. Multivariable log-binomial models were used to explore the associations between predictive factors and psychotropic medications use. RESULTS: Among 9337 patients, 1868 patients (20.0%) were newly prescribed with psychotropic medications after cancer diagnoses, most commonly hypnotics (50.3%) and antidepressants (32.8%). About one-third (31.4%) were prescribed chronic psychotropics (≥90 days). Approximately 48.3% of patients who were prescribed psychotropic medications received their prescriptions within 1 year after diagnosed with cancer. Only 18.6% of those prescribed psychotropic medications had a registered psychiatric diagnosis. Patients with multiple comorbidities (adjusted risk ratio[aRR] = 2.74; CI = 2.46-3.05) and diagnosed with oral (aRR = 1.89; CI = 1.52-2.35) or respiratory cancers (aRR = 1.62; CI = 1.36-1.93) were more likely to be prescribed psychotropics. CONCLUSIONS: The use of psychotropic medication is common (20%) among patients with cancer. Our findings highlight the importance of identification and documentation of psychiatric needs among patients with cancer.

PRECIOUS demonstrated satisfactory measurement properties for assessing the quality of care for children with serious illnesses.

OBJECTIVES: To determine the measurement properties of PaRental Experience with care for Children with serIOUS illnesses (PRECIOUS), a parent-reported measure of Quality of Care for seriously ill children across care settings and illness trajectories. STUDY DESIGN AND SETTING: Parents self-administered baseline and 2-week follow-up surveys online. Exploratory Factor Analysis was used to determine PRECIOUS's factor structure and select items. Internal consistency was evaluated with Cronbach's α, test-retest reliability with intraclass correlation coefficients, and convergent validity with Spearman's correlations between PRECIOUS scales and subscales of Measure of Processes of Care and Quality of Children's Palliative Care Instrument. RESULTS: Of 152 parents [108 (71%) mothers, 44 (29%) fathers] who completed the baseline survey, 123 (81%) completed follow-up. Exploratory Factor Analysis grouped PRECIOUS into five scales: collaborative and goal-concordant care (12 items), caregiver support and respectful care (15 items), access to financial and medical resources (five items), reducing caregiving stressors (nine items), and hospitalization-specific processes (four items). Root Mean Square Error of Approximation was 0.040 and Comparative Fit Index was 0.980. Cronbach's α ranged from 0.85 to 0.96. Intraclass correlation coefficients ranged from 0.72 to 0.86. Significant correlations with Measure of Processes of Care and Quality of Children's Palliative Care Instrument confirmed convergent validity. The original 56-item tool was reduced to 45 items. CONCLUSION: PRECIOUS demonstrates satisfactory measurement properties for assessing Quality of Care for seriously ill children.

ENABLE-SG (Educate, Nurture, Advise, Before Life Ends for Singapore) as a proactive palliative care model: protocol for a hybrid type 1 effectiveness-implementation randomized wait-list controlled trial.

BACKGROUND: Specialist palliative care is often provided late in the patient's disease trajectory in response to uncontrolled symptoms. Shifting from this reactionary illness-stress paradigm to a proactive health-wellness approach, the ENABLE (Educate, Nurture, Advise, Before Life Ends) telehealth model aims to enhance the coping, stress and symptom management, self-care, and advance care planning skills of patients with advanced cancers and their caregivers. The ENABLE model has been culturally adapted to Singapore (ENABLE-SG) and pilot-tested. A hybrid type 1 effectiveness-implementation design will be used to evaluate the effectiveness of ENABLE-SG while collecting real-world implementation data. METHODS: This single-centre, assessor-blind, wait-list (immediately vs. 6 months) randomized controlled trial will recruit 300 adult patients within 60 days of an advanced cancer diagnosis and their family caregivers from the National Cancer Centre of Singapore. ENABLE-SG comprises structured psychoeducational sessions with a telehealth coach, covering essential topics of early palliative care. Participants will be assessed at baseline and every 3 months until patient's death, 12 months (caregivers), or end of study (patients). The primary outcome is patient quality of life 6 months after baseline. Secondary patient-reported outcomes include mood, coping, palliative care concerns, and health status. Secondary caregiver-reported outcomes include caregiver quality of life, mood, coping, and care satisfaction. Mixed-effects regression modelling for repeated measurements will be used. To assess the effectiveness of ENABLE-SG versus usual care, patient and caregiver outcomes at 6 months will be compared. To compare earlier versus delayed ENABLE-SG, patient and caregiver outcomes at 12 months will be compared. Within the hybrid type 1 effectiveness-implementation design, implementation outcomes will be evaluated in both the early and delayed groups. Acceptability, adoption, appropriateness, and feasibility will be assessed using a feedback survey and semi-structured interviews with a purposive sample of patients, caregivers, and healthcare providers. Transcribed interviews will be analysed thematically. Other implementation outcomes of penetration, fidelity, and cost will be assessed using records of study-related processes and summarized using descriptive statistics. A cost-effectiveness analysis will also be conducted. DISCUSSION: This study will assess both effectiveness and implementation of ENABLE-SG. Insights into implementation processes can facilitate model expansion and upscaling. TRIAL REGISTRATION: Registered prospectively on ClinicalTrials.gov, NCT06044441. Registered on 21/09/2023.

