Upstrapping to determine futility: predicting future outcomes nonparametrically from past data.

BACKGROUND: Clinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring. METHODS: Upstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility. RESULTS: The method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O'Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2-22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0-15% lower. CONCLUSIONS: In this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.

Laryngeal Recalibration Therapy Improves Laryngopharyngeal Symptoms in Patients With Suspected Laryngopharyngeal Reflux Disease.

INTRODUCTION: Laryngopharyngeal symptoms such as cough, throat clearing, voice change, paradoxic vocal fold movement, or laryngospasm are hyper-responsive behaviors resulting from local irritation (e.g., refluxate) and heightened sympathetic tone. Laryngeal recalibration therapy (LRT) guided by a speech-language pathologist (SLP) provides mechanical desensitization and cognitive recalibration to suppress hyper-responsive laryngeal patterns. The aim of this study was to assess symptom response to LRT among patients with chronic laryngopharyngeal symptoms undergoing evaluation of gastroesophageal reflux disease (GERD). METHODS: Adults with chronic laryngopharyngeal symptoms referred for evaluation of GERD to a single center were prospectively followed. Inclusion criteria included ≥2 SLP-directed LRT sessions. Data from endoscopy, ambulatory reflux monitoring, and patient-reported outcomes were collected when available. The primary outcome was symptom response. RESULTS: Sixty-five participants completed LRT: mean age 55.4 years (SD 17.2), 46 (71%) female, mean body mass index 25.6 kg/m 2 (6.8), and mean of 3.7 (1.9) LRT sessions. Overall, 55 participants (85%) met criteria for symptom response. Specifically, symptom response was similar between those with isolated laryngopharyngeal symptoms (13/15, 87%) and concomitant laryngopharyngeal/esophageal symptoms (42/50, 84%). Among participants who underwent reflux monitoring, symptom response was similar between those with proven, inconclusive for, and no GERD (18/21 [86%], 8/9 [89%], 10/13 [77%]). DISCUSSION: Eighty-five percent of patients with chronic laryngopharyngeal symptoms referred for GERD evaluation who underwent LRT-experienced laryngeal symptom response. Rates of symptom response were maintained across patients with or without proven GERD and patients with or without concomitant esophageal reflux symptoms. SLP-directed LRT is an effective approach to incorporate into multidisciplinary management of chronic laryngopharyngeal symptoms/laryngopharyngeal reflux disease.

Low-risk pneumatosis intestinalis in the pediatric surgical population.

BACKGROUND: Pneumatosis intestinalis (PI, presence of air in bowel wall) develops in a variety of settings and due to a variety of insults which is then characterized by varying severity and clinical course. Anecdotally, many of these cases are benign with few clinical sequelae; however, we lack evidence-based guidelines to help guide management of such lower-risk cases. We aimed to describe the clinical entity of low-risk PI, characterize the population of children who develop this form of PI, determine if management approach or clinical outcomes differed depending on the managing physician's field of practice, and finally determine if a shortened course of NPO and antibiotics was safe in the population of children with low-risk PI. METHODS: We performed a retrospective review of all children over age 1 year treated at Children's Hospital Colorado (CHCO), between 2009 and 2019 with a diagnosis of PI who did not also have a diagnosis of cancer or history of bone marrow transplant (BMT). Data including demographic variables, clinical course, and outcomes were obtained from the electronic medical record. Low-risk criteria included no need for ICU admission, vasopressor use, or urgent surgical intervention. RESULTS: Ninety-one children were treated for their first episode of PI during the study period, 72 of whom met our low-risk criteria. Among the low-risk group, rates of complications including hemodynamic decompensation during treatment, PI recurrence, Clostridium difficile colitis, and death did not differ between those who received 3 days or less of antibiotics and those who received more than 3 days of antibiotics. Outcomes also did not differ between children cared for by surgeons or pediatricians. CONCLUSIONS: Here, we define low-risk PI as that which occurs in children over age 1 who do not have a prior diagnosis of cancer or prior BMT and who do not require ICU admission, vasopressor administration, or urgent surgical intervention. It is likely safe to treat these children with only 3 days of antibiotic therapy and NPO. LEVEL OF EVIDENCE: Level III.

