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Recurrent laryngeal nerve (RLN) injury during neck surgery can cause significant morbidity related to vocal cord (VC) dysfunction. VC electromyography (EMG) is used to aid in the identification of the RLN and can reduce the probability of inadvertent surgical injury. Errors in the placement of specialized EMG endotracheal tubes (ETT) can result in unreliable signals, false-negative responses, or no response when stimulating the RLN. We describe a novel educational protocol developed to optimize uniformity in the placement of ETTs to improve the reliability of RLN monitoring. An intraoperative neuromonitoring database was queried for all neck surgeries requiring RLN monitoring. Data points extracted for all cases requiring EMG monitoring for neck procedures. Free running and stimulated EMG were monitored and continuously recorded by a certified technologist. Alerts were compared between 2013-14 and 2015-18 using a two-sample test of proportions. Significant reductions in alerts were demonstrated after protocol implementation (7.5% pre-implementation to 2.1% post). Alerts were compared between 2013-14 (overall alert rate of 1.8%, pre-implementation period) and 2015-18 (overall alert rate of 2.8%, post-implementation period). Protocolization for placement of EMG-ETT improved accuracy in EMG monitoring. In the follow-up cohort of 1,080 patients, use of this protocol continued to reduce the rate of alerts related to ETT malposition, confirming the sustainability of this intervention through routine education. The risk of nerve injury is reduced when the rate of alerts is minimized. Scheduled or continuous protocol education of anesthesia personnel should continue to ensure compliance with protocol.

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., (Copyright © 2024 by The American College of Gastroenterology.)

This discussion provides commentary on the paper by Ethan M. Alt, Xiuya Chang, Xun Jiang, Qing Liu, May Mo, H. Amy Xia, and Joseph G. Ibrahim entitled "LEAP: the latent exchangeability prior for borrowing information from historical data". The authors propose a novel method to bridge the incorporation of supplemental information into a study while also identifying potentially exchangeable subgroups to better facilitate information sharing. In this discussion, we highlight the potential relationship with other Bayesian model averaging approaches, such as multisource exchangeability modeling, and provide a brief numeric case study to illustrate how the concepts behind latent exchangeability prior may also improve the performance of existing methods. The results provided by Alt et al. are exciting, and we believe that the method represents a meaningful approach to more efficient information sharing., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

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 β 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., (Copyright © 2023 by The American College of Gastroenterology.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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/mm 2 ) and EGJOO (1.2 mmHg/mm 2 ) versus type 2 (2.3 mmHg/mm 2 ) and type 1 achalasia (2.9 mmHg/mm 2 )., 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., (© 2023 John Wiley & Sons Ltd.)

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., Competing Interests: LBG none; EJB none; JLH speaker and consultant for Pacira BioSciences, consultant and stockholder of Insitu Biologics, consultant for AtriCure, former consultant for AcelRX; AAB consultant for Pacira BioSciences and AtriCure; AJK none; and NEC none., (© The Author(s) 2023.)

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 β-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 β-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 β-adrenergic response) had lower FHR. Maternal β-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 β-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., Competing Interests: Conflict of interest: M.J.A. is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. M.J.A. and Mayo Clinic are involved in equity/intellectual property/royalty relationships with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. A.A.M.W. is a consultant for Thryv Therapeutics with minor financial interest. S.P.E. is involved with Spaulding Research with minor financial interest., (Published by Oxford University Press on behalf of the European Society of Cardiology 2023.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

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., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

Gastroesophageal reflux disease (GERD) is primarily diagnosed based on symptoms and response to a proton-pump inhibitor (PPI) trial. Gold standard testing requires an invasive endoscopic procedure, often with ambulatory pH monitoring. Salivary pepsin is a potential noninvasive modality for GERD diagnosis. This study aimed to assess diagnostic performance of salivary pepsin thresholds for GERD and determine optimal collection protocol of saliva in an external validation cohort. Over 10 months, adults with symptoms of GERD undergoing esophagogastroduodenoscopy with wireless pH-monitoring off PPI were enrolled. Saliva was self-collected by participants over 4 days across three different time points: fasting ante meridiem (AM), post-prandial, and bedtime (PM). Pepsin levels were calculated via Peptest. Pepsin variability and agreement were determined using linear mixed effects models and intraclass correlation. Validation of diagnostic threshold and performance characteristics were evaluated by receiver-operator curve analysis. Twenty participants enrolled in the study; 50% with physiologic acid exposure (acid exposure time < 4% no GERD) and 50% with elevated acid exposure (GERD). Mean pepsin concentrations were significantly lower in the AM (22.6 ± 25.2 ng/mL) compared to post-prandial (44.5 ± 36.7 ng/mL) and PM (55.4 ± 47.0 ng/mL). Agreement between pepsin concentrations across 3 days was substantial for AM samples (kappa 0.61), with lower agreement for post-prandial and PM samples. A single AM pepsin concentration of 25 ng/mL was 67% accurate for GERD with 56% sensitivity and 78% specificity. This validation study highlights fair accuracy and performance characteristics of a single fasting AM salivary pepsin concentration for the diagnosis of GERD., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19., Methods: This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1)., Results: Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups., Conclusion: LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04372628., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Bayesian meta-analyses offer several advantages over traditional approaches, including improved accuracy when using a small number of studies and enhanced estimation of heterogeneity. However, psychological trauma research has yet to see widespread adoption of these statistical methods, potentially due to researchers' unfamiliarity with the processes involved. The purpose of this article is to provide a practical tutorial for conducting random-effects Bayesian meta-analyses., Method: Explanations and recommendations are provided for completing the primary steps of a Bayesian meta-analysis, ranging from model specification to interpretation of results. Furthermore, an illustrative example is used to demonstrate the application of each step. In the example, results are synthesized from six studies included in a previously published systematic review (Holliday et al., 2020), with a combined sample size of 21,244,109, examining the association between posttraumatic stress disorder and risk of suicide in veterans and military personnel., Results: The posterior distributions for each model estimate, such as the pooled effect size and the heterogeneity parameter, are discussed and interpreted with regard to the probability of increased suicide risk., Conclusions: Our hope is that this tutorial, along with the provided data and code, facilitate the use of Bayesian meta-analyses in the study of psychological trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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).

Purpose: Infection with COVID-19 during pregnancy has been associated with a hypercoagulable state. It is unknown if maternal COVID-19 infection results in congenital anomalies secondary to intrauterine vascular accidents. This study sought to determine if the rate of in-utero vascular complications (intestinal atresia and limb abnormalities) that may be attributable to the hypercoagulable states associated with COVID-19 and pregnancy increased after the onset of the pandemic., Methods: Pregnancy, neonatal, and congenital defect data from a single academic medical center and the partner's children's hospital were collected and compared to the period prior to onset of the pandemic. A subanalysis including pregnant woman 18 years or greater with documented COVID-19 infection during gestation between March 2020-2021 was performed., Results: Rates of intestinal atresia did not differ prior to or after the onset of the pandemic (3.78% vs 7.23%, p = 0.21) nor did rates of limb deficiency disorders (4.41% vs 9.65%, p = 0.09). On subanalysis, there were 194 women with COVID-19 infection included in analysis: 135 (69.6%) were positive during delivery admission and 59 (30.4%) were positive earlier in their pregnancy. There was one infant born with intestinal atresia., Conclusion: We report a low incidence of congenital anomalies in infants born to mothers with COVID-19 infection. It remains unclear if the impact of COVID-19 on the coagulative state augments the normal pro-thrombotic state of pregnancy; ongoing surveillance is warranted.

