Estimating the effect of diuretics and inhaled corticosteroids for evolving bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Off-label treatment of extremely preterm infants with diuretics and inhaled corticosteroids (ICS) for evolving bronchopulmonary dysplasia (BPD) is common. Their effectiveness in reducing mortality or BPD severity, and optimal treatment timing, are unclear. OBJECTIVES: To determine whether diuretic treatment or ICS administration for infants with early evolving (between 10-27 days postnatal) and progressively evolving (28th-day-36th-week postnatal) BPD are independently associated with reduced mortality and moderate or severe BPD at 36-weeks postmenstrual age (PMA). METHODS: We examined neonates born before 28 weeks' gestation and admitted to neonatal intensive care units on postnatal Day 0 between 2006 and 2016 using data collected during routine care recorded within the Paediatric Health Information System (PHIS). An early evolving BPD cohort consisted of infants treated with oxygen, positive pressure or mechanical ventilation at 10 days postnatal. The progressively evolving BPD cohort consisted of infants treated with these modalities at 28 days. In new users, we evaluated the effect of diuretic and ICS treatment on mortality or BPD severity at 36 weeks PMA, adjusting for time-dependent confounding by respiratory status using marginal structural models. RESULTS: Early evolving BPD was present in 10,135 patients; progressively evolving BPD in 11,728. New diuretic exposure during early evolving BPD (adjusted risk ratio [aRR] 0.77, 95% confidence interval [CI] 0.65, 0.93) was associated with decreased mortality or moderate/severe BPD risk. New diuretics (aRR 0.86, 95% CI 0.75, 0.99) during progressively evolving BPD between 28-days-36-weeks PMA were less strongly associated with mortality or moderate/severe BPD reduction. There was no strong association for ICS in patients with early evolving (aRR: 1.40; 95% CI: 0.79, 2.51) or progressively evolving BPD (aRR 1.16, 95% CI 0.95, 1.49). CONCLUSION: Diuretics, but not ICS, for evolving BPD were associated with mortality and BPD risk reduction.

A comparison of computational algorithms for the Bayesian analysis of clinical trials.

BACKGROUND: Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. METHODS: Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. RESULTS: The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. CONCLUSION: Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

A large, multi-center survey assessing health, social support, literacy, and self-management resources in patients with heart failure.

BACKGROUND: Most patients with heart failure (HF) have multimorbidity which may cause difficulties with self-management. Understanding the resources patients draw upon to effectively manage their health is fundamental to designing new practice models to improve outcomes in HF. We describe the rationale, conceptual framework, and implementation of a multi-center survey of HF patients, characterize differences between responders and non-responders, and summarize patient characteristics and responses to the survey constructs among responders. METHODS: This was a multi-center cross-sectional survey study with linked electronic health record (EHR) data. Our survey was guided by the Chronic Care Model to understand the distribution of patient-centric factors, including health literacy, social support, self-management, and functional and mental status in patients with HF. Most questions were from existing validated questionnaires. The survey was administered to HF patients aged ≥ 30 years from 4 health systems in PCORnet® (the National Patient-Centered Clinical Research Network): Essentia Health, Intermountain Health, Mayo Clinic, and The Ohio State University. Each health system mapped their EHR data to a standardized PCORnet Common Data Model, which was used to extract demographic and clinical data on survey responders and non-responders. RESULTS: Across the 4 sites, 10,662 patients with HF were invited to participate, and 3330 completed the survey (response rate: 31%). Responders were older (74 vs. 71 years; standardized difference (95% CI): 0.18 (0.13, 0.22)), less racially diverse (3% vs. 12% non-White; standardized difference (95% CI): -0.32 (-0.36, -0.28)), and had higher prevalence of many chronic conditions than non-responders, and thus may not be representative of all HF patients. The internal reliability of the validated questionnaires in our survey was good (range of Cronbach's alpha: 0.50-0.96). Responders reported their health was generally good or fair, they frequently had cardiovascular comorbidities, > 50% had difficulty climbing stairs, and > 10% reported difficulties with bathing, preparing meals, and using transportation. Nearly 80% of patients had family or friends sit with them during a doctor visit, and 54% managed their health by themselves. Patients reported generally low perceived support for self-management related to exercise and diet. CONCLUSIONS: More than half of patients with HF managed their health by themselves. Increased understanding of self-management resources may guide the development of interventions to improve HF outcomes.

