Impact of Local Tailoring on Acute Stroke Care in 21 Disparate Emergency Departments: A Prospective Stepped Wedge Type III Hybrid Effectiveness-Implementation Study.

BACKGROUND: Faster delivery of tPA (tissue-type plasminogen activator) results in better health outcomes for eligible patients with stroke. Standardization of stroke protocols in emergency departments (EDs) has been difficult, especially in nonstroke centers. We measured the effectiveness of a centrally led implementation strategy with local site tailoring to sustain adherence to an acute stroke protocol to improve door-to-needle (DTN) times across disparate EDs in a multihospital health system. METHODS: Prospective, type III hybrid effectiveness-implementation cohort study measuring performance at 21 EDs in Utah and Idaho (stroke centers [4]/nonstroke centers [17]) from January 2018 to February 2020 using a nonrandomized stepped-wedge design, monthly repeated site measures and multilevel hierarchical modeling. Each site received the implementation strategies in 1 of 6 steps providing control and intervention data. Co-primary outcomes were percentage of DTN times ≤60 minutes and median DTN time. Secondary outcomes included percentage of door-to-activation of neurological consult times ≤10 minutes and clinical effectiveness outcomes. Results were stratified between stroke and nonstroke centers. RESULTS: A total of 855 474 ED patient encounters occurred with 5325 code stroke activations (median age, 69 [IQR, 56-79] years; 51.8% female patients]. Percentage of door-to-activation times ≤10 minutes increased from 47.5% to 59.9% (adjusted odds ratio, 1.93 [95% CI, 1.40-2.67]). A total of 615 patients received tPA of ≤3 hours from symptom onset (median age, 71 [IQR, 58-80] years; 49.6% female patients). The percentage of DTN times ≤60 minutes increased from 72.5% to 86.1% (adjusted odds ratio, 3.38, [95% CI, 1.47-7.78]; stroke centers (77.4%-90.0%); nonstroke centers [59.3%-72.1%]). Median DTN time declined from 46 to 38 minutes (adjusted median difference, -9.68 [95% CI, -17.17 to -2.20]; stroke centers [41-35 minutes]; nonstroke centers [55-52 minutes]). No differences were observed in clinical effectiveness outcomes. CONCLUSIONS: A centrally led implementation strategy with local site tailoring led to faster delivery of tPA across disparate EDs in a multihospital system with no change in clinical effectiveness outcomes including rates of complication. Disparities in performance persisted between stroke and nonstroke centers.

Association Between Self-Reported Medication Adherence and Therapeutic Inertia in Hypertension: A Secondary Analysis of SPRINT (Systolic Blood Pressure Intervention Trial).

BACKGROUND: Therapeutic inertia (TI), failure to intensify antihypertensive medication when blood pressure (BP) is above goal, remains prevalent in hypertension management. The degree to which self-reported antihypertensive adherence is associated with TI with intensive BP goals remains unclear. METHODS AND RESULTS: Cross-sectional analysis was performed of the 12-month visit of participants in the intensive arm of SPRINT (Systolic Blood Pressure Intervention Trial), which randomized adults to intensive (<120 mm Hg) versus standard (<140 mm Hg) systolic BP goals. TI was defined as no increase in antihypertensive regimen intensity score, which incorporates medication number and dose, when systolic BP is ≥120 mm Hg. Self-reported adherence was assessed using the 8-Item Morisky Medication Adherence Scale (MMAS-8) and categorized as low (MMAS-8 score <6), medium (MMAS-8 score 6 to <8), and high (MMAS-8 score 8). Poisson regressions estimated prevalence ratios (PRs) and 95% CIs for TI associated with MMAS-8. Among 1009 intensive arm participants with systolic BP >120 mm Hg at the 12-month visit (mean age, 69.6 years; 35.2% female, 28.8% non-Hispanic Black), TI occurred in 50.8% of participants. Participants with low adherence (versus high) were younger and more likely to be non-Hispanic Black or smokers. The prevalence of TI among patients with low, medium, and high adherence was 45.0%, 53.5%, and 50.4%, respectively. After adjustment, neither low nor medium adherence (versus high) were associated with TI (PR, 1.11 [95% CI, 0.87-1.42]; PR, 1.08 [95% CI, 0.84-1.38], respectively). CONCLUSIONS: Although clinician uncertainty about adherence is often cited as a reason for why antihypertensive intensification is withheld when above BP goals, we observed no evidence of an association between self-reported adherence and TI.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

New Users of Angiotensin II Receptor Blocker-Versus Angiotensin-Converting Enzyme Inhibitor-Based Antihypertensive Medication Regimens and Cardiovascular Disease Events: A Secondary Analysis of ACCORD-BP and SPRINT.

BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) block distinct components of the renin-angiotensin system. Whether this translates into differential effects on cardiovascular disease events remains unclear. METHODS AND RESULTS We used the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial and the SPRINT (Systolic Blood Pressure Intervention Trial) to emulate target trials of new users of ARBs versus ACEIs on cardiovascular disease events (primary outcome) and death (secondary outcome). We estimated marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions with inverse probability of treatment weights. We identified 3298 new users of ARBs or ACEIs (ACCORD-BP: 374 ARB versus 884 ACEI; SPRINT: 727 ARB versus 1313 ACEI). For participants initiating ARBs versus ACEIs, the inverse probability of treatment weight rate of the primary outcome was 3.2 versus 3.5 per 100 person-years in ACCORD-BP (HR, 0.91 [95% CI, 0.63-1.31]) and 1.8 versus 2.2 per 100 person-years in SPRINT (HR, 0.81 [95% CI, 0.56-1.18]). There were no appreciable differences in pooled analyses, except that ARBs versus ACEIs were associated with a lower death rate (HR, 0.56 [95% CI, 0.37-0.85]). ARBs were associated with a lower rate of the primary outcome among subgroups of male versus female participants, non-Hispanic Black versus non-Hispanic White participants, and those randomly assigned to standard versus intensive blood pressure (Pinteraction: <0.01, 0.05, and <0.01, respectively). CONCLUSIONS In this secondary analysis of ACCORD-BP and SPRINT, new users of ARB- versus ACEI-based antihypertensive medication regimens experienced similar cardiovascular disease events rates, with important subgroup differences and lower rates of death overall. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01206062, NCT00000620.

Identifying Patients for Intensive Blood Pressure Treatment Based on Cognitive Benefit: A Secondary Analysis of the SPRINT Randomized Clinical Trial.

Importance: Intensive vs standard treatment to lower systolic blood pressure (SBP) reduces risk of mild cognitive impairment (MCI) or dementia; however, the magnitude of cognitive benefit likely varies among patients. Objective: To estimate the magnitude of cognitive benefit of intensive vs standard systolic BP (SBP) treatment. Design, Setting, and Participants: In this ad hoc secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), 9361 randomized clinical trial participants 50 years or older with high cardiovascular risk but without a history of diabetes, stroke, or dementia were followed up. The SPRINT trial was conducted between November 1, 2010, and August 31, 2016, and the present analysis was completed on October 31, 2022. Intervention: Systolic blood pressure treatment to an intensive (<120 mm Hg) vs standard (<140 mm Hg) target. Main Outcomes and Measures: The primary outcome was a composite of adjudicated probable dementia or amnestic MCI. Results: A total of 7918 SPRINT participants were included in the analysis; 3989 were in the intensive treatment group (mean [SD] age, 67.9 [9.2] years; 2570 [64.4%] men; 1212 [30.4%] non-Hispanic Black) and 3929 were in the standard treatment group (mean [SD] age, 67.9 [9.4] years; 2570 [65.4%] men; 1249 [31.8%] non-Hispanic Black). Over a median follow-up of 4.13 (IQR, 3.50-5.88) years, there were 765 and 828 primary outcome events in the intensive treatment group and standard treatment group, respectively. Older age (hazard ratio [HR] per 1 SD, 1.87 [95% CI, 1.78-1.96]), Medicare enrollment (HR per 1 SD, 1.42 [95% CI, 1.35-1.49]), and higher baseline serum creatinine level (HR per 1 SD, 1.24 [95% CI, 1.19-1.29]) were associated with higher risk of the primary outcome, while better baseline cognitive functioning (HR per 1 SD, 0.43 [95% CI, 0.41-0.44]) and active employment status (HR per 1 SD, 0.44 [95% CI, 0.42-0.46]) were associated with lower risk of the primary outcome. Risk of the primary outcome by treatment goal was estimated accurately based on similar projected and observed absolute risk differences (C statistic = 0.79). Higher baseline risk for the primary outcome was associated with greater benefit (ie, larger absolute reduction of probable dementia or amnestic MCI) of intensive vs standard treatment across the full range of estimated baseline risk. Conclusions and Relevance: In this secondary analysis of the SPRINT trial, participants with higher baseline projected risk of probable dementia or amnestic MCI gained greater absolute cognitive benefit from intensive vs standard SBP treatment in a monotonic fashion. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

An efficient approach for optimizing the cost-effective individualized treatment rule using conditional random forest.