Background: Postoperative pain associated with open partial hepatectomy can be intense and persistent. The multimodal approach used to lessen this problem includes an intraoperative intravenous infusion of lidocaine hydrochloride. Decreased hepatic metabolism after resection raises concerns about safe lidocaine dosing in this patient population. The hypothesis was that the elimination clearance of lidocaine and its metabolites, monoethylglycinexylidide and glycinexylidide, is reduced after a partial hepatectomy, as reflected by observed plasma concentrations that are higher and have a longer half-life than expected based on pharmacokinetic modeling (estimated for normal liver function). Secondarily, this study postulated that plasma concentrations of lidocaine, monoethylglycinexylidide, and glycinexylidide do not reach toxic concentrations with institutional protocol up to 24 h after surgery., Methods: Blood samples were collected from 15 patients undergoing a partial hepatectomy for living liver donation, at the following specific time points: before and immediately after induction of anesthesia, during hepatectomy, 30 min after hepatectomy completion, at case end, and 24 h after the end of surgery. Plasma concentrations of lidocaine and metabolites were measured by liquid chromatography-mass spectrometry. The population lidocaine pharmacokinetics were estimated, and total body weight and the fraction of remaining liver mass as potential model covariates were evaluated. The detection of any lidocaine, monoethylglycinexylidide, or glycinexylidide toxic plasma concentrations at any time point during and after hepatectomy were also evaluated., Results: The typical value for lidocaine elimination clearance was 0.55 ± 0.12 l/min (± standard error of the estimate) which, on average, was reduced to about one third of the baseline clearance, 0.17 ± 0.02 l/min, once the donor graft was surgically isolated, and remained so for 24 h according to the current data and model. The fraction of remaining liver was a significant covariate for the posthepatectomy lidocaine clearance' such that if 50% of the liver is removed the clearance is reduced by approximately 60%. Plasma concentrations of lidocaine and its metabolites remained below their theoretical combined toxic threshold concentrations throughout the surgical and postoperative course in all patients, with one exception obtained near induction of anesthesia. Plasma lidocaine concentrations decreased at case end and postoperatively, while metabolite concentrations continued to rise at the end of surgery with reduction postoperatively. Pharmacokinetic modeling revealed that the only significant covariate in the model was the fraction of liver remaining after isolation of the donor graft., Conclusions: Intravenous lidocaine infusions are an acceptable option for multimodal pain management in patients undergoing a hepatectomy for living donation if the lidocaine infusion is stopped when the liver resection is complete. Clearance of lidocaine is decreased proportionally to the remaining liver mass, which should guide lidocaine infusion administration or dosing adjustments for patients undergoing liver resection surgery., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Introduction: Efforts to develop biomarker-targeted anti-cancer therapies have progressed rapidly in recent years. With efforts to expedite regulatory reviews of promising therapies, several targeted cancer therapies have been granted accelerated approval on the basis of evidence acquired in single-arm phase II clinical trials. And yet, in the absence of randomization, patient prognosis for progression-free survival and overall survival may not have been studied under standard of care chemotherapies for emerging biomarker subpopulations prior to the submission of an accelerated approval application. Historical control rates used to design and evaluate emerging targeted therapies often arise as population averages, lacking specificity to the targeted genetic or immunophenotypic profile. Thus, historical trial results are inherently limited for inferring the potential "comparative efficacy" of novel targeted therapies. Consequently, randomization may be unavoidable in this setting. Innovations in design methodology are needed, however, to enable efficient implementation of randomized trials for agents that target biomarker subpopulations., Methods: This article proposes three randomized designs for early phase biomarker-guided oncology clinical trials. Each design utilizes the optimal efficiency predictive probability method to monitor multiple biomarker subpopulations for futility. Only designs with type I error between 0.05 and 0.1 and power of at least 0.8 were considered when selecting an optimal efficiency design from among the candidate designs formed by different combinations of posterior and predictive threshold. A simulation study motivated by the results reported in a recent clinical trial studying atezolizumab treatment in patients with locally advanced or metastatic urothelial carcinoma is used to evaluate the operating characteristics of the various designs., Results: Out of a maximum of 300 total patients, we find that the enrichment design has an average total sample size under the null of 101.0 and a total average sample size under the alternative of 218.0, as compared to 144.8 and 213.8 under the null and alternative, respectively, for the stratified control arm design. The pooled control arm design enrolled a total of 113.2 patients under the null and 159.6 under the alternative, out of a maximum of 200. These average sample sizes that are 23-48% smaller under the alternative and 47-64% smaller under the null, as compared to the realized sample size of 310 patients in the phase II study of atezolizumab., Discussion: Our findings suggest that potentially smaller phase II trials to those used in practice can be designed using randomization and futility stopping to efficiently obtain more information about both the treatment and control groups prior to phase III study., Competing Interests: BH declares advising/consulting for Amgen, Bayer HealthCare Pharmaceuticals Inc., Telperian, and STCube Pharmaceuticals. NP declares advising/consulting for AstraZeneca, Merck, Pfizer, Eli Lilly/LOXO, Genentech, BMS, Amgen, Mirati, Inivata, G1 Therapeutics, Viosera, Xencor, Janssen, Boehringer Ingelheim, and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zabor, Kaizer, Pennell and Hobbs.)

