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ObjectiveTo examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they show differences in MRI-based regional brain volumes, cognitive domains, and certain plasma biomarkers.MethodsProfessional fighters 35 years of age or older and/or retired were included. Participants were categorised as either having TES (TES+) or not (non-TES). TES+ participants were further subtyped by their cognitive profile. Multiple linear regression models were used to compare MRI-based regional brain volumes, cognitive performance, plasma tau and neurofilament light levels between TES– and TES+ groups.Results176 participants (110 boxers and 66 MMA) were included in the analysis. 72 (41%)/176 were categorised as having TES, the likelihood of TES increasing with age. TES+ participants tended to be boxers, started fighting at a younger age, had more professional fights and knocked out more frequently. The TES+ group had lower regional brain volumes including both grey and white matter structures. TES+ also had lower scores on simple and choice reaction time, psychomotor speed and Trails A .ConclusionThe new TES criteria does distinguish a group of fighters with differences in regional brain volumes and reduced cognitive function. Our findings support the use of the NINDS criteria for TES in further research of the long-term effects of repetitive head impacts.

Background: Severe headaches are common after subarachnoid hemorrhage. Guidelines recommend treatment with acetaminophen and opioids, but patient data show that headaches often persist despite multimodal treatment approaches. Considering an overall slim body of data for a common complaint affecting patients with SAH during their intensive care stay, we set out to assess practice patterns in headache management among clinicians who treat patients with SAH. Methods: We conducted an international cross-sectional study through a 37-question Web-based survey distributed to members of five professional societies relevant to intensive and neurocritical care from November 2021 to January 2022. Responses were characterized through descriptive analyses. Fisher’s exact test was used to test associations. Results: Of 516 respondents, 329 of 497 (66%) were from North America and 121 of 497 (24%) from Europe. Of 435 respondents, 379 (87%) reported headache as a major management concern for patients with SAH. Intensive care teams were primarily responsible for analgesia during hospitalization (249 of 435, 57%), whereas responsibility shifted to neurosurgery at discharge (233 of 501, 47%). Most used medications were acetaminophen (90%), opioids (66%), corticosteroids (28%), and antiseizure medications (28%). Opioids or medication combinations including opioids were most frequently perceived as most effective by 169 of 433 respondents (39%, predominantly intensivists), followed by corticosteroids or combinations with corticosteroids (96 of 433, 22%, predominantly neurologists). Of medications prescribed at discharge, acetaminophen was most common (303 of 381, 80%), followed by opioids (175 of 381, 46%) and antiseizure medications (173 of 381, 45%). Opioids during hospitalization were significantly more prescribed by intensivists, by providers managing higher numbers of patients with SAH, and in Europe. At discharge, opioids were more frequently prescribed in North America. Of 435 respondents, 299 (69%) indicated no change in prescription practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers and while inpatient versus at discharge were found. Conclusions: Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in use and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.

Biomedical studies, such as clinical trials, often require the comparison of measurements from two correlated tests in which each unit of observation is associated with a binary outcome of interest via relative risk. The associated confidence interval is crucial because it provides an appreciation of the spectrum of possible values, allowing for a more robust interpretation of relative risk. Of the available confidence interval methods for relative risk, the asymptotic score interval is the most widely recommended for practical use. We propose a modified score interval for relative risk and we also extend an existing nonparametric U-statistic-based confidence interval to relative risk. In addition, we theoretically prove that the original asymptotic score interval is equivalent to the constrained maximum likelihood-based interval proposed by Nam and Blackwelder. Two clinically relevant oncology trials are used to demonstrate the real-world performance of our methods. The finite sample properties of the new approaches, the current standard of practice, and other alternatives are studied via extensive simulation studies. We show that, as the strength of correlation increases, when the sample size is not too large the new score-based intervals outperform the existing intervals in terms of coverage probability. Moreover, our results indicate that the new nonparametric interval provides the coverage that most consistently meets or exceeds the nominal coverage probability.