The Registry-Based Randomized Trial - A Pragmatic Study Design.

Randomized controlled trials are the gold standard of clinical research for comparing therapies in well-defined groups of participants.1 Randomization avoids confounding due to unmeasured variables or to treatment selection and enables a causal interpretation of the estimated treatment effect. It has long been recognized, however, that standard explanatory clinical trials are slow, costly, and subject to participant selection. To preserve the strengths of randomized trials while mitigating their weaknesses, pragmatic randomized clinical trials emerged; these trials aim to facilitate decision-making rather than explicate a mechanism of action and enroll a diverse set of participants using existing structures and data sources.2.

Staffing and Antipsychotic Medication Use in Nursing Homes and Neighborhood Deprivation.

Importance: Inappropriate use of antipsychotic medications in nursing homes is a growing public health concern. Residents exposed to higher levels of socioeconomic deprivation in the area around a nursing home may be currently exposed, or have a long history of exposure, to more noise pollution, higher crime rates, and have less opportunities to safely go outside the facility, which may contribute to psychological stress and increased risk of receiving antipsychotic medications inappropriately. However, it is unclear whether neighborhood deprivation is associated with use of inappropriate antipsychotic medications and whether this outcome is different by facility staffing levels. Objective: To evaluate whether reported inappropriate antipsychotic medication use differs in severely and less severely deprived neighborhoods, and whether these differences are modified by higher levels of total nurse staffing. Design, Setting, and Participants: This was a cross-sectional analysis of a national sample of nursing homes that linked across 3 national large-scale data sets for the year 2019. Analyses were conducted between April and June 2023. Exposure: Neighborhood deprivation status (severe vs less severe) and total staffing hours (registered nurse, licensed practical nurse, certified nursing assistant). Main Outcome and Measures: This study estimated the association between neighborhood deprivation and the percentage of long-stay residents who received an antipsychotic medication inappropriately in the nursing home at least once in the past week and how this varied by nursing home staffing through generalized estimating equations. Analyses were conducted on the facility level and adjusted for state fixed effects. Results: This study included 10 966 nursing homes (1867 [17.0%] in severely deprived neighborhoods and 9099 [83.0%] in less deprived neighborhoods). Unadjusted inappropriate antipsychotic medication use was greater in nursing homes located in severely deprived neighborhoods (mean [SD], 15.9% [10.7%] of residents) than in those in less deprived neighborhoods (mean [SD], 14.2% [8.8%] of residents). In adjusted models, inappropriate antipsychotic medication use was higher in severely deprived neighborhoods vs less deprived neighborhoods (19.2% vs 17.1%; adjusted mean difference, 2.0 [95% CI, 0.35 to 3.71] percentage points) in nursing homes that fell below critical levels of staffing (less than 3 hours of nurse staffing per resident-day). Conclusions and Relevance: These findings suggest that levels of staffing modify disparities seen in inappropriate antipsychotic medication use among nursing homes located in severely deprived neighborhoods compared with nursing homes in less deprived neighborhoods. These findings may have important implications for improving staffing in more severely deprived neighborhoods.

A randomized, pilot trial comparing vaginal hyaluronic acid to vaginal estrogen for the treatment of genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study was to compare the efficacy of a non-hormone alternative, vaginal hyaluronic acid (HLA), to a standard-of-care therapy, vaginal estrogen, for the treatment of genitourinary syndrome of menopause (GSM). METHODS: This was a randomized, parallel arm pilot trial. Women with GSM were randomized to an HLA vaginal suppository or vaginal estrogen cream for 12 wk to compare the primary outcome, the vulvovaginal symptom questionnaire (VSQ) score. Secondary outcomes included the following: the female sexual function index (FSFI), the vaginal symptom index (VSI), visual analog scale (VAS) for dyspareunia, vaginal itching, and vaginal dryness, patient global impression of improvement (PGI-I) at follow-up, vaginal maturation index, and vaginal pH. Differences between treatment groups were estimated using the two-sided, two-sample t-test and 95% confidence intervals. RESULTS: Forty-nine women were randomized and 45 participants (vaginal estrogen = 23, vaginal HLA = 22) provided data at week 12. Baseline characteristics were similar in both groups. On the VSQ, there was no observed difference in overall scores between the HLA and vaginal estrogen groups at 12 wk (P = 0.81). Improvement was seen within both treatment groups on the VSQ after 12 wk. The VAS score, total VSI score, total FSFI score, and vaginal pH improved over time; however, improvement did not differ between study arms. Over 90% participants noted improvement on the PGI-I in both groups (P = 0.61). No treatment-related serious adverse events occurred. CONCLUSIONS: There were no clinically meaningful differences between vaginal HLA and vaginal estrogen for the treatment of GSM after 12 wk. Vaginal HLA may be a promising non-hormone therapy for GSM.