Background: The risk of fetal atrioventricular block in anti-Ro/SSA antibody-exposed pregnancies with no previous affected offspring is approximately 2%. A high antibody titer is necessary but not sufficient for atrioventricular block, and specific antibody titers do not predict risk. However, there are no data on the negative predictive value of antibody titer to identify pregnancies at low risk of fetal atrioventricular block, and may not require surveillance., Objective: This study aimed to define anti-Ro52 and anti-Ro60 antibody thresholds for the identification of fetuses unlikely to develop atrioventricular block using clinically validated and research laboratory tests., Study Design: This study performed a multicenter review of pregnant subjects who tested positive in their local commercial laboratories for anti-Ro/SSA antibodies at the University of Colorado Children's Hospital (2014-2021) and Phoenix Children's Hospital (2014-2021) and enrolled in the Research Registry for Neonatal Lupus (RRNL) at New York University Langone Medical Center (2002-2021). The subjects were referred on the basis of rheumatologic symptoms or history of atrioventricular block in a previous pregnancy and were retrospectively grouped on the basis of pregnancy outcome. Group 1 indicated no fetal atrioventricular block in current or past pregnancies; group 2 indicated fetal atrioventricular block in the current pregnancy; and group 3 indicated normal current pregnancy but with fetal atrioventricular block in a previous pregnancy. Maternal sera were analyzed for anti-Ro52 and anti-Ro60 antibodies using a clinically validated multiplex bead assay (Associated Regional and University Pathologists Laboratories, Salt Lake City, UT) and a research enzyme-linked immunosorbent immunoassay (New York University). This study calculated the negative predictive value separately for anti-Ro52 and anti-Ro60 antibodies and for the 2 combined using a logistic regression model and a parallel testing strategy., Results: This study recruited 270 subjects (141 in group 1, 66 in group 2, and 63 in group 3). Of note, 89 subjects in group 1 had data on hydroxychloroquine treatment: anti-Ro/SSA antibody titers were no different between those treated (n=46) and untreated (n=43). Mean anti-Ro52 and anti-Ro60 titers were the lowest in group 1 and not different between groups 2 and 3. No case of fetal atrioventricular block developed among subjects with anti-Ro52 and anti-Ro60 titers of <110 arbitrary units per milliliter using the multiplex bead assay of the Associated Regional and University Pathologists Laboratories (n=141). No case of fetal atrioventricular block developed among subjects with research laboratory anti-Ro52 titers of <650 and anti-Ro60 of <4060 enzyme-linked immunosorbent immunoassay units (n=94). Using these 100% negative predictive value thresholds, more than 50% of the anti-Ro/SSA antibody pregnancies that ultimately had no fetal atrioventricular block could be excluded from surveillance based on clinical and research titers, respectively., Conclusion: Study data suggested that there is a clinical immunoassay level of maternal anti-Ro/SSA antibodies below which the pregnancy is at low risk of fetal atrioventricular block. This study speculated that prospectively applying these data may avert the costly serial echocardiograms currently recommended for all anti-Ro/SSA-antibody positive pregnancies and guide future management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Advances in biology and immunology have elucidated genetic and immunologic origins of cancer. Innovations in sequencing technologies revealed that distinct cancer histologies shared common genetic and immune phenotypic traits. Pharmacologic developments made it possible to target these alterations, yielding novel classes of targeted agents whose therapeutic potential span multiple tumor types. Basket trials, one type of master protocol, emerged as a tool for evaluating biomarker-targeted therapies among multiple tumor histologies. Conventionally conducted within the phase II setting and designed to estimate high and durable objective responses, basket trials pose challenges to statistical design and interpretation of results. This article reviews basket trials implemented in oncology studies and discusses issues related to their statistical design and analysis.

Background: Diagnostic prediction models are useful guides when considering lesions suspicious for cancer, as they provide a quantitative estimate of the probability that a lesion is malignant. However, the decision to intervene ultimately rests on patient and physician preferences. The appropriate intervention in many clinical situations is typically defined by clinically relevant, actionable subgroups based upon the probability of malignancy. However, the "all-or-nothing" approach of threshold-based decisions is in practice incorrect., Methods: Here, we present a novel approach to understanding clinical decision-making, the intervention probability curve (IPC). The IPC models the likelihood that an intervention will be chosen as a continuous function of the probability of disease. We propose the cumulative distribution function as a suitable model. The IPC is explored using the National Lung Screening Trial and the Prostate Lung Colorectal and Ovarian Screening Trial datasets., Results: Fitting the IPC results in a continuous curve as a function of pretest probability of cancer with high correlation (R2 &gt; 0.97 for each) with fitted parameters closely aligned with professional society guidelines., Conclusions: The IPC allows analysis of intervention decisions in a continuous, rather than threshold-based, approach to further understand the role of biomarkers and risk models in clinical practice., Impact: We propose that consideration of IPCs will yield significant insights into the practical relevance of threshold-based management strategies and could provide a novel method to estimate the actual clinical utility of novel biomarkers., (©2022 American Association for Cancer Research.)

The consistency of reporting results for patient-derived xenograft (PDX) studies is an area of concern. The PDX method commonly starts by implanting a derivative of a human tumor into a mouse, then comparing the tumor growth under different treatment conditions. Currently, a wide array of statistical methods (e.g., t-test, regression, chi-squared test) are used to analyze these data, which ultimately depend on the outcome chosen (e.g., tumor volume, relative growth, categorical growth). In this simulation study, we provide empirical evidence for the outcome selection process by comparing the performance of both commonly used outcomes and novel variations of common outcomes used in PDX studies. Data were simulated to mimic tumor growth under multiple scenarios, then each outcome of interest was evaluated for 10 000 iterations. Comparisons between different outcomes were made with respect to average bias, variance, type-1 error, and power. A total of 18 continuous, categorical, and time-to-event outcomes were evaluated, with ultimately 2 outcomes outperforming the others: final tumor volume and change in tumor volume from baseline. Notably, the novel variations of the tumor growth inhibition index (TGII)-a commonly used outcome in PDX studies-was found to perform poorly in several scenarios with inflated type-1 error rates and a relatively large bias. Finally, all outcomes of interest were applied to a real-world dataset., (© 2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: The American Association of Medical Colleges deemed performing lifesaving procedures, such as airway management, a necessary medical student competency for transitioning to residency. Anesthesiology clerkships provide the unique opportunity for medical students to practice these procedures in a safe and controlled environment. We aimed to develop a checklist that assesses medical students' ability to perform the main steps of a general anesthesia induction with endotracheal intubation in the clinical setting., Methods: We created a Checklist containing items aligned with our clerkship objectives. We modified it after receiving feedback and trialing it in the clinical setting. Medical students were evaluated with the Checklist using a pre- and post-clerkship study design: (1) in a simulation setting at the beginning of the clerkship; and (2) in the operating room at the end of the clerkship. Using paired t -tests, we calculated pre- and post-clerkship Checklist scores to determine curriculum efficacy. A P value of <.05 was determined to be statistically significant. We examined rater agreement between overall scores with intraclass correlation coefficients (ICC)., Results: Thirty medical students participated in the study. The ICC for agreement was 0.875 (95% confidence interval [CI], 0.704-0.944). The ICC for consistency was 0.897 (95% CI, 0.795-0.950). There was a statistically significant improvement in the score from baseline to final evaluation of 3.6 points (95% CI, 2.5-5.2; P = .001)., Conclusions: The statistically significant change in Checklist scores suggests that our medical students gained knowledge and experience during the introductory clerkship inducing general anesthesia and were able to demonstrate their knowledge in a clinical environment.