Evidence from observational studies has become increasingly important for supporting healthcare policy making via cost-effectiveness analyses. Similar as in comparative effectiveness studies, health economic evaluations that consider subject-level heterogeneity produce individualized treatment rules that are often more cost-effective than one-size-fits-all treatment. Thus, it is of great interest to develop statistical tools for learning such a cost-effective individualized treatment rule under the causal inference framework that allows proper handling of potential confounding and can be applied to both trials and observational studies. In this paper, we use the concept of net-monetary-benefit to assess the trade-off between health benefits and related costs. We estimate cost-effective individualized treatment rule as a function of patients' characteristics that, when implemented, optimizes the allocation of limited healthcare resources by maximizing health gains while minimizing treatment-related costs. We employ the conditional random forest approach and identify the optimal cost-effective individualized treatment rule using net-monetary-benefit-based classification algorithms, where two partitioned estimators are proposed for the subject-specific weights to effectively incorporate information from censored individuals. We conduct simulation studies to evaluate the performance of our proposals. We apply our top-performing algorithm to the NIH-funded Systolic Blood Pressure Intervention Trial to illustrate the cost-effectiveness gains of assigning customized intensive blood pressure therapy.

Risk of Mild Cognitive Impairment or Probable Dementia in New Users of Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors: A Secondary Analysis of Data From the Systolic Blood Pressure Intervention Trial (SPRINT).

Importance: The cardiovascular and renal outcomes of angiotensin-II receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) treatment are well-known; however, few studies have evaluated initiation of these agents and cognitive impairment. Objective: To emulate a target trial to evaluate the cognitive outcomes of initiating an ARB- vs ACEI-based antihypertensive regimen in individuals at risk for mild cognitive impairment (MCI) and probable dementia (PD). Design, Setting, and Participants: Active comparator, new-user observational cohort study design using data from the Systolic Blood Pressure Intervention Trial (SPRINT), conducted November 2010 through July 2018. Marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions were estimated with inverse probability (IP) weighting to account for confounding. Participants were using neither an ARB nor ACEI at baseline. Data analysis was conducted from April 7, 2021, to April 26, 2022. Exposures: New users of ARB vs ACEI during the first 12 months of trial follow-up. Main Outcomes and Measures: Composite of adjudicated amnestic MCI or PD. Results: Of 9361 participants, 727 and 1313 new users of an ARB or ACEI, respectively, with well-balanced baseline characteristics between medication exposure groups after inverse probability weighting (mean [SD] age, 67 [9.5] years; 1291 ]63%] male; 240 [33%] Black; 89 [12%] Hispanic; 383 [53%] White; and 15 [2%] other race or ethnicity. In the primary analysis, during a median follow-up of 4.9 years, the inverse probability-weighted rate of amnestic MCI or PD was 4.3 vs 4.6 per 100 person-years among participants initiating ARB vs ACEI (HR, 0.93; 95% CI, 0.76-1.13). In subgroup analyses, new users of an ARB vs ACEI had a lower rate of amnestic MCI or PD among those in the standard systolic blood pressure treatment arm (HR, 0.61; 95% CI, 0.41-0.91) but not in the intensive arm (HR, 1.17; 95% CI, 0.90-1.52) (P = .007 for interaction). Conclusions and Relevance: In this observational cohort study of US adults at high cardiovascular disease risk, there was no difference in the rate of amnestic MCI or PD among new users of an ARB compared with ACEI, although 95% CIs were wide.

Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment.