The Adherence to an Intraoperative Blood Product Transfusion Algorithm Is Associated With Reduced Blood Product Transfusions in Cardiac Surgical Patients Undergoing Coronary Artery Bypass Grafts and Aortic and/or Valve Replacement Surgery: A Single-Center, Observational Study.

OBJECTIVE: To demonstrate the value of a viscoelastic-based intraoperative transfusion algorithm to reduce non-RBC product administration in adult cardiac surgical patients. DESIGN: A prospective observational study. SETTING: At a quaternary academic teaching hospital. PARTICIPANTS: Cardiac surgical patients. INTERVENTIONS: Viscoelastic-based intraoperative transfusion algorithm. MEASUREMENTS AND MAIN RESULTS: The study authors compared intraoperative blood product transfusion rates in 184 cardiac surgical patients to 236 historic controls after implementing a viscoelastic-based algorithm. The authors found a non-significant reduction in transfusion of 23.8% for fresh frozen plasma (FFP) units (0.84 ± 1.4 v 0.64 ± 1.38; p = ns), 33.4% for platelet units (0.90 ± 1.39 v 0.60 ± 131; p = ns), and 15.8% for cryoprecipitate units (0.19 ± 0.54 v 0.16 ± 0.50; p = ns). They found a 43.9% reduction in red blood cell (RBC) units transfused (1.98 ± 2.24 v 0.55 ± 1.36; p = 0.008). There were no statistically significant differences in time to extubation (8.0 hours (4.0-21.0) v 8.0 (4.0-22.3), reoperation for bleeding (15 [12.3%] v 10 [10.6%]), intensive care unit length of stay (ICU LOS) (51.0 hours [28.0-100.5] v 53.5 [33.3-99.0]) or hospital LOS (9.0 days [6.0-15.0] v 10.0 [7.0-17.0]). Deviation from algorithm adherence was 32.7% (48/147). Packed RBC, FFP, platelets, cryoprecipitate, and cell saver were significantly reduced in the Algorithm Compliant Cohort compared with historic controls, whereas times to extubation, ICU LOS, and hospital LOS did not reach significance. CONCLUSIONS: After the implementation of a viscoelastic-based algorithm, patients received fewer packed RBC, FFP, platelets, cryoprecipitate, and cell saver. Algorithm-compliant patients received fewer transfusions; however, reductions in times to extubation, ICU LOS, and hospital LOS were not statistically significant compared with historic controls.

Validated Clinical Score to Predict Gastroesophageal Reflux in Patients With Chronic Laryngeal Symptoms: COuGH RefluX.

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict the likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms. METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and ß coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model. RESULTS: A total of 856 adults, 304 in the training cohort and 552 in the validation cohort, were included. In the training phase, the optimal predictive model (area under the curve, 0.68; 95% CI, 0.62-0.74), was the Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX (COuGH RefluX) score, with a lower threshold of 2.5 and an upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an area under the curve of 0.67 (95% CI, 0.62-0.71), with 79% sensitivity and 81% specificity for proven GERD. CONCLUSIONS: The externally validated COuGH RefluX score is a clinically practical model to predict the likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.

A practical guide to adopting Bayesian analyses in clinical research.

Background: Bayesian statistical approaches are extensively used in new statistical methods but have not been adopted at the same rate in clinical and translational (C&T) research. The goal of this paper is to accelerate the transition of new methods into practice by improving the C&T researcher's ability to gain confidence in interpreting and implementing Bayesian analyses. Methods: We developed a Bayesian data analysis plan and implemented that plan for a two-arm clinical trial comparing the effectiveness of a new opioid in reducing time to discharge from the post-operative anesthesia unit and nerve block usage in surgery. Through this application, we offer a brief tutorial on Bayesian methods and exhibit how to apply four Bayesian statistical packages from STATA, SAS, and RStan to conduct linear and logistic regression analyses in clinical research. Results: The analysis results in our application were robust to statistical package and consistent across a wide range of prior distributions. STATA was the most approachable package for linear regression but was more limited in the models that could be fitted and easily summarized. SAS and R offered more straightforward documentation and data management for the posteriors. They also offered direct programming of the likelihood making them more easily extendable to complex problems. Conclusion: Bayesian analysis is now accessible to a broad range of data analysts and should be considered in more C&T research analyses. This will allow C&T research teams the ability to adopt and interpret Bayesian methodology in more complex problems where Bayesian approaches are often needed.

