A Bayesian adaptive design for clinical trials of rare efficacy outcomes with multiple definitions.

INTRODUCTION: Bayesian adaptive designs for clinical trials have gained popularity in the recent years due to the flexibility and efficiency that they offer. We consider the scenario where the outcome of interest comprises events with relatively low risk of occurrence and different case definitions resulting in varying control group risk assumptions. This is a scenario that occurs frequently for infectious diseases in global health research. METHODS: We propose a Bayesian adaptive design that incorporates different case definitions of the outcome of interest that vary in stringency. A set of stopping rules are proposed where superiority and futility may be concluded with respect to different outcome definitions and therefore maintain a realistic probability of stopping in trials with low event rates. Through a simulation study, a variety of stopping rules and design configurations are compared. RESULTS: The simulation results are provided in an interactive web application that allows the user to explore and compare the design operating characteristics for a variety of assumptions and design parameters with respect to different outcome definitions. The results for select simulation scenarios are provided in the article. DISCUSSION: Bayesian adaptive designs offer the potential for maximizing the information learned from the data collected through clinical trials. The proposed design enables monitoring and utilizing multiple composite outcomes based on rare events to optimize the trial design operating characteristics.

Robust demographically-adjusted normative data for the Montreal Cognitive Assessment (MoCA): Results from the systolic blood pressure intervention trial.

To generate robust, demographically-adjusted regression-based norms for the Montreal Cognitive Assessment (MoCA) using a large sample of diverse older US adults.Baseline MoCA scores were examined for participants in the Systolic Blood Pressure Intervention Trial (SPRINT). A robust, cognitively-normal sample was drawn from individuals not subsequently adjudicated with cognitive impairment through 4 years of follow-up. Multivariable Beta-Binomial regression was used to model the association of demographic variables with MoCA performance and to create demographically-stratified normative tables.Participants' (N = 5,338) mean age was 66.9 ± 8.8 years, with 35.7% female, 63.1% White, 27.4% Black, 9.5% Hispanic, and 44.5% with a college or graduate education. A large proportion scored below published MoCA cutoffs: 61.4% scored below 26 and 29.2% scored below 23. A disproportionate number falling below these cutoffs were Black, Hispanic, did not graduate from college, or were ≥75 years of age. Multivariable modeling identified education, race/ethnicity, age, and sex as significant predictors of MoCA scores (p<.001), with the best fitting model explaining 24.4% of the variance. Model-based predictions of median MoCA scores were generally 1 to 2 points lower for Black and Hispanic participants across combinations of age, sex, and education. Demographically-stratified norm-tables based on regression modeling are provided to facilitate clinical use, along with our raw data.By using regression-based strategies that more fully account for demographic variables, we provide robust, demographically-adjusted metrics to improve cognitive screening with the MoCA in diverse older adults.

Incidence and Outcomes of Acute Heart Failure With Preserved Versus Reduced Ejection Fraction in SPRINT.

BACKGROUND: In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes. METHODS: Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%. RESULTS: Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF (P value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission. CONCLUSIONS: In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Detection of Cognitive Impairment after Critical Illness with the Medicare Annual Wellness Visit: A Cohort Study.

Rationale: Cognitive impairment after critical illness is common in observational studies of older intensive care unit (ICU) survivors. The rate of screening for and diagnosis of cognitive impairment in ICU survivors in nonresearch settings is unknown. Objectives: To determine how often cognitive impairment was detected in older adults in the year after critical illness at an academic medical center as part of 1) the Medicare Annual Wellness Visit (AWV) and 2) routine clinical care. Methods: This study was a retrospective cohort study conducted at an urban academic medical center. The study included 696 patients aged 65 years and older admitted to the medical ICU between October 1, 2016, and October 1, 2018, and discharged alive. Patients were also required to have a health system-affiliated primary care provider. Patients were followed for 1 year. We defined cognitive impairment detected in the AWV as either an indicated diagnosis of cognitive impairment or dementia or patient, family, or provider indication of memory concerns during the AWV. We modeled the incidence of AWV completion and the detection of cognitive impairment using semiparametric additive models accounting for the competing risk of death. Results: Over 1 year of follow-up, the cumulative incidence of mortality was 23.0% (95% confidence interval [CI], 19.9-26.1%), with 24.7% (95% CI, 21.5-27.9%) completing the AWV. The cumulative incidence of cognitive impairment first detected through the AWV was 3.4% (95% CI, 1.8-5.0%) at 1 year, with a higher cumulative incidence for diagnoses of cognitive impairment or dementia first indicated via encounter diagnosis codes or the electronic health record problem list (5.9%; 95% CI, 3.9-7.9%). Conclusions: The results of our study suggest that the currently implemented AWV is unlikely to be an adequate mechanism for detecting cognitive impairment in a high-risk population such as those recovering from critical illness.

Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes.

[Figure: see text].

Automated Frailty Screening At-Scale for Pre-Operative Risk Stratification Using the Electronic Frailty Index.

BACKGROUND: Frailty is associated with numerous post-operative adverse outcomes in older adults. Current pre-operative frailty screening tools require additional data collection or objective assessments, adding expense and limiting large-scale implementation. OBJECTIVE: To evaluate the association of an automated measure of frailty integrated within the Electronic Health Record (EHR) with post-operative outcomes for nonemergency surgeries. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center. PARTICIPANTS: Patients 65 years or older that underwent nonemergency surgery with an inpatient stay 24 hours or more between October 8th, 2017 and June 1st, 2019. EXPOSURES: Frailty as measured by a 54-item electronic frailty index (eFI). OUTCOMES AND MEASUREMENTS: Inpatient length of stay, requirements for post-acute care, 30-day readmission, and 6-month all-cause mortality. RESULTS: Of 4,831 unique patients (2,281 females (47.3%); mean (SD) age, 73.2 (5.9) years), 4,143 (85.7%) had sufficient EHR data to calculate the eFI, with 15.1% categorized as frail (eFI > 0.21) and 50.9% pre-frail (0.10 < eFI ≤ 0.21). For all outcomes, there was a generally a gradation of risk with higher eFI scores. For example, adjusting for age, sex, race/ethnicity, and American Society of Anesthesiologists class, and accounting for variability by service line, patients identified as frail based on the eFI, compared to fit patients, had greater needs for post-acute care (odds ratio (OR) = 1.68; 95% confidence interval (CI) = 1.36-2.08), higher rates of 30-day readmission (hazard ratio (HR) = 2.46; 95%CI = 1.72-3.52) and higher all-cause mortality (HR = 2.86; 95%CI = 1.84-4.44) over 6 months' follow-up. CONCLUSIONS: The eFI, an automated digital marker for frailty integrated within the EHR, can facilitate pre-operative frailty screening at scale.

Burn Scar Biomechanics after Pressure Garment Therapy.

BACKGROUND: The current standard of care for the prevention and treatment of scarring after burn injury is pressure garment therapy. Although this therapy has been used clinically for many years, controversy remains regarding its efficacy. The authors evaluated the efficacy of pressure garment therapy in a female red Duroc pig burn model in which wound depth could be tightly controlled. METHODS: Full-thickness burn wounds were generated on female red Duroc pigs. At day 28 after burn, pressure garment therapy was applied to half the wounds (10 mmHg), with control wounds covered with garments that exerted no compression. Scar area, perfusion, hardness, and elasticity were quantified at days 0, 28, 42, 56, and 72 using computerized planimetry, laser Doppler, and torsional ballistometry. Scar morphology was assessed at days 28, 56, and 76 using histology, immunohistochemistry, and transmission electron microscopy. RESULTS: Pressure garment therapy significantly hindered scar contraction, with control scars contracting to 64.6 percent + 13.9 percent original area at day 72, whereas pressure garment therapy scars contracted to 82.7 percent + 17.9 percent original area. Pressure garments significantly reduced skin hardness and increased skin strength by 1.3 times. No difference in perfusion or blood vessel density was observed. The average collagen fiber diameter was greater in control burns than in pressure garment therapy. CONCLUSIONS: Pressure garment therapy was effective at reducing scar contraction and improving biomechanics compared with control scars. These results confirm the efficacy of pressure garments and highlight the need to further investigate the role of pressure magnitude and the time of therapy application to enhance efficacy for optimal biomechanics and patient mobility.

Plant-derived human collagen scaffolds for skin tissue engineering.

Tissue engineering scaffolds are commonly formed using proteins extracted from animal tissues, such as bovine hide. Risks associated with the use of these materials include hypersensitivity and pathogenic contamination. Human-derived proteins lower the risk of hypersensitivity, but possess the risk of disease transmission. Methods engineering recombinant human proteins using plant material provide an alternate source of these materials without the risk of disease transmission or concerns regarding variability. To investigate the utility of plant-derived human collagen (PDHC) in the development of engineered skin (ES), PDHC and bovine hide collagen were formed into tissue engineering scaffolds using electrospinning or freeze-drying. Both raw materials were easily formed into two common scaffold types, electrospun nonwoven scaffolds and lyophilized sponges, with similar architectures. The processing time, however, was significantly lower with PDHC. PDHC scaffolds supported primary human cell attachment and proliferation at an equivalent or higher level than the bovine material. Interleukin-1 beta production was significantly lower when activated THP-1 macrophages where exposed to PDHC electrospun scaffolds compared to bovine collagen. Both materials promoted proper maturation and differentiation of ES. These data suggest that PDHC may provide a novel source of raw material for tissue engineering with low risk of allergic response or disease transmission.