Can an Integrated Palliative and Oncology Co-rounding Model Reduce Aggressive Care at the End of Life? Secondary Analysis of an Open-label Stepped-wedge Cluster-randomized Trial.

BACKGROUND: Clinical trial evidence on the effect of palliative care models in reducing aggressive end-of-life care is inconclusive. We previously reported on an integrated inpatient palliative care and medical oncology co-rounding model that significantly reduced hospital bed-days and postulate additional effect on reducing care aggressiveness. OBJECTIVES: To compare the effect of a co-rounding model vs usual care in reducing receipt of aggressive treatment at end-of-life. METHODS: Secondary analysis of an open-label stepped-wedge cluster-randomized trial comparing two integrated palliative care models within the inpatient oncology setting. The co-rounding model involved pooling specialist palliative care and oncology into one team with daily review of admission issues, while usual care constituted discretionary specialist palliative care referrals by the oncology team. We compared odds of receiving aggressive care at end-of-life: acute healthcare utilization in last 30 days of life, death in hospital, and cancer treatment in last 14 days of life between patients in two trial arms. RESULTS: 2145 patients were included in the analysis, and 1803 patients died by 4th April 2021. Median overall survival was 4.90 (4.07 - 5.72) months in co-rounding and 3.75 (3.22 - 4.21) months in usual care, with no difference in survival (P = .12). We found no significant differences between both models with respect to receipt of aggressive care at end-of-life. (Odds Ratio .67 - 1.27; all P > .05). CONCLUSION: The co-rounding model within an inpatient setting did not reduce aggressiveness of care at end-of-life. This could be due in part to the overall focus on resolving episodic admission issues.

Cluster randomized trial designs for modeling time-varying intervention effects.

Stepped-wedge cluster randomized trials (SW-CRTs) are typically analyzed assuming a constant intervention effect. In practice, the intervention effect may vary as a function of exposure time, leading to biased results. The estimation of time-on-intervention (TOI) effects specifies separate discrete intervention effects for each elapsed period of exposure time since the intervention was first introduced. It has been demonstrated to produce results with minimum bias and nominal coverage probabilities in the analysis of SW-CRTs. Due to the design's staggered crossover, TOI effect variances are heteroskedastic in a SW-CRT. Accordingly, we hypothesize that alternative CRT designs will be more efficient at modeling certain TOI effects. We derive and compare the variance estimators of TOI effects between a SW-CRT, parallel CRT (P-CRT), parallel CRT with baseline (PB-CRT), and novel parallel CRT with baseline and an all-exposed period (PBAE-CRT). We also prove that the time-averaged TOI effect variance and point estimators are identical to that of the constant intervention effect in both P-CRTs and PB-CRTs. We then use data collected from a hospital disinvestment study to simulate and compare the differences in TOI effect estimates between the different CRT designs. Our results reveal that the SW-CRT has the most efficient estimator for the early TOI effect, whereas the PB-CRT typically has the most efficient estimator for the long-term and time-averaged TOI effects. Overall, the PB-CRT with TOI effects can be a more appropriate choice of CRT design for modeling intervention effects that vary by exposure time.