The impact of multimorbidity and functional limitation on quality of life in patients with heart failure: A multi-site study.

BACKGROUND: Multimorbidity and functional limitation are associated with poor outcomes in heart failure (HF). However, the individual and combined effect of these on health-related quality of life in patients with HF is not well understood. METHODS: Patients aged ≥30 years with two or more HF diagnostic codes and one or more HF-related prescription drugs from four U.S. institutions were mailed a survey to measure patient-centric factors including functional status (activities of daily living [ADLs]) and health-related quality of life (PROMIS-29 Health Profile). Patients with HF from January 1, 2013 to February 1, 2018 were included. Multimorbidity was defined as ≥2 non-cardiovascular comorbidities; functional limitation as any limitation in at least one of eight ADLs. Patients were categorized into four groups by multimorbidity (Yes/No) and functional limitation (Yes/No). We dichotomized the PROMIS-29 sub-scale scores at the median and calculated odd ratios for the four multimorbidity/functional limitation groups. RESULTS: A total of 3330 patients with HF returned the survey (response rate 31%); 3020 completed the questions of interest and were retained. Among these patients (45% female; mean age 73 [standard deviation: 12] years), 29% had neither multimorbidity nor functional limitation, 24% had multimorbidity only, 22% had functional limitation only, and 25% had both. After adjustment, having functional limitation only was associated with higher anxiety (odds ratio [OR]: 3.44, 95% confidence interval [CI]: 2.66-4.45), depression (OR: 3.11, 95% CI: 2.39-4.06), and fatigue (OR: 4.19, 95% CI: 3.25-5.40); worse sleep (OR: 2.14, 95% CI: 1.69-2.72) and pain (OR: 6.73, 95% CI: 5.15-8.78); and greater difficulty with social activities (OR: 9.40, 95% CI: 7.19-12.28) compared with having neither. Results were similar for having both multimorbidity and functional limitation. CONCLUSION: Patients with only functional limitation have similar poor health-related quality of life scores as those with both multimorbidity and functional limitation, underscoring the important role that physical functioning plays in the well-being of patients with HF.

Assets for integrating task-sharing strategies for hypertension within HIV clinics: Stakeholder's perspectives using the PEN-3 cultural model.

BACKGROUND: Access to antiretroviral therapy has increased life expectancy and survival among people living with HIV (PLWH) in African countries like Nigeria. Unfortunately, non-communicable diseases such as cardiovascular diseases are on the rise as important drivers of morbidity and mortality rates among this group. The aim of this study was to explore the perspectives of key stakeholders in Nigeria on the integration of evidence-based task-sharing strategies for hypertension care (TASSH) within existing HIV clinics in Nigeria. METHODS: Stakeholders representing PLWH, patient advocates, health care professionals (i.e. community health nurses, physicians and chief medical officers), as well as policymakers, completed in-depth qualitative interviews. Stakeholders were asked to discuss facilitators and barriers likely to influence the integration of TASSH within HIV clinics in Akwa Ibom, Nigeria. The interviews were transcribed, keywords and phrases were coded using the PEN-3 cultural model as a guide. Framework thematic analysis guided by the PEN-3 cultural model was used to identify emergent themes. RESULTS: Twenty-four stakeholders participated in the interviews. Analysis of the transcribed data using the PEN-3 cultural model as a guide yielded three emergent themes as assets for the integration of TASSH in existing HIV clinics. The themes identified are: 1) extending continuity of care among PLWH; 2) empowering health care professionals and 3) enhancing existing workflow, staff motivation, and stakeholder advocacy to strengthen the capacity of HIV clinics to integrate TASSH. CONCLUSION: These findings advance the field by providing key stakeholders with knowledge of assets within HIV clinics that can be harnessed to enhance the integration of TASSH for PLWH in Nigeria. Future studies should evaluate the effect of these assets on the implementation of TASSH within HIV clinics as well as their effect on patient-level outcomes over time.