Importance: Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, this association with cognitive outcomes in hypertension trials, with blood pressure levels in the range of current guidelines, has not been evaluated. Objective: To examine the association between use of exclusively antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors on mild cognitive impairment (MCI) or dementia. Design, Setting, and Participants: This cohort study is a secondary analysis (April 2011 to July 2018) of participants in the randomized Systolic Blood Pressure Intervention Trial (SPRINT), which recruited individuals 50 years or older with hypertension and increased cardiovascular risk but without a history of diabetes, stroke, or dementia. Data analysis was conducted from March 16 to July 6, 2021. Exposures: Prevalent use of angiotensin II receptor type 2 and 4-stimulating or -inhibiting antihypertensive medication regimens at the 6-month study visit. Main Outcomes and Measures: The primary outcome was a composite of adjudicated amnestic MCI or probable dementia. Results: Of the 8685 SPRINT participants who were prevalent users of antihypertensive medication regimens at the 6-month study visit (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; and 935 [10.8%] Hispanic, 2605 [30.0%] non-Hispanic Black, 4983 [57.4%] non-Hispanic White, and 162 [1.9%] who responded as other race or ethnicity), 2644 (30.4%) were users of exclusively stimulating, 1536 (17.7%) inhibiting, and 4505 (51.9%) mixed antihypertensive medication regimens. During a median of 4.8 years of follow-up (95% CI, 4.7-4.8 years), there were 45 vs 59 cases per 1000 person-years of amnestic MCI or probable dementia among prevalent users of regimens that contained exclusively stimulating vs inhibiting antihypertensive medications (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87). When comparing stimulating-only vs inhibiting-only users, amnestic MCI occurred at rates of 40 vs 54 cases per 1000 person-years (HR, 0.74; 95% CI, 0.64-0.87) and probable dementia at rates of 8 vs 10 cases per 1000 person-years (HR, 0.80; 95% CI, 0.57-1.14). Negative control outcome analyses suggested the presence of residual confounding. Conclusions and Relevance: In this secondary analysis of SPRINT, prevalent users of regimens that contain exclusively antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors had lower rates of incident cognitive impairment. Residual confounding cannot be ruled out. If these results are replicated in randomized clinical trials, certain antihypertensive medications could be prioritized to prevent cognitive decline.

Analysis of Therapeutic Inertia and Race and Ethnicity in the Systolic Blood Pressure Intervention Trial: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Therapeutic inertia may contribute to racial and ethnic differences in blood pressure (BP) control. Objective: To determine the association between race and ethnicity and therapeutic inertia in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, Setting, and Participants: This cross-sectional study was a secondary analysis of data from SPRINT, a randomized clinical trial comparing intensive (<120 mm Hg) vs standard (<140 mm Hg) systolic BP treatment goals. Participants were enrolled between November 8, 2010, and March 15, 2013, with a median follow-up 3.26 years. Participants included adults aged 50 years or older at high risk for cardiovascular disease but without diabetes, previous stroke, or heart failure. The present analysis was restricted to participant visits with measured BP above the target goal. Analyses for the present study were performed in from October 2020 through March 2021. Exposures: Self-reported race and ethnicity, mutually exclusively categorized into groups of Hispanic, non-Hispanic Black, or non-Hispanic White participants. Main Outcomes and Measures: Therapeutic inertia, defined as no antihypertensive medication intensification at each study visit where the BP was above target goal. The association between self-reported race and ethnicity and therapeutic inertia was estimated using generalized estimating equations and stratified by treatment group. Antihypertensive medication use was assessed with pill bottle inventories at each visit. Blood pressure was measured using an automated device. Results: A total of 8556 participants, including 4141 in the standard group (22 844 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1467 women [35.4%]) and 4415 in the intensive group (35 453 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1584 women [35.9%]) with at least 1 eligible study visit were included in the present analysis. Among non-Hispanic White, non-Hispanic Black, and Hispanic participants, the overall prevalence of therapeutic inertia in the standard vs intensive groups was 59.8% (95% CI, 58.9%-60.7%) vs 56.0% (95% CI, 55.2%-56.7%), 56.8% (95% CI, 54.4%-59.2%) vs 54.5% (95% CI, 52.4%-56.6%), and 59.7% (95% CI, 56.5%-63.0%) vs 51.0% (95% CI, 47.4%-54.5%), respectively. The adjusted odds ratios in the standard and intensive groups for therapeutic inertia associated with non-Hispanic Black vs non-Hispanic White participants were 0.85 (95% CI, 0.79-0.92) and 0.94 (95% CI, 0.88-1.01), respectively. The adjusted odds ratios for therapeutic inertia comparing Hispanic vs non-Hispanic White participants were 1.00 (95% CI, 0.90-1.13) and 0.89 (95% CI, 0.79-1.00) in the standard and intensive groups, respectively. Conclusions and Relevance: Among SPRINT participants above BP target goal, this cross-sectional study found that therapeutic inertia prevalence was similar or lower for non-Hispanic Black and Hispanic participants compared with non-Hispanic White participants. These findings suggest that a standardized approach to BP management, as used in SPRINT, may help ensure equitable care and could reduce the contribution of therapeutic inertia to disparities in hypertension. Trial Registration: ClinicalTrials.gov identifier: NCT01206062.

N-myristoyltransferase 2-based Blood Test for the Detection of Colorectal Adenomatous Polyps and Cancer.