The association of regional cerebral oximetry and neurologically intact survival in a porcine model of cardiac arrest.

Background: The objective of this study was to determine if regional cerebral oximetry (rSO2) assessed during CPR would be predictive of survival with favorable neurological function in a prolonged model of porcine cardiac arrest. This study also examined the relative predictive value of rSO2 and end-tidal carbon dioxide (ETCO2), separately and together. Methods: This study is a post-hoc analysis of data from a previously published study that compared conventional CPR (C-CPR) and automated head-up positioning CPR (AHUP-CPR). Following 10 min of untreated ventricular fibrillation, 14 pigs were treated with either C-CPR (C-CPR) or AHUP-CPR. rSO2, ETCO2, and other hemodynamic parameters were measured continuously. Pigs were defibrillated after 19 min of CPR. Neurological function was assessed 24 h later. Results: There were 7 pigs in the neurologically intact group and 7 pigs in the poor outcomes group. Within 6 min of starting CPR, the mean difference in rSO2 by 95% confidence intervals between the groups became statistically significant (p < 0.05). The receiver operating curve for rSO2 to predict survival with favorable neurological function reached a maximal area under the curve value after 6 min of CPR (1.0). The correlation coefficient between rSO2 and ETCO2 during CPR increased towards 1.0 over time. The combined predictive value of both parameters was similar to either parameter alone. Conclusion: Significantly higher rSO2 values were observed within less than 6 min after starting CPR in the pigs that survived versus those that died. rSO2 values were highly predictive of survival with favorable neurological function.

Intraoperative neurophysiological monitoring and spinal cord stimulator implantation.

INTRODUCTION: Spinal cord injury (SCI) is one of the most dreaded complications after spinal cord stimulation (SCS) implantation surgery. As a result, intraoperative neurophysiological monitoring (IONM) has been proposed to avoid accidental damage to nervous structures under anesthesia and confirm positioning for optimal stimulation. Our study uses a large administrative claims database to determine the 30-day risk of SCI after SCS implantation. METHODS: This retrospective cohort study used the IBM MarketScan Commercial and Medicare Supplemental Databases from 2016 to 2019. Adult patients undergoing SCS surgical procedures with at least 90 days of follow-up, IONM use, the type of sedation used during the procedure, and subsequent SCI were identified using administrative codes. In addition, logistic regression was used to examine the relationship between various risk factors and subsequent SCI. RESULTS: A total of 9676 patients underwent SCS surgery (64.7% percutaneous implants) during the study period. Nine hundred and forty-four (9.75%) patients underwent SCS implantation with IONM. Conscious sedation, Monitored Anesthesia Care anesthesia, and general anesthesia were used in patients with 0.9%, 60.2%, and 28.6%, respectively. Eighty-one (0.8%) patients developed SCI within 30 days after SCS implant surgery. The SCI rate was higher in the group that underwent IONM (2% vs 0.7%, p value <0.001) during the implantation procedure, reflecting the underlying risk. After adjustment for other factors, the OR of SCI is 2.39 (95% CI: 1.33 to 4.14, p value=0.002) times higher for those with IONM than those without IONM. CONCLUSIONS: Increased SCI risk among patients with IONM likely reflects higher baseline risk, and further research is needed for risk mitigation.

Diagnostic Yield of Ambulatory Reflux Monitoring Systems for Evaluation of Chronic Laryngeal Symptoms.