Background: Single-injection interscalene brachial plexus blocks are used for analgesia for rotator cuff repair (RCR) but have limited duration. The value of adding liposomal bupivacaine (LB) to prolong single-injection interscalene blocks is unclear. The purpose of this trial is to evaluate the addition of LB to regular bupivacaine interscalene blocks for patients undergoing arthroscopic RCR., Methods: In this prospective, randomized trial, 70 patients undergoing primary RCR with equal group allocation were randomized by random number generator to receive an interscalene block with 20 mL of 0.5% bupivacaine or 10 mL 0.5% bupivacaine plus 133 mg LB. The primary outcome was cumulative opioid consumption within 72 hours of the procedure. Secondary outcomes included maximum pain scores and quality of recovery 15 survey scores., Results: 70 of the 80 randomized patients were included in final analysis following exclusion for protocol violations and loss to follow-up. Cumulative opioid consumption (oral morphine equivalents) within 72 hours in patients receiving LB was a median (IQR) of 31.9 mg (0, 73.1) compared with 45.0 mg (15.0, 108.8) among patients receiving bupivacaine alone (p=0.312). Patients receiving LB demonstrated mixed results regarding worst pain scores with improvements at 24 hours and 72 hours, but not 48 hours., Conclusions: LB added to bupivacaine interscalene blocks does not reduce opioid consumption within 72 hours following arthroscopic RCR., Trial Registration Number: NCT03587584., Competing Interests: Competing interests: JLH is a speaker, consultant, and has received research funds from Pacira Bioscience, he is a consultant and owns stock with Insitu Biologics, is a consultant and speaker for Acel RX, a consultant for Worrell, received research funds from Avanos, and was a consultant for Johnson and Johnson. AAB is a consultant for Pacira Bioscience., (© American Society of Regional Anesthesia & Pain Medicine 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Coronavirus disease 2019 (COVID-19) has a heterogeneous outcome in individuals from remaining asymptomatic to death. In a majority of cases, mild symptoms are present that do not require hospitalization and can be successfully treated in the outpatient setting, though symptoms may persist for a long duration. We hypothesize that drugs suitable for decentralized study in outpatients will have efficacy among infected outpatients METHODS: The TREAT NOW platform is designed to accommodate testing multiple agents with the ability to incorporate new agents in the future. TREAT NOW is an adaptive, blinded, multi-center, placebo-controlled superiority randomized clinical trial which started with two active therapies (hydroxychloroquine and lopinavir/ritonavir) and placebo, with the hydroxychloroquine arm dropped shortly after enrollment began due to external evidence. Each arm has a target enrollment of 300 participants who will be randomly assigned in an equal allocation to receive either an active therapy or placebo twice daily for 14 days with daily electronic surveys collected over days 1 through 16 and on day 29 to evaluate symptoms and a modified COVID-19 ordinal outcome scale. Participants are enrolled remotely by telephone and consented with a digital interface, study drug is overnight mailed to study participants, and data collection occurs electronically without in-person interactions., Discussion: If effective treatments for COVID-19 can be identified for individuals in the outpatient setting before they advance to severe disease, it will prevent progression to more severe disease, reduce the need for hospitalization, and shorten the duration of symptoms. The novel decentralized, "no touch" approach used by the TREAT NOW platform has distinction advantages over traditional in-person trials to reach broader populations and perform study procedures in a pragmatic yet rigorous manner., Trial Registration: ClinicalTrials.gov NCT04372628. Registered on April 30, 2020. First posted on May 4, 2020., (© 2022. The Author(s).)

Background & Aims: Heterogeneous presentations and disease mechanisms among patients with laryngeal symptoms account for misdiagnosis of laryngopharyngeal reflux (LPR), variations in testing, and suboptimal outcomes. We aimed to derive phenotypes of patients with laryngeal symptoms based on clinical and physiologic data and to compare characteristics across phenotypes., Methods: A total of 302 adult patients with chronic laryngeal symptoms were prospectively enrolled at 3 centers between January 2018 to October 2020 (age 57.2 ± 15.2 years; 30% male; body mass index 27.2 ± 6.0 kg/m 2 ). Discriminant analysis of principal components (DAPC) was applied to 12 clinical and 11 physiologic variables collected in stable condition to derive phenotypic groups., Results: DAPC identified 5 groups, with significant differences across symptoms, hiatal hernia size, and number of reflux events (P < .01). Group A had the greatest hiatal hernia size (3.1 ± 1.0 cm; P < .001) and reflux events (37.5 ± 51; P < .001), with frequent cough, laryngeal symptoms, heartburn, and regurgitation. Group B had the highest body mass index (28.2 ± 4.6 kg/m 2 ; P < .001) and salivary pepsin (150 ± 157 ng/mL; P = .03), with frequent cough, laryngeal symptoms, globus, heartburn, and regurgitation. Group C frequently reported laryngeal symptoms (93%; P < .001), and had fewest esophageal symptoms (9.6%; P < .001) and reflux events (10.7 ± 11.0; P < .001). Group D commonly reported cough (88%; P < .001) and heartburn. Group E (18%) was oldest (62.9 ± 14.3 years; P < .001) and distinguished by highest integrated relaxation pressure., Conclusions: DAPC identified distinct clinicophysiologic phenotypes of patients with laryngeal symptoms referred for reflux evaluation: group A, LPR and gastroesophageal reflux disease (GERD) with hiatal hernia; group B, mild LPR/GERD; group C, no LPR/No GERD; group D, reflex cough; and group E, mixed/possible obstructive esophagogastric junction. Phenotypic differences may inform targeted clinical trials design and improve outcomes., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Interscalene blocks provide analgesia for shoulder surgery but also cause phrenic nerve paralysis. Liposomal bupivacaine is approved for use in interscalene blocks with the potential to provide longer pain control. However, the impact of liposomal bupivacaine on the phrenic nerve has not been evaluated. It was hypothesized that patients who received an interscalene block with both bupivacaine and liposomal bupivacaine would have a decreased diaphragmatic excursion when compared to bupivacaine alone at 24 h., Methods: This was a double-blinded study of adult patients who were randomized to receive an interscalene block with either 20 ml 0.5% bupivacaine (bupivacaine group) or 10 ml 0.5% bupivacaine plus 10 ml liposomal bupivacaine (liposomal bupivacaine group). Twenty-six patients were randomized with 22 included in the analysis. Diaphragmatic excursion (via ultrasound) and spirometry were assessed before the block, in the postanesthesia care unit, and at 24 h postblock. The primary outcome was diaphragm excursion with sigh. No adverse events were observed., Results: At 24 h, the liposomal bupivacaine group median [25th, 75th], had a greater percent change in diaphragmatic excursion during sigh breath compared to the bupivacaine group, -24% [-30, -9] versus 9% [-8, 26], difference in location, 32 (95% CI, 12 to 52), P = 0.007. Five patients in the liposomal bupivacaine group had a greater than 25% reduction in diaphragmatic excursion at 24 h versus zero in the bupivacaine group. They also had a significantly greater percent reduction in forced expiratory volume in 1 s and forced vital capacity compared with the bupivacaine group at 24 h (median decrease of 22% vs. 2%, P = 0.006, and median decrease of 19% vs. 1%, P = 0.049, respectively)., Conclusions: The addition of liposomal bupivacaine to bupivacaine in an interscalene block results in statistically significant reductions in diaphragm excursion and pulmonary function testing 24 h after block placement when compared to bupivacaine alone. This reduction, however, falls within the range of normal diaphragmatic function., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Epidermolysis bullosa (EB) is a group of rare epithelial disorders caused by abnormal or absent structural proteins at the epidermal-dermal junction. As a result, patients experience blisters and wounds from mild shearing forces. Some forms of EB are complicated by resultant scarring and contractures. The perioperative anesthetic management of patients with EB is complex and requires a systems-based approach to limit harm. We reviewed our experience with providing general anesthesia to patients at our tertiary EB referral center, including adverse events related to anesthetic care, outcomes in the immediate perioperative period, and details of anesthetic management., Methods: We retrospectively reviewed the charts of all patients with EB anesthetized at the Children's Hospital Colorado between January 2011 and December 2016. A subset of pediatric anesthesiologists cared for all patients using a standardized clinical care pathway. Patient demographics, detailed anesthetic methods, immediate perioperative outcomes, and adverse events were characterized., Results: Over a 6-year period, 37 patients underwent 202 general anesthetics. Most patients (75.7%) had dystrophic EB (DEB). Female patients comprised 48.6%. The majority (56.7%) traveled >50 miles to receive care, and many (35.1%) traveled >150 miles for their care. Common adaptations to care included avoidance of electrocardiogram leads (88.6%) and temperature probes (91.6%). Nasal fiberoptic intubation (n = 160) was performed, or natural airway/mask (n = 27) was maintained for most patients. Supraglottic devices were not used for airway management during any of the anesthetics. Anesthesia preparation time was longer (average 25.8 minutes [standard deviation {SD} = 12.7]) than our average institutional time (14 minutes). Succinylcholine was never used, and nondepolarizing muscle relaxants were used in only 1.5% of patient encounters. Blood was transfused in 16.3% of cases and iron infused in 24.8%. Average length of stay in the postanesthesia care unit was comparable to our institutional average (average 40.1 [SD = 28.6] vs 39 minutes). New skin or mucosal injury occurred in 8 encounters (4%), and desaturation occurred in 43 cases (21.3%). There were no major adverse events., Conclusions: By using a specialized team and a standardized clinical care pathway, our institution was able to minimize adverse events caused by the anesthetic and surgical care of patients with EB. We recommend natural airway or nasal fiberoptic airway management, meticulous avoidance of shear stress on the skin, and a multidisciplinary approach to care. Supportive therapy such as perioperative blood transfusions and iron infusions are feasible for the treatment of chronic anemia in this population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Introduction: Determining the need, optimal timing, amount, and type of fluid for volume expansion in hypovolemic infants is challenging, due to their small intravascular volumes and robust compensatory reserve. To assess markers of fluid responsiveness in hypovolemic infants, we studied those undergoing cranial vault reconstructive surgery-a procedure associated with significant blood loss. We aimed to determine the ability of the Compensatory Reserve Index (CRI) monitor, which provides a continuous, individual-specific, beat-to-beat estimate of central volume status, to distinguish fluid responders from non-responders., Methods: A prospective observational pilot study of infants undergoing cranial vault reconstructive surgery for craniosynostosis was performed from May 2019-January 2020. A CardioQ-Esophageal Doppler Monitor, which measures changes in peak aortic velocity, was utilized to distinguish fluid responders- defined as those who demonstrated an increase in peak aortic velocity > 15% following a crystalloid bolus (10 mL/kg). Several static and dynamic variables were analyzed, including the CRI monitor. Each variable's performance was compared using area under the receiver operator curves (AUC), adjusting for age and bolus volume., Results: Twenty subjects were included and a total of 23 boluses (19 crystalloid and 4 blood) were administered. Of all boluses, 7 (all crystalloid) were provided to fluid responders and 16 to non-responders. There were no statistically significant differences in bolus volumes or bolus durations between responders and non-responders. While adjusting for age and bolus volume, CRI performed similarly to other bedside tools to predict fluid responsiveness with an AUC of 0.7024 (95% CI = 0.459, 0.946)., Conclusion: Distinguishing infants who are fluid responders from those who are not can be challenging. CRI is a continuous, non-invasive measure that was developed using adult waveform data, yet even in very young patients is able to identify those who may benefit from additional volume expansion., Study Type: Therapeutic/Care management., Level of Evidence: Level II., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Ltd.)