Background: Colorectal cancer is the second leading cause of cancer-related deaths. This study demonstrates the utility of a simple blood test with high sensitivity and specificity for colorectal adenomatous polyps and cancer. A simple blood test with high sensitivity and specificity for adenomas would help identify individuals for a follow-up colonoscopy during which any adenomatous polyps found could be removed, thus preventing colorectal cancer (CRC). Methods: We determined the H-score by using immunohistochemical analyses of N-myristoyltransferase 2 (NMT2) in peripheral blood mononuclear cells (PBMC) isolated from the blood. We determined the sensitivity and specificity of the NMT2-based blood test in identifying colorectal adenomatous polyps and cancer. Design: All experimental procedures were performed by research personnel blinded to the colonoscopy status of the participants. Setting: In this cohort study, participants were recruited from those coming for an outpatient colonoscopy at a referral center. Participants: PBMC were collected from 74 subjects at the Health Sciences Centre, Winnipeg, Canada. Samples were collected from colonoscopy patients prior to colonoscopy. All 74 subjects were included in CRC vs. non-CRC analysis, whereas only 70 subjects were analyzed for colorectal adenomatous polyps and cancer versus individuals with no evidence of disease and non-adenomatous polyps. NMT2 expression was tested in samples by immunohistochemistry. Results: The expression of NMT2 was significantly higher in PBMC of subjects with colorectal adenomatous polyps and cancer (n = 34) compared with individuals with non-adenomatous polyps or no evidence of disease (n = 36) (P < 0.0001). The test had an overall sensitivity of 91% (95% confidence intervals: 84.49-97.80) and specificity of 81% (95% confidence intervals: 71.28-89.83) in detecting colorectal adenomatous polyps and cancer (all stages). Conclusions: Our results suggest that the sensitivity of NMT2 in detecting adenomatous polyps is high (91%). A simple blood-based CRC screening test using NMT2 expression detects colorectal adenomatous polyps and cancer with high sensitivity and specificity has the potential of increasing the compliance for CRC screening as has been reported for other blood-based CRC screening tests.

Estimating the optimal individualized treatment rule from a cost-effectiveness perspective.

Optimal individualized treatment rules (ITRs) provide customized treatment recommendations based on subject characteristics to maximize clinical benefit in accordance with the objectives in precision medicine. As a result, there is growing interest in developing statistical tools for estimating optimal ITRs in evidence-based research. In health economic perspectives, policy makers consider the tradeoff between health gains and incremental costs of interventions to set priorities and allocate resources. However, most work on ITRs has focused on maximizing the effectiveness of treatment without considering costs. In this paper, we jointly consider the impact of effectiveness and cost on treatment decisions and define ITRs under a composite-outcome setting, so that we identify the most cost-effective ITR that accounts for individual-level heterogeneity through direct optimization. In particular, we propose a decision-tree-based statistical learning algorithm that uses a net-monetary-benefit-based reward to provide nonparametric estimations of the optimal ITR. We provide several approaches to estimating the reward underlying the ITR as a function of subject characteristics. We present the strengths and weaknesses of each approach and provide practical guidelines by comparing their performance in simulation studies. We illustrate the top-performing approach from our simulations by evaluating the projected 15-year personalized cost-effectiveness of the intensive blood pressure control of the Systolic Blood Pressure Intervention Trial (SPRINT) study.

Study protocol for a randomised clinical trial of a decision aid and values clarification method for parents of a fetus or neonate diagnosed with a life-threatening congenital heart defect.

INTRODUCTION: Parents who receive the diagnosis of a life-threatening, complex heart defect in their fetus or neonate face a difficult choice between pursuing termination (for fetal diagnoses), palliative care or complex surgical interventions. Shared decision making (SDM) is recommended in clinical contexts where there is clinical equipoise. SDM can be facilitated by decision aids. The International Patient Decision Aids Standards collaboration recommends the inclusion of values clarification methods (VCMs), yet little evidence exists concerning the incremental impact of VCMs on patient or surrogate decision making. This protocol describes a randomised clinical trial to evaluate the effect of a decision aid (with and without a VCM) on parental mental health and decision making within a clinical encounter. METHODS AND ANALYSIS: Parents who have a fetus or neonate diagnosed with one of six complex congenital heart defects at a single tertiary centre will be recruited. Data collection for the prospective observational control group was conducted September 2018 to December 2020 (N=35) and data collection for two intervention groups is ongoing (began October 2020). At least 100 participants will be randomised 1:1 to two intervention groups (decision aid only vs decision aid with VCM). For the intervention groups, data will be collected at four time points: (1) at diagnosis, (2) postreceipt of decision aid, (3) postdecision and (4) 3 months postdecision. Data collection for the control group was the same, except they did not receive a survey at time 2. Linear mixed effects models will assess differences between study arms in distress (primary outcome), grief and decision quality (secondary outcomes) at 3-month post-treatment decision. ETHICS AND DISSEMINATION: This study was approved by the University of Utah Institutional Review Board. Study findings have and will continue to be presented at national conferences and within scientific research journals. TRIAL REGISTRATION NUMBER: NCT04437069 (Pre-results).

Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans.

BACKGROUND: Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses. METHODS AND FINDINGS: In this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days). CONCLUSIONS: This observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials.

Computerized Mortality Prediction for Community-acquired Pneumonia at 117 Veterans Affairs Medical Centers.

Rationale: Computerized severity assessment for community-acquired pneumonia could improve consistency and reduce clinician burden. Objectives: To develop and compare 30-day mortality-prediction models using electronic health record data, including a computerized score with all variables from the original Pneumonia Severity Index (PSI) except confusion and pleural effusion ("ePSI score") versus models with additional variables. Methods: Among adults with community-acquired pneumonia presenting to emergency departments at 117 Veterans Affairs Medical Centers between January 1, 2006, and December 31, 2016, we compared an ePSI score with 10 novel models employing logistic regression, spline, and machine learning methods using PSI variables, age, sex and 26 physiologic variables as well as all 69 PSI variables. Models were trained using encounters before January 1, 2015; tested on encounters during and after January 1, 2015; and compared using the areas under the receiver operating characteristic curve, confidence intervals, and patient event rates at a threshold PSI score of 970. Results: Among 297,498 encounters, 7% resulted in death within 30 days. When compared using the ePSI score (confidence interval [CI] for the area under the receiver operating characteristic curve, 0.77-0.78), performance increased with model complexity (CI for the logistic regression PSI model, 0.79-0.80; CI for the boosted decision-tree algorithm machine learning PSI model using the Extreme Gradient Boosting algorithm [mlPSI] with the 19 original PSI factors, 0.83-0.85) and the number of variables (CI for the logistic regression PSI model using all 69 variables, 0.84-085; CI for the mlPSI with all 69 variables, 0.86-0.87). Models limited to age, sex, and physiologic variables also demonstrated high performance (CI for the mlPSI with age, sex, and 26 physiologic factors, 0.84-0.85). At an ePSI score of 970 and a mortality-risk cutoff of <2.7%, the ePSI score identified 31% of all patients as being at "low risk"; the mlPSI with age, sex, and 26 physiologic factors identified 53% of all patients as being at low risk; and the mlPSI with all 69 variables identified 56% of all patients as being at low risk, with similar rates of mortality, hospitalization, and 7-day secondary hospitalization being determined. Conclusions: Computerized versions of the PSI accurately identified patients with pneumonia who were at low risk of death. More complex models classified more patients as being at low risk of death and as having similar adverse outcomes.

A Sequential Multiple-Assignment Randomized Trial (SMART) for Stepped Care Management of Low Back Pain in the Military Health System: A Trial Protocol.

BACKGROUND: The Defense Health Agency has prioritized system-level pain management initiatives within the Military Health System (MHS), with low back pain as one of the key focus areas. A stepped care model focused on nonpharmacologic treatment to promote self-management is recommended. Implementation of stepped care is complicated by lack of information on the most effective nonpharmacologic strategies and how to sequence and tailor the various available options. The Sequential Multiple-Assignment Randomization Trial for Low Back Pain (SMART LBP) is a multisite pragmatic trial using a SMART design to assess the effectiveness of nonpharmacologic treatments for chronic low back pain. DESIGN: This SMART trial has two treatment phases. Participants from three military treatment facilities are randomized to 6 weeks of phase I treatment, receiving either physical therapy (PT) or Army Medicine's holistic Move2Health (M2H) program in a package specific to low back pain. Nonresponders to treatment in phase I are again randomized to phase II treatment of combined M2H + PT or mindfulness-based treatment using the Mindfulness-Oriented Recovery Enhancement (MORE) program. The primary outcome is the Patient-Reported Outcomes Measurement Information System pain interference computer-adapted test score. SUMMARY: This trial is part of an initiative funded by the National Institutes of Health, Veterans Affairs, and the Department of Defense to establish a national infrastructure for effective system-level management of chronic pain with a focus on nonpharmacologic treatments. The results of this study will provide important information on nonpharmacologic care for chronic LBP in the MHS embedded within a stepped care framework.