INTRODUCTION: Among patients with chronic laryngeal symptoms, ambulatory reflux monitoring off acid suppression is recommended to evaluate for laryngopharyngeal reflux (LPR). However, reflux monitoring systems are diverse in configuration and monitoring capabilities, which present a challenge in creating a diagnostic reference standard in these patients. This study aimed to compare diagnostic yield and performance between reflux monitoring systems in patients with chronic laryngeal symptoms. METHODS: This multicenter, international study of adult patients referred for evaluation of LPR over a 5-year period (March 2018-May 2023) assessed and compared diagnostic yield of pathologic gastroesophageal reflux (GER+) on ambulatory reflux monitoring off acid suppression. RESULTS: Of 813 patients, 296 (36%) underwent prolonged wireless pH, 532 (65%) underwent 24-hour pH-impedance monitoring, and 15 (2%) underwent both tests. Overall diagnostic yield for GER+ was 36% and greater for prolonged wireless pH compared with that for 24-hour pH-impedance monitoring (50% vs 27%; P < 0.01). Among 15 patients who underwent both prolonged wireless pH and 24-h pH-impedance monitoring, concordance between systems for GER+ was 40%. The most common source of discordance was strong evidence of GER+ across multiple days on prolonged wireless pH compared with no evidence of GER+ on pH-impedance. DISCUSSION: In this multicenter international study of patients with chronic laryngeal symptoms referred for LPR evaluation, diagnostic yield of ambulatory reflux monitoring off acid suppression was 36% and rose to 50% when using wireless pH monitoring. In patients referred for chronic laryngeal symptoms, 24-hour pH-impedance monitoring may risk a low negative predictive value in patients with unproven GER+ disease.

Esophageal anatomy and physiology vary across spastic and non-spastic phenotypes of disorders of esophagogastric junction outflow.

BACKGROUND: Pathophysiologic mechanisms of disorders of esophagogastric junction (EGJ) outflow are poorly understood. We aimed to compare anatomic and physiologic characteristics among patients with disorders of EGJ outflow and normal motility. METHODS: We retrospectively evaluated adult patients with achalasia types 1, 2, 3, EGJ outflow obstruction (EGJOO) or normal motility on high-resolution manometry who underwent endoscopic ultrasound (EUS) from January 2019 to August 2022. Thickened circular muscle was defined as ≥1.6 mm. Characteristics from barium esophagram (BE) and functional lumen imaging probe (FLIP) were additionally assessed. KEY RESULTS: Of 71 patients (mean age 56.2 years; 49% male), there were 8 (11%) normal motility, 58 (82%) had achalasia (5 (7%) type 1, 32 (45%) classic type 2, 21 (30%) type 3 [including 12 type 2 with FEPs]), and 7 (7%) had EGJOO. A significantly greater proportion of type 3 achalasia had thickened distal circular muscle (76.2%) versus normal motility (0%; p < 0.001) or type 2 achalasia (25%; p < 0.001). Type 1 achalasia had significantly wider mean maximum esophageal diameter on BE (57.8 mm) compared to type 2 achalasia (32.8 mm), type 3 achalasia (23.4 mm), EGJOO (15.9 mm), and normal motility (13.5 mm). 100% type 3 achalasia versus 0% type 1 achalasia/normal motility had tertiary contractions on BE. Mean EGJ distensibility index on FLIP was lower for type 3 achalasia (1.2 mmHg/mm2 ) and EGJOO (1.2 mmHg/mm2 ) versus type 2 (2.3 mmHg/mm2 ) and type 1 achalasia (2.9 mmHg/mm2 ). CONCLUSIONS: Our findings suggest distinct pathologic pathways may exist: type 3 achalasia and EGJOO may represent a spastic outflow phenotype consisting of a thickened, spastic circular muscle, which is distinct from type 1 and 2 achalasia consisting of a thin caliber circular muscle layer with more prominent esophageal dilation.

Assessing the clinical utility of biomarkers using the intervention probability curve (IPC).

BACKGROUND: Assessing the clinical utility of biomarkers is a critical step before clinical implementation. The reclassification of patients across clinically relevant subgroups is considered one of the best methods to estimate clinical utility. However, there are important limitations with this methodology. We recently proposed the intervention probability curve (IPC) which models the likelihood that a provider will choose an intervention as a continuous function of the probability, or risk, of disease. OBJECTIVE: To assess the potential impact of a new biomarker for lung cancer using the IPC. METHODS: The IPC derived from the National Lung Screening Trial was used to assess the potential clinical utility of a biomarker for suspected lung cancer. The summary statistics of the change in likelihood of intervention over the population can be interpreted as the expected clinical impact of the added biomarker. RESULTS: The IPC analysis of the novel biomarker estimated that 8% of the benign nodules could avoid an invasive procedure while the cancer nodules would largely remain unchanged (0.1%). We showed the benefits of this approach compared to traditional reclassification methods based on thresholds. CONCLUSIONS: The IPC methodology can be a valuable tool for assessing biomarkers prior to clinical implementation.