Over half of hospital revenue results from perioperative patient care, thus emphasizing the importance of efficient resource utilization within a hospital's suite of operating rooms (ORs). Predicting surgical case duration, including Anesthesia-controlled time (ACT) and Surgical-controlled time (SCT) has been significantly detailed throughout the literature as a means to help manage and predict OR scheduling. However, this information has previously been divided by surgical specialty, and only limited benchmarking data regarding ACT and SCT exists. We hypothesized that advancing the granularity of the ACT and SCT from surgical specialty to specific Current Procedural Terminology (CPT ® ) codes will produce data that is more accurate, less variable, and therefore more useful for OR schedule modeling and management. This single center study was conducted using times from surgeries performed at the University of Colorado Hospital (UCH) between September 2018 - September 2019. Individual cases were categorized by surgical specialty based on the specialty of the primary attending surgeon and CPT codes were compiled from billing data. Times were calculated as defined by the American Association of Clinical Directors. I 2 values were calculated to assess heterogeneity of mean ACT and SCT times while Levene's test was utilized to assess heterogeneity of ACT and SCT variances. Statistical analyses for both ACT and SCT were calculated using JMP Statistical Discovery Software from SAS (Cary, NC) and R v3.6.3 (Vienna, Austria). All surgical cases (n = 87,537) performed at UCH from September 2018 to September 2019 were evaluated and 30,091 cases were included in the final analysis. All surgical subspecialties, with the exception of Podiatry, showed significant variability in ACT and SCT values between CPT codes within each surgical specialty. Furthermore, the variances of ACT and SCT values were also highly variable between CPT codes within each surgical specialty. Finally, benchmarking values of mean ACT and SCT with corresponding standard deviations are provided. Because each mean ACT and SCT value varies significantly between different CPT codes within a surgical specialty, using this granularity of data will likely enable improved accuracy in surgical schedule modeling compared to using mean ACT and SCT values for each surgical specialty as a whole. Furthermore, because there was significant variability of ACT and SCT variances between CPT codes, incorporating variance into surgical schedule modeling may also improve accuracy. Future investigations should include real-time simulations, logistical modeling, and labor utilization analyses as well as validation of benchmarking times in private practice settings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The customary approach to early-phase clinical trial design, where the focus is on identification of the maximum tolerated dose, is not always suitable for noncytotoxic or other targeted therapies. Many trials have continued to follow the 3 + 3 dose-escalation design, but with the addition of phase I dose-expansion cohorts to further characterize safety and assess efficacy. Dose-expansion cohorts are not always planned in advance nor rigorously designed. We introduce an approach to the design of phase I expansion cohorts on the basis of sequential predictive probability monitoring., Methods: Two optimization criteria are proposed that allow investigators to stop for futility to preserve limited resources while maintaining traditional control of type I and type II errors. We demonstrate the use of these designs through simulation, and we elucidate their implementation with a redesign of the phase I expansion cohort for atezolizumab in metastatic urothelial carcinoma., Results: A sequential predictive probability design outperforms Simon's two-stage designs and posterior probability monitoring with respect to both proposed optimization criteria. The Bayesian sequential predictive probability design yields increased power while significantly reducing the average sample size under the null hypothesis in the context of the case study, whereas the original study design yields too low type I error and power. The optimal efficiency design tended to have more desirable properties, subject to constraints on type I error and power, compared with the optimal accuracy design., Conclusion: The optimal efficiency design allows investigators to preserve limited financial resources and to maintain ethical standards by halting potentially large dose-expansion cohorts early in the absence of promising efficacy results, while maintaining traditional control of type I and II error rates., Competing Interests: Elizabeth Garrett-MayerConsulting or Advisory Role: Deciphera Brian P. HobbsStock and Other Ownership Interests: PresagiaConsulting or Advisory Role: STCube Pharmaceuticals Inc, BayerResearch Funding: Amgen(OPTIONAL) Uncompensated Relationships: PresagiaNo other potential conflicts of interest were reported.