Background Multidrug-resistant Acinetobacter baumannii remains challenging to treat. Although eravacycline has in vitro activity against this pathogen, there are no studies evaluating outcomes. Objective To assess the efficacy of eravacycline compared with best previously available therapy in adults with difficult-to-treat resistant (DTR) A. baumannii pneumonia. Methods This was a retrospective study of adults hospitalized for pneumonia with DTR A. baumannii. Patients receiving eravacycline were compared with those receiving best previously available therapy. The primary outcome was 30-day in-hospital mortality. Secondary outcomes included clinical cure at Day 14, hospital and intensive care unit (ICU) length of stay, microbiologic cure, and readmission within 90 days with a positive A. baumannii respiratory culture. Results Ninety-three patients were included, with 27 receiving eravacycline. Eravacycline was associated with higher 30-day mortality (33% vs 15%; P = 0.048), lower microbiologic cure (17% vs 59%; P = 0.004), and longer durations of mechanical ventilation (10.5 vs 6.5 days; P = 0.016). At baseline, eravacycline patients had more A. baumannii bacteremia and coinfection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Among bacteremic patients, all 4 receiving eravacycline died by Day 30 and both patients receiving best previously available therapy survived. Upon exclusion of patients with bacteremia and SARS-CoV-2, there were no differences between the groups across any outcomes. Conclusions Eravacycline-based combination therapy had similar outcomes to best previously available combination therapy for adults with DTR A. baumannii pneumonia. However, eravacycline should be used with caution in the setting of bacteremia as outcomes were poor in this population.

Confidence interval for the difference of two proportions has been studied for decades. Many methods were developed to improve the approximation of the limiting distribution of test statistics, such as the profile likelihood method, the score method, and the Wilson method. For the Wilson interval developed by Beal (Biometrics 43:941, 1987), the approximation of the Z test statistic to the standard normal distribution may be further improved by utilizing the continuity correction, in the observation of anti-conservative intervals from the Wilson interval. We theoretically prove that the Wilson interval is nested in the continuity corrected Wilson interval under mild conditions. We compare the continuity corrected Wilson interval with the commonly used methods with regards to coverage probability, interval width, and mean squared error of coverage probability. The proposed interval has good performance in many configurations. An example from a Phase II cancer trial is used to illustrate the application of these methods.

Cross-validation (CV) is a resampling approach to evaluate machine learning models when sample size is limited. The number of all possible combinations of folds for the training data, known as CV rounds, are often very small in leave-one-out CV. Alternatively, Monte Carlo cross-validation (MCCV) can be performed with a flexible number of simulations when computational resources are feasible for a study with limited sample size. We conduct extensive simulation studies to compare accuracy between MCCV and CV with the same number of simulations for a study with binary outcome (e.g., disease progression or not). Accuracy of MCCV is generally higher than CV although the gain is small. They have similar performance when sample size is large. Meanwhile, MCCV is going to provide reliable performance metrics as the number of simulations increases. Two real examples are used to illustrate the comparison between MCCV and CV.

Purpose To determine the relationship of advanced pharmacy practice experience (APPE) grading schemes and other pharmacy program variables (ie, program age and funding) with pharmacy residency match rates. Summary A 12-question survey was disseminated to experiential administrators of pharmacy programs in October 2018. Respondents identified their program’s APPE grading scheme (pass/fail, letter grades, or other) and associated pros and cons. Responding programs were categorized by age and funding status. Survey responses were correlated with the American Society of Health-System Pharmacists residency match rates for 2016 through 2018. Data were analyzed using descriptive statistics and logistic regression models as well as by attributes via thematic analysis. Most pharmacy programs (62%) reported using letter grades for APPEs compared to pass/fail (30%) or other (8%) schemes. Pharmacy programs using pass/fail grading were more likely to have students match to postgraduate year 1 (PGY1) (P < 0.001) and postgraduate year 2 (PGY2) (P = 0.0074) residencies. Older pharmacy programs for each grading scheme were more likely to have higher match rates; however, for PGY1 match rates, older programs utilizing letter grades correlated to lower match rates than those utilizing pass/fail grading (P < 0.0001). Likewise, both public and private pharmacy programs using pass/fail grading had higher PGY1 match rates than those using letter grades (P = 0.0006 and P = 0.0014). Conclusion Pass/fail grading in APPEs does not hinder PGY1 or PGY2 residency placement compared to other grading schemes both overall and in combination with certain pharmacy program variables. Grading scheme strengths and weaknesses should be considered when deciding on optimal assessment strategies for APPEs and when evaluating candidates for residencies.