Effects of cohort, genotype, variant, and maternal ß-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

AIMS: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal ß-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. METHODS AND RESULTS: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal ß-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or ß-adrenergic response) had lower FHR. Maternal ß-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. CONCLUSION: Genotype, LQT1 variant, and maternal ß-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

Recovery From Idiopathic Sudden Sensorineural Hearing Loss: Association With Cardiovascular Disease Risk.

PURPOSE: The purpose of this study is to investigate the association between cardiovascular disease (CVD) risk factors and idiopathic sudden sensorineural hearing loss (ISSNHL) disease severity and recovery. METHOD: A retrospective medical chart review was performed on 90 patients (n = 48 men; Mage = 59.8 years, SD = 15.8) evaluated for ISSNHL. Major CVD risk factors (current tobacco smoking, diabetes, total cholesterol ≥ 240 mg/dl or treatment, and hypertension [systolic blood pressure [BP]/diastolic BP ≥ 140/ ≥ 90 mmHg or treatment]) determined two CVD risk groups: lower (no major risk factors) and higher (one or more risk factors). Two pure-tone averages (PTAs) were computed: PTA0.5,1,2 and PTA3,4,6,8. Complete recovery of ISSNHL was defined as PTAinitial - PTAfollow-up ≥ 10 dB. Logistic regression estimated the odds of ISSNHL recovery by CVD risk status adjusting for age, sex, body mass index, noise exposure, and treatment. RESULTS: Most patients (67.8%) had one or more CVD risk factors. Severity of initial low- and high-frequency hearing loss was similar between CVD risk groups. Recovery was 53.2% for PTA0.5,1,2 and 32.9% for PTA3,4,6,8. With multivariable adjustment, current/former smoking was associated with lower odds of PTA0.5,1,2 recovery (OR = 0.27; 95% CI [0.08, 0.92]). Neither higher CVD risk status nor individual CVD risk factors had a significant association with recovery. For every one-unit increase in Framingham Risk Score, odds of PTA3,4,6,8 recovery were 0.95 times lower (95% CI [0.90, 1.00]) after accounting for age, sex, body mass index, noise exposure, and treatment/time-to-treatment grouping (p = .056). CONCLUSIONS: The prognosis of low-frequency ISSNHL recovery is worse among current/former smokers than nonsmokers. Other CVD risk factors and aggregate risk are not significantly related to recovery.

Diagnostic methods to measure spastic segment and guide tailored myotomy length in type 3 achalasia.

BACKGROUND: Myotomy length in type 3 achalasia is generally tailored based on segment of spasticity on high-resolution manometry (HRM). Potential of length of tertiary contractions on barium esophagram (BE) or length of thickened circular muscle on endoscopic ultrasound (EUS) to guide tailored myotomy is less understood. This study aimed to assess agreement between spastic segments lengths on HRM, BE, and EUS among patients with type 3 achalasia. METHODS: This retrospective study included adults with type 3 achalasia on HRM between November 2019 and August 2022 who underwent evaluation with EUS and/or BE. Spastic segments were defined as HRM-distance between proximal borders of lower esophageal sphincter and high-pressure area (isobaric contour ≥70 mmHg); EUS-length of thickened circular muscle (≥1.2 mm) from proximal border of esophagogastric junction (EGJ) to the transition to a non-thickened circular muscle; BE-distance between EGJ to proximal border of tertiary contractions. Pairwise comparisons assessed for correlation (Pearson's) and intraclass correlation classification (ICC) agreement. KEY RESULTS: Twenty-six patients were included: mean age 66.9 years (SD 13.8), 15 (57.7%) male. Spastic segments were positively correlated on HRM and BE with good agreement (ICC 0.751, [95% CI 0.51, 0.88]). Spastic segments were negatively correlated with poor agreement on HRM and EUS (ICC -0.04, [-0.45, 0.39]) as well as BE and EUS (ICC -0.03, [-0.47, 0.42]). CONCLUSIONS & INFERENCES: Length of spastic segment was positively correlated on HRM and BE while negatively correlated when compared to EUS, supporting the common use of HRM and highlighting the uncertain role for EUS in tailoring myotomy length for type 3 achalasia.