Aim of the Study: Postoperative pain management is a significant challenge in patients undergoing Nuss repair for pectus excavatum chest wall deformity. Therapeutic anesthetic options primarily include patient-controlled intravenous analgesia, thoracic epidural analgesia (TEA), and cryoanalgesia. However, TEA is limited to inpatient use and both TEA and cryoanalgesia can result in neurologic injury. The novel technique of ultrasound-guided erector spinae plane regional analgesia has been used recently in our patients undergoing the Nuss repair and has shown impressive pain relief, but without the potential complications of other modalities. Erector spinae plane block (ESPB) postoperative pain management outcomes were studied as compared to TEA., Methods: Thirty consecutive patients with severe pectus excavatum undergoing Nuss repair and placement of ultrasound-guided ESPB were each paired to a historical cohort control patient with TEA postoperative pain management. The cohort patient match was defined by age (± 2 years), gender, and CT pectus index (± 15%). Study variables included hospital length of stay (LOS), pain scores, and pain medication usage., Results: Pain scores as measured by area under the curve per hour (Day 1: 2.72 (SD = 1.37) vs. 3.90 (SD = 1.81), P = 0.006; Day 2: 2.83 (SD = 1.32) vs. 3.97 (SD = 1.82), P = 0.007) and oral morphine equivalent (OME) pain medication usage (Day 1: 11.9 (SD = 4.9) vs 56.0 (SD = 32.2), P < 0.001; Day 2: 14.7 (SD = 7.1) vs. 38.0 (SD = 21.7), P < 0.001) were higher for the first two postoperative days in the ESPB group. However, mean hospital LOS was nearly one day shorter for ESPB patients (3.78 (SD = 0.82) vs. 2.90 (SD = 0.87), P < 0.001) who were discharged home with the catheter in place until removal, typically at 5-7 days postoperatively., Conclusion: Ultrasound-guided ESPB is thus a feasible, safe, and effective alternative to TEA in postoperative pain management after Nuss repair and results in decreased hospital stay., Level of Evidence: III., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To compare rates of successful tympanic membrane (TM) closure in primary pediatric tympanoplasty between various autologous and non-autologous tissues., Methods: A retrospective chart review was performed examining all primary pediatric tympanoplasties over a 20-year period at a single institution., Results: In 564 pediatric tympanoplasties, no statistically significant difference existed between success rates of autologous and non-autologous grafts (p = 0.083). Compared with fascia, the hazard ratios (and 95% confidence intervals [CI]) for failure for each graft were as follows: human pericardial collagen (HR 0.90, CI 0.54-1.50, p = 0.680), porcine submucosal collagen (HR 1.07, CI 0.56-2.05, p = 0.830), human acellular dermal collagen (HR 1.66, CI 0.95-2.87, p = 0.073), and "multiple grafts" (HR 0.72, CI 0.26-1.98, p = 0.520). Survival curves demonstrated that 75% of graft failures occurred by 6 months after surgery, the rest occurring between 6 and 12 months postoperatively. Larger perforations encompassing more than or equal to 50% of the TM had lower success rates (HR 1.50, CI 1.02-2.21, p = 0.041) than smaller perforations encompassing less than 50% of the TM. Age was not correlated with success (HR 0.98, CI 0.93-1.03, p = 0.390)., Conclusion: This study found that non-autologous collagen grafts provide equivalent rates of healing when compared with autologous tissue in primary pediatric tympanoplasty. In addition to the potential for reduced operative time and donor site morbidity, these materials provide a viable graft alternative in fascia-depleted ears.Level of Evidence: Level 4., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021, Otology & Neurotology, Inc.)

Purpose: To assess whether iCare HOME rebound tonometry can detect therapy-related changes during self-monitoring of intraocular pressure (IOP)., Design: Prospective clinical trial., Participants: A total of 43 eyes (n = 27 subjects) with open-angle glaucoma or ocular hypertension were enrolled during standard-of-care clinic visits. Participants were grouped into control eyes managed on stable therapy (n = 18 eyes) or therapy change eyes undergoing selective laser trabeculoplasty (SLT, n = 8 eyes), initiating topical therapy (n = 8 eyes), or adding a second medication to existing monotherapy (n = 9 eyes)., Methods: Subjects recorded IOP 4 times daily for 1 week using iCare HOME tonometry. Upon tonometer return, subjects underwent SLT or new medication start; an additional week of iCare HOME measurements was collected after 4 to 6 weeks. Control subjects recorded an additional week of measurements after 6 weeks. Measurements were grouped into 4 time periods (5-10 am, 10 am to 3 pm, 3-8 pm, 8 pm to 1 am). Goldmann applanation tonometry (GAT) was performed at each study visit for comparison., Main Outcome Measures: Detection of therapy response defined as an IOP reduction of ≥20%., Results: For eyes that demonstrated a therapy response by GAT (n = 11), iCare HOME detected a therapy response in 90.9% of eyes in ≥1 time period and 45.5% of eyes in all 4 time periods. In eyes without a GAT-measured therapy response (n = 14), iCare HOME detected a response for 71.4% (n = 10) of eyes in ≥1 time period and for 7.1% of eyes (n = 1) at all 4 time periods. In treatment eyes, intraday and interday average minimum and maximum IOP, as well as interday IOP range, were significantly reduced after therapy without a significant change in intraday IOP range. Control group eyes did not demonstrate a significant change in average IOP minimum, maximum, or range between study weeks., Conclusions: Home tonometry with iCare HOME reliably detects therapy-related IOP changes in patients with glaucoma and ocular hypertension. Treatment responses correlated well with in-office GAT and may detect treatment responses missed by GAT. Intraocular pressure measurements via home tonometry provide additional clinical information regarding intraday and interday IOP fluctuation beyond standard of care in office GAT measurements. The iCare HOME is a valuable tool to monitor therapeutic efficacy in patients with glaucoma., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Management of sinonasal malignancy (SNM) often includes surgical resection as part of the multimodality treatment. Treatment-related surgical morbidity can occur, yet risk factors associated with complications in this population have not been sufficiently investigated., Methods: Adult patients with histologically confirmed SNM whose primary treatment included surgical resection were prospectively enrolled into an observational, multi-institutional cohort study from 2015 to 2020. Sociodemographic, disease, and treatment data were collected. Complications assessed included cerebrospinal fluid leak, orbital injury, intracranial injury, diplopia, meningitis, osteoradionecrosis, hospitalization for neutropenia, and subsequent chronic rhinosinusitis. The surgical approach was categorized as endoscopic resection (ER) or open/combined resection (O/CR). Associations between factors and complications were analyzed using Student's t test, Fisher's exact test, and logistic regression modeling., Results: Overall, 142 patients met the inclusion criteria. Twenty-three subjects had at least 1 complication (16.2%). On unadjusted analysis, adjuvant radiation therapy was associated with developing a complication (91.3% vs 65.5%, p = 0.013). Compared with the ER group (n = 98), the O/CR group (n = 44) had a greater percentage of higher T-stage lesions (p = 0.004) and more frequently received adjuvant radiation (84.1% vs 64.4%, p = 0.017) and chemotherapy (50.0% vs 30.6%, p = 0.038). Complication rates were similar between the ER and O/CR groups without controlling for other factors. Regression analysis that retained certain factors showed O/CR was associated with increased odds of experiencing a complication (odds ratio, 3.34; 95% confidence interval, 1.06-11.19)., Conclusions: Prospective, multicenter evaluation of SNM treatment outcomes is feasible. Undergoing O/CR was associated with increased odds of developing a complication after accounting for radiation therapy. Further studies are warranted to build upon these findings., (© 2021 ARS-AAOA, LLC.)