Introduction This study sought to assess the impact student pharmacist-led health outreach events had on participants in the Health Belief Model domains of perceived severity of disease, perceived barriers, perceived benefits, and self-efficacy. Methods This study was an observational pre‐/post-survey design conducted between January and December 2019 at student pharmacist-led community health outreach events in the Salt Lake City, Utah metropolitan area. The survey was developed partially based on the Health Belief Model and consisted of seven items with a five-point Likert scale (1 = strongly disagree to 5 = strongly agree). The survey was completed by participants before and immediately after engaging in the outreach event. Results A total of 31 participants across a variety of demographics and educational backgrounds completed the study. The surveys from the outreach events showed statistically significant increases in the participants' perceived severity of disease, perceived barriers, and self-efficacy. Perceived benefits was not significantly changed. Conclusions Student pharmacist-led community health outreach events significantly increase participants' perceived severity of disease, perceived barriers, and self-efficacy, which may indicate increased willingness to adopt the recommended health behavior.

Asymptotic approaches are traditionally used to calculate confidence intervals for intraclass correlation coefficient in a clustered binary study. When sample size is small to medium, or correlation or response rate is near the boundary, asymptotic intervals often do not have satisfactory performance with regard to coverage. We propose using the importance sampling method to construct the profile confidence limits for the intraclass correlation coefficient. Importance sampling is a simulation based approach to reduce the variance of the estimated parameter. Four existing asymptotic limits are used as statistical quantities for sample space ordering in the importance sampling method. Simulation studies are performed to evaluate the performance of the proposed accurate intervals with regard to coverage and interval width. Simulation results indicate that the accurate intervals based on the asymptotic limits by Fleiss and Cuzick generally have shorter width than others in many cases, while the accurate intervals based on Zou and Donner asymptotic limits outperform others when correlation and response rate are close to their boundaries.

Background: Severe headaches are common after subarachnoid hemorrhage (SAH). Guidelines recommend treatment with acetaminophen and opioids, but patient data show that headaches often persist despite multimodal treatment approaches. Considering an overall slim body of data for a common complaint affecting SAH patients during their intensive care stay, we set out to assess practice patterns in headache management among clinicians who treat patients with SAH.Methods: We conducted an international cross-sectional study through a 37-question web-based survey distributed to members of 5 professional societies relevant to intensive and neurocritical care from 11/2021-1/2022. Responses were characterized through descriptive analyses; Fisher’s exact test was used to test associations.Results: Of 516 responses, 329/497 (66%) were from North America and 121/497 (24%) from Europe. 379/435 (87%) reported headache as major management concern for SAH patients. Intensive-care-teams were primarily responsible for analgesia during hospitalization (249/435, 57%), while responsibility shifted to neurosurgery at discharge (233/501, 47%). Most used medications were acetaminophen (90%), opioids (66%), corticosteroids (28%) and antiseizure medications (28%). Opioids or medication combinations including opioids were most frequently perceived as most effective, by 169/433 (39%, predominantly intensivists), followed by corticosteroids or combinations with corticosteroids (96/433, 22%, predominantly neurologists). Of medications prescribed at discharge, acetaminophen was most common (303/381, 80%), followed by opioids (175/381 [46%]), and antiseizure medications