Consistent hearing aid use is associated with lower fall prevalence and risk in older adults with hearing loss.

BACKGROUND: Falls and their sequelae cost more than $50 billion every year. Older adults with hearing loss are at 2.4 times greater risk of falls than their normal hearing peers. Current research is inconclusive about whether hearing aids can offset this increased fall risk, and no previous studies considered if outcomes differed based on the consistency of hearing aid use. METHODS: Individuals 60 years and older with bilateral hearing loss completed a survey consisting of the Fall Risk Questionnaire (FRQ) and questions about hearing loss history, hearing aid use, and other common fall risk factors. In this cross-sectional study, fall prevalence, as well as fall risk (based on FRQ score), was compared between hearing aid users and non-users. A separate group of consistent hearing-aid users (at least 4 h daily use for more than 1 year) was also compared with inconsistent/non-users. RESULTS: Responses from 299 surveys were analyzed. Bivariate analysis found 50% reduced odds of experiencing a fall for hearing aid users compared with non-users (OR = 0.50 [95% CI: 0.29-0.85], p = 0.01). After adjusting for age, sex, hearing loss severity, and medication usage, those who reported any hearing aid use still had lower odds of falls (OR = 0.48 [95% CI: 0.26-0.90], p = 0.02) and lower odds of being at risk for falls (OR = 0.36 [95% CI: 0.19-0.66] p < 0.001) than non-users. Results for consistent hearing aid users demonstrate an even stronger association of lowered odds of falling (OR = 0.35 [95% CI: 0.19-0.67], p < 0.001) and lower odds of being at risk for falls (OR = 0.32 [95% CI: 0.12-0.59], p < 0.001), suggesting a potential dose-response relationship. CONCLUSIONS: These findings suggest that use of hearing aids-especially consistent hearing aid use-is associated with lower odds of experiencing a fall or being classified as at risk for falls in older individuals with hearing loss.

Guidance on interim analysis methods in clinical trials.

Interim analyses in clinical trials can take on a multitude of forms. They are often used to guide Data and Safety Monitoring Board (DSMB) recommendations to study teams regarding recruitment targets for large, later-phase clinical trials. As collaborative biostatisticians working and teaching in multiple fields of research and across a broad array of trial phases, we note the large heterogeneity and confusion surrounding interim analyses in clinical trials. Thus, in this paper, we aim to provide a general overview and guidance on interim analyses for a nonstatistical audience. We explain each of the following types of interim analyses: efficacy, futility, safety, and sample size re-estimation, and we provide the reader with reasoning, examples, and implications for each. We emphasize that while the types of interim analyses employed may differ depending on the nature of the study, we would always recommend prespecification of the interim analytic plan to the extent possible with risk mitigation and trial integrity remaining a priority. Finally, we posit that interim analyses should be used as tools to help the DSMB make informed decisions in the context of the overarching study. They should generally not be deemed binding, and they should not be reviewed in isolation.

Recent innovations in adaptive trial designs: A review of design opportunities in translational research.

Clinical trials are constantly evolving in the context of increasingly complex research questions and potentially limited resources. In this review article, we discuss the emergence of "adaptive" clinical trials that allow for the preplanned modification of an ongoing clinical trial based on the accumulating evidence with application across translational research. These modifications may include terminating a trial before completion due to futility or efficacy, re-estimating the needed sample size to ensure adequate power, enriching the target population enrolled in the study, selecting across multiple treatment arms, revising allocation ratios used for randomization, or selecting the most appropriate endpoint. Emerging topics related to borrowing information from historic or supplemental data sources, sequential multiple assignment randomized trials (SMART), master protocol and seamless designs, and phase I dose-finding studies are also presented. Each design element includes a brief overview with an accompanying case study to illustrate the design method in practice. We close with brief discussions relating to the statistical considerations for these contemporary designs.