Objective: While it is known that nonresponse might produce biased results and impair the precision of results in survey research studies, the pattern of the impact on the precision of estimates due to the nonresponse in different survey stages is historically overlooked. Having this type of information is essential when creating recruitment plans. This study proposes to examine and compare the effect of nonresponse in different stages on the precision of prevalence estimates in multi-stage survey studies. Based on data from a state level survey, a simulation approach was used to generate datasets with different nonresponse rates in three stages. The margin of error was then compared between the datasets with nonresponse at three different survey stages for 12 outcomes., Results: At the same nonresponse rate, the mean margin of error was greater for the data with nonresponse at higher stages. Additionally, as the nonresponse rate increased, precision was more inflated within the data with higher stage nonresponse. This suggests that the effort used to recruit the primary sampling units is more crucial to improve the precision of estimates in multi-stage survey studies., (© 2021. The Author(s).)

Multisource exchangeability models (MEMs), a BayeTsian approach for dynamically integrating information from multiple clinical trials, are a promising approach for gaining efficiency in randomized controlled trials. When the supplementary trials are considerably larger than the primary trial, care must be taken when integrating supplementary data to avoid overwhelming the primary trial. In this paper, we propose "capping priors," which controls the extent of dynamic borrowing by placing an a priori cap on the effective supplemental sample size. We demonstrate the behavior of this technique via simulation, and apply our method to four randomized trials of very low nicotine content cigarettes.

Introduction: Leaders in anesthesiology are promoting increased involvement of anesthesiologists in perioperative medicine (POM). Academic leaders are calling for a corresponding increase in resident and medical student education in this evolving medical discipline. Formalized POM programs are new to most academic anesthesiology programs, and very little has been written about development of these programs for anesthesiology residents or medical students. We describe the creation of a longitudinal medical student clerkship in POM using established curriculum design methods with minimal capital resources., Methods: This is a descriptive account of the process of clerkship design. It includes a qualitative analysis of participants' satisfaction with the novel clerkship., Results: Design and implementation of a new, advanced medical student clerkship in POM using no additional capital resources was successful. Medical students indicated appreciation for the unique longitudinal design. Students also demonstrated understanding of the expanding role of anesthesiology in perioperative care of patients, a primary goal of the educational process., Conclusions: The principles of the American Society of Anesthesiology's Perioperative Surgical Home can be taught systematically and successfully to advanced medical students with little additional expenditure of departmental resources., Competing Interests: Conflicts of interest: None of the authors have commercial associations that represent a conflict of interest in connection with the work submitted. No financial support was received for this research., (© 2021 Society for Education in Anesthesia.)

(1) Background: Research has demonstrated that early intervention for children who are hard-of-hearing (CHH) facilitates improved language development. Early speech perception abilities may impact CHH outcomes and guide future intervention. The objective of this study was to examine the use of a conditioned head turn (CHT) task as a measure of speech discrimination in CHH using a clinically feasible protocol. (2) Methods: Speech perception was assessed for a consonant and vowel contrast among 57 CHH and 70 children with normal hearing (CNH) aged 5-17 months using a CHT paradigm. (3) Results: Regardless of hearing status, 74% of CHH and 77% of CNH could discriminate /a-i/, and 55% of CHH and 56% of CNH could discriminate /ba-da/. Regression models revealed that both CHH and CNH performed better on /ba-da/ at 70 dBA compared to 50 dBA. Performance by hearing age showed no speech perception differences for CNH and children with mild hearing loss for either contrast. However, children with hearing losses ≥ 41 dB HL performed significantly poorer than CNH for /a-i/. (4) Conclusions: This study demonstrates the clinical feasibility of assessing early speech perception in infants with hearing loss and replicates previous findings of speech perception abilities among CHH and CNH.

Background: Miscommunication during clinical handover can lead to partial information transfer and healthcare provider dissatisfaction. We hypothesised that a quality improvement project to standardise the cardiovascular intensive care unit (CVICU) handover could improve healthcare provider satisfaction and reduce information omission., Methods: After institutional review board approval, the operating room (OR) to CVICU handover was audited prior, post and 1 year after standardisation implementation. The medical information transferred, healthcare provider participation and satisfaction, and patient outcome data were collected. Additionally, surveys were sent to the OR and CVICU staff by email., Results: There were 68 handover processes observed. The odds of greater satisfaction with handover for providers were 18 times higher with the process post implementation (p<0.0001) and 26 times higher 1 year after implementation (p<0.0001). There was statistically significant difference between intensive care unit resident presence (45% vs 76% vs 91%, p=0.004), surgical faculty presence (10% vs 36% vs 45%, p=0.034) and surgical fellow presence (15% vs 64% vs 62%, p=0.001) between the three time periods. More information related to the surgeon (5% vs 52% vs 27%, p=0.002), the medical history (65% vs 96% vs 91%, p=0.014) and the cardiopulmonary bypass (47% vs 88% vs 76%, p=0.017) was conveyed. The duration of mechanical ventilation was shorter after implementation (2.2±2.6 days vs 1.2±1.9 days vs 0.5±1.2 days, p=0.026)., Conclusions: One year after the OR to CVICU standardised handover implementation, the healthcare provider satisfaction remained increased, more team members participated and the information transfer increased. Although some clinical outcomes improved, further studies are recommended to prove causality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR <0.1 level ( q = 0.071), including transport of small molecules and inositol phosphate metabolism. While the causal pathways in our mediation models require further investigation to better understand the biological mechanisms, we identified seven methylation sites that may improve our understanding of epigenetic protection against T1D as mediated by the metabolome.