Factors That Contribute to Cost Differences Based on ICU of Admission in Neonates Undergoing Congenital Heart Surgery: A Novel Decomposition Analysis.

OBJECTIVES: We leveraged decomposition analysis, commonly used in labor economics, to understand determinants of cost differences related to location of admission in children undergoing neonatal congenital heart surgery. DESIGN: A retrospective cohort study. SETTING: Pediatric Health Information Systems database. PATIENTS: Neonates (<30 d old) undergoing their index congenital heart surgery between 2004 and 2013. MEASUREMENTS AND MAIN RESULTS: A decomposition analysis with bootstrapping determined characteristic (explainable by differing covariate levels) and structural effects (if covariates are held constant) related to cost differences. Covariates included center volume, age at admission, prematurity, sex, race, genetic or major noncardiac abnormality, Risk Adjustment for Congenital Heart Surgery-1 score, payor, admission year, cardiac arrest, infection, and delayed sternal closure.Of 19,984 infants included (10,491 [52%] to cardiac ICU/PICU and 9,493 [48%] to neonatal ICU), admission to the neonatal ICU had overall higher average costs ($24,959 ± $3,260; p < 0.001) versus cardiac ICU/PICU admission. Characteristic effects accounted for higher costs in the neonatal ICU ($28,958 ± $2,044; p < 0.001). Differing levels of prematurity, genetic syndromes, hospital volume, age at admission, and infection contributed to higher neonatal ICU costs, with infection rate providing the most significant contribution ($13,581; p < 0.001). Aggregate structural effects were not associated with cost differences for those admitted to the neonatal ICU versus cardiac ICU/PICU (p = 0.1). Individually, prematurity and age at admission were associated with higher costs due to structural effects for infants admitted to the neonatal ICU versus cardiac ICU/PICU. CONCLUSIONS: The difference in cost between neonatal ICU and cardiac ICU/PICU admissions is largely driven by differing prevalence of risk factors between these units. Infection rate was a modifiable factor that accounted for the largest difference in costs between admitting units.

Comparison of As-Needed and Scheduled Posthospitalization Follow-up for Children Hospitalized for Bronchiolitis: The Bronchiolitis Follow-up Intervention Trial (BeneFIT) Randomized Clinical Trial.

Importance: Posthospitalization follow-up visits are prescribed frequently for children with bronchiolitis. The rationale for this practice is unclear, but prior work has indicated that families value these visits for the reassurance provided. The overall risks and benefits of scheduled visits have not been evaluated. Objective: To assess whether an as-needed posthospitalization follow-up visit is noninferior to a scheduled posthospitalization follow-up visit with respect to reducing anxiety among parents of children hospitalized for bronchiolitis. Design, Setting, and Participants: This open-label, noninferiority randomized clinical trial, performed between January 1, 2018, and April 31, 2019, assessed children younger than 24 months of age hospitalized for bronchiolitis at 2 children's hospitals (Primary Children's Hospital, Salt Lake City, Utah, and Lucile Packard Children's Hospital, Palo Alto, California) and 2 community hospitals (Intermountain Riverton Hospital, Riverton, Utah, and Packard El Camino Hospital, Mountain View, California). Data analysis was performed in an intention-to-treat manner. Interventions: Randomization (1:1) to a scheduled (n = 151) vs an as-needed (n = 153) posthospitalization follow-up visit. Main Outcome and Measures: The primary outcome was parental anxiety 7 days after hospital discharge, measured using the anxiety portion of the Hospital Anxiety and Depression Scale, which ranged from 0 to 28 points, with higher scores indicating greater anxiety. Fourteen prespecified secondary outcomes were assessed. Results: Among 304 children randomized (median age, 8 months; interquartile range, 3-14 months; 179 [59%] male), the primary outcome was available for 269 patients (88%). A total of 106 children (81%) in the scheduled follow-up group attended a scheduled posthospitalization visit compared with 26 children (19%) in the as-needed group (absolute difference, 62%; 95% CI, 53%-71%). The mean (SD) 7-day parental anxiety score was 3.9 (3.5) among the as-needed posthospitalization follow-up group and 4.2 (3.5) among the scheduled group (absolute difference, -0.3 points; 95% CI, -1.0 to 0.4 points), with the upper bound of the 95% CI within the prespecified noninferiority margin of 1.1 points. Aside from a decreased mean number of clinic visits (absolute difference, -0.6 visits per patient; 95% CI, -0.4 to -0.8 visits per patient) among the as-needed group, there were no significant between-group differences in secondary outcomes, including readmissions (any hospital readmission before symptom resolution: absolute difference, -1.6%; 95% CI, -5.7% to 2.5%) and symptom duration (time from discharge to cough resolution: absolute difference, -0.6 days; 95% CI, -2.4 to 1.2 days; time from discharge to child reported "back to normal": absolute difference, -0.8 days; 95% CI, -2.7 to 1.0 days; and time from discharge to symptom resolution: absolute difference, -0.6 days; 95% CI, -2.5 to 1.3 days). Conclusions and Relevance: Among parents of children hospitalized for bronchiolitis, an as-needed posthospitalization follow-up visit is noninferior to a scheduled posthospitalization follow-up visit with respect to reducing parental anxiety. These findings support as-needed follow-up as an effective posthospitalization follow-up strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT03354325.