What is the role of neutropenia in pediatric cancer patients with pneumatosis intestinalis?

BACKGROUND: We aimed to identify prognostic indicators in pneumatosis intestinalis (PI) in a pediatric oncology population. We hypothesized that neutropenia would be an independent risk factor for adverse outcomes, including the need for abdominal operation to treat PI and for the development of recurrent PI. METHODS: We performed a retrospective review of all patients treated for PI between 2009 and 2019 with a diagnosis of cancer or history of bone marrow transplant (BMT). RESULTS: Sixty-eight children were treated for their first episode of PI; 15 (22%) were not neutropenic at presentation; eight underwent urgent abdominal operation (12%). Patients with neutropenia were more likely to receive TPN, had a longer course of NPO, and received a longer course of antibiotics. Neutropenia at presentation was associated with a decreased risk of PI recurrence (40% vs 13%, p = 0.03). Children who required an abdominal operation were more likely to require vasopressors at diagnosis (50% vs 10%, p = 0.013). CONCLUSIONS: Among pediatric cancer patients, need for vasopressors at the time of PI is a marker of severe PI, with increased likelihood of requiring operative intervention. The presence of neutropenia is associated with lower rates of PI recurrence. LEVEL OF EVIDENCE: Level III.

Approaches to analyzing binary data for large-scale A/B testing.

An industry-academic collaboration was established to evaluate the choice of statistical test and study design for A/B testing in larger-scale industry experiments. Specifically, the standard approach at the industry partner was to apply a t-test for all outcomes, both continuous and binary, and to apply naïve interim monitoring strategies that had not evaluated the potential implications on operating characteristics such as power and type I error rates. Although many papers have summarized the robustness of the t-test, its performance for the A/B testing context of large-scale proportion data, with or without interim analyses, is needed. Investigating the effect of interim analyses on the robustness of the t-test is important, because interim analyses rely on a fraction of the total sample size and one should ensure that desired properties are maintained when a t-test is implemented not just at the end of the study, but for making interim decisions. Through simulation studies, the performance of the t-test, Chi-squared test, and Chi-squared test with Yate's correction when applied to binary outcomes data is evaluated. Further, interim monitoring through a naïve approach with no correction for multiple testing versus the O'Brien-Fleming boundary are considered in designs that allow early termination for futility, difference, or both. Results indicate that the t-test achieves similar power and type I error rates for binary outcomes data with the large sample sizes used in industrial A/B tests with and without interim monitoring, and naïve interim monitoring without corrections leads to poorly performing studies.

The unique association of posttraumatic stress disorder with hypertension among veterans: A replication of Kibler et al. (2009) using Bayesian estimation and data from the United States-Veteran Microbiome Project.

OBJECTIVE: Kibler et al. (2009) reported that hypertension was related to PTSD independent of depression. These two conditions have significant diagnostic overlap. The present study sought to conceptually replicate this work with a veteran sample, using Bayesian estimation to directly update past results, as well as examine symptom severity scores in relation to hypertension. METHOD: This was a secondary analysis of data obtained from the United States-Veteran Microbiome Project. Lifetime diagnoses of PTSD and major depressive disorder (MDD) were obtained from a structured clinical interview and hypertension diagnoses were extracted from electronic medical records. PTSD and depressive symptom severity were obtained from self-report measures. Logistic regressions with Bayesian estimation were used to estimate the associations between hypertension and (a) psychiatric diagnostic history and (b) symptom severity scores. RESULTS: Compared with veterans without lifetime diagnoses of either disorder, the PTSD-only group was estimated to have a 29% increase in hypertension risk, and the PTSD + MDD group was estimated to have a 66% increase in hypertension risk. Additionally, higher levels of PTSD symptom severity were associated with a higher risk of hypertension. CONCLUSION: PTSD diagnosis and symptom severity are uniquely associated with hypertension, independent of MDD or depressive symptom severity. These results support previous findings that PTSD might be a modifiable risk factor for the prevention and treatment of hypertension. (PsycInfo Database Record (c) 2023 APA, all rights reserved).