Background: Pain medicine physicians (PMP) are a group of physicians with background training in various primary specialties with interest and expertise in managing chronic pain disorders. Our objective is to analyze prescription drug (PD) claims from the Medicare Part D program associated with PMP to gain insights into patterns, associated costs, and potential cost savings areas., Methods: The primary data source for Part D claims data is the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Data Warehouse, which contains Medicare Part D prescription drug events (PDE) records received through the claims submission cutoff date. Only providers with taxonomies of pain management (PM) and interventional pain management (IPM) were included in the study. The analysis of PDE was restricted to drugs with >250 claims. The distribution of claims and costs were analyzed based on drug class and provider specialty. Subsequently, we explored claims and expenses for opioid drug prescriptions in detail. Prescribing characteristics of the top 5% of providers by costs and claims were examined to gain additional insights. The costs and claims were explored for the top 10 drugs prescribed by PMP in 2017., Results: There were a total of unique 3280 PMP-prescribed drugs with an associated expense of 652 million dollars in the 2017 Medicare Part D program. Prescriptions related to PMP account for a tiny fraction of the program's drug expenditure (0.4%). Opioids, anticonvulsants, and gabapentinoids were associated with the largest number of claims and the largest expenses within this fraction. Among opioid drug prescriptions, brand-named drugs account for a small fraction of claims (8%) compared to generic drugs. However, the expenses associated with brand name drugs were higher than generic drugs. Prescribers in the top 5% by PD costs had a higher number of claims, prescribed a higher proportion of branded medications, and had prescriptions associated with longer day supply compared to an average PMP. There were several opioid medications in the top 10 PD list by cost associated with PMP., Conclusions: Opioids were the most common medications among Medicare part D claims prescribed by PMP. Only 12% of the total opioid PD claims were by PMP. The top 5% of PMP prescribers had 10 times more claims than the average PMP., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Children who sustain moderate to large surface area burns present in a hypermetabolic state with increased caloric and protein requirements. A policy was implemented at our institution in 2017 to initiate enteral nutrition (EN) in pediatric burn patients within 4 hours of admission. The authors hypothesize that early EN (initiated within 4 hours of admission) is more beneficial than late EN (initiated ≥ 4 hours from admission) for pediatric burn patients and is associated with decreased rates of pneumonia, increased calorie and protein intake, fewer feeding complications, a shorter Intensive Care Unit (ICU) length of stay (LOS), and a reduced hospital LOS. Children who sustained a total body surface area (TBSA) burn injury ≥ 10% between 2011 and 2018 were identified in a prospectively maintained burn registry at Children's Hospital Colorado. Patients were stratified into two groups for comparison: early EN and late EN. The authors identified 132 pediatric burn patients who met inclusion criteria, and most (60%) were male. Approximately half (48%) of the study patients were in the early EN group. The early EN group had lower rates of underfeeding during the first week (P = .014) and shorter ICU LOS (P = .025). Achieving and sustaining adequate nutrition in pediatric burn patients with moderate to large surface area burn injuries are critical to recovery. Early EN in pediatric burn patients is associated with decreased underfeeding and reduced ICU LOS. The authors recommend protocols to institute feeding for patients with burns ≥ 10% TBSA within 4 hours of admission at all pediatric burn centers., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Breakthroughs in cancer biology have defined new research programs emphasizing the development of therapies that target specific pathways in tumor cells. Innovations in clinical trial design have followed with master protocols defined by inclusive eligibility criteria and evaluations of multiple therapies and/or histologies. Consequently, characterization of subpopulation heterogeneity has become central to the formulation and selection of a study design. However, this transition to master protocols has led to challenges in identifying the optimal trial design and proper calibration of hyperparameters. We often evaluate a range of null and alternative scenarios; however, there has been little guidance on how to synthesize the potentially disparate recommendations for what may be optimal. This may lead to the selection of suboptimal designs and statistical methods that do not fully accommodate the subpopulation heterogeneity. This article proposes novel optimization criteria for calibrating and evaluating candidate statistical designs of master protocols in the presence of the potential for treatment effect heterogeneity among enrolled patient subpopulations. The framework is applied to demonstrate the statistical properties of conventional study designs when treatments offer heterogeneous benefit as well as identify optimal designs devised to monitor the potential for heterogeneity among patients with differing clinical indications using Bayesian modeling.

Objective: To compare the difference in pre- to postoperative speech performance of patients qualifying for a cochlear implant (CI) in quiet, +10 dB signal-to-noise ratio (SNR), and +5 dB SNR., Study Design: Retrospective., Setting: Tertiary referral center., Patients: Fifty-eight post-lingually deafened, unilateral CI recipients from three Groups were included: 1) those who met CI candidacy criteria with AzBio sentences in quiet, 2) in noise at +10 dB SNR but not in quiet, 3) and in noise at +5 dB SNR but not in quiet or +10 dB SNR., Intervention: Unilateral CI., Main Outcome Measures: Pre- and 1 year postoperative speech recognition scores., Results: Best-aided AzBio speech recognition of individuals in Group 1 improved significantly for all test conditions and improved significantly for Groups 2 and 3 in the +10 and +5 dB SNR test conditions postoperatively. When tested with their CI alone however, while AzBio speech recognition of individuals in Group 1 and Group 2 improved significantly in the quiet and +10 dB SNR conditions, speech recognition was not significantly changed postoperatively under any testing condition for individuals in Group 3., Conclusions: While individuals qualifying for a CI only in the +5 dB SNR condition may derive significant benefit from implantation in best aided conditions, speech understanding outcomes can be more variable thus warranting additional counseling before implantation and case-by-case consideration of listening needs and goals., Competing Interests: Conflicts of interest and sources of funding: Author M.C.A. has nonremunerated research funding from Advanced Bionics, LLC for work unrelated to this article. Author S.G. is on the advisory board for Sirocco Therapeutics, Cystic Fibrosis Foundation, Applied Genetic Technologies Corporation and Roche. He also is a consultant for Cochlear Corporation and Decibel Therapeutics and receives research funding from NIH/NIDCD and Med-El Corporation. All other authors declare there is no conflict of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2020, Otology & Neurotology, Inc.)

Objective: Following metabolic and bariatric surgery (MBS), most adolescents experience weight loss and improvement of many obesity-associated complications (OACs). The relationship between weight loss and remission of OACs after MBS in adolescents has not been well described., Methods: The Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) is a multi-institutional prospective observational study of adolescents who underwent MBS between 2007 and 2012. Lower-weight-loss responders (LWLRs) were defined as having <20% total body weight loss (TBWL) and higher-weight-loss responders (HWLRs) were defined as having ≥20% TBWL at 5 years after MBS. The prevalence of OACs was compared at baseline and 5 years after MBS., Results: Both LWLRs (n = 114) and HWLRs (n = 78) lost significant weight within the first year following MBS; however, the TBWL at 5 years for the LWLRs was 8.6% ± 9.5% compared with 33.8% ± 9.2% for the HWLRs. Those in the HWLR group were more likely to experience durable remission of composite dyslipidemia at 5 years, whereas there were no differences between groups in remission rates of all other OACs., Conclusions: Greater weight loss after MBS in adolescents was associated with greater remission of composite dyslipidemia; however, remission of other OACs was not dependent on major sustained weight loss., (© 2020 The Obesity Society.)