Contextual Factors Influencing Implementation of Evidence-Based Care for Children Hospitalized With Asthma.

BACKGROUND AND OBJECTIVES: The translation of research findings into routine care remains slow and challenging. We previously reported successful implementation of an asthma evidence-based care process model (EB-CPM) at 8 (1 tertiary care and 7 community) hospitals, leading to a high health care provider (HCP) adherence with the EB-CPM and improved outcomes. In this study, we explore contextual factors perceived by HCPs to facilitate successful EB-CPM implementation. METHODS: Structured and open-ended questions were used to survey HCPs (n = 260) including physicians, nurses, and respiratory therapists, about contextual factors perceived to facilitate EB-CPM implementation. Quantitative analysis was used to identify significant factors (correlation coefficient ≥0.5; P ≤ .05) and qualitative analysis to assess additional facilitators. RESULTS: Factors perceived by HCPs to facilitate EB-CPM implementation were related to (1) inner setting (leadership support, adequate resources, communication and/or collaboration, culture, and previous experience with guideline implementation), (2) intervention characteristics (relevant and applicable to the HCP's practice), (3) individuals (HCPs) targeted (agreement with the EB-CPM and knowledge of supporting evidence), and (4) implementation process (participation of HCPs in implementation activities, teamwork, implementation team with a mix of expertise and professional's input, and data feedback). Additional facilitators included (1) having appropriate preparation and (2) providing education and training. CONCLUSIONS: Multiple factors were associated with successful EB-CPM implementation and may be used by others as a guide to facilitate implementation and dissemination of evidence-based interventions for pediatric asthma and other chronic diseases in the hospital setting.

Association of Total Medication Burden With Intensive and Standard Blood Pressure Control and Clinical Outcomes: A Secondary Analysis of SPRINT.

Total medication burden (antihypertensive and nonantihypertensive medications) may be associated with poor systolic blood pressure (SBP) control. We investigated the association of baseline medication burden and clinical outcomes and whether the effect of the SBP intervention varied according to baseline medication burden in SPRINT (Systolic Blood Pressure Intervention Trial). Participants were randomized to intensive or standard SBP goal (below 120 or 140 mm Hg, respectively); n=3769 participants with high baseline medication burden (≥5 medications) and n=5592 with low burden (<5 medications). PRIMARY OUTCOME: differences in SBP. SECONDARY OUTCOMES: 8-item Morisky Medication Adherence Scale and modified Treatment Satisfaction Questionnaire for Medications measured at baseline and 12 months and incident cardiovascular disease events and serious adverse events throughout the trial. Participants in the intensive group with high versus low medication burden were less likely to achieve their SBP goal at 12 months (risk ratio, 0.91; 95% CI, 0.85-0.97) but not in the standard group (risk ratio, 0.98; 95% CI, 0.93-1.03; Pinteraction<0.001). High medication burden was associated with increased cardiovascular disease events (hazard ratio, 1.39; 95% CI, 1.14-1.70) and serious adverse events (hazard ratio, 1.34; 95% CI, 1.24-1.45), but the effect of intensive versus standard treatment did not vary between medication burden groups (Pinteraction>0.5). Medication burden had minimal association with adherence or satisfaction. High baseline medication burden was associated with worse intensive SBP control and higher rates of cardiovascular disease events and serious adverse events. The relative benefits and risks of intensive SBP goals were similar regardless of medication burden. CLINICAL TRIAL REGISTRATION- URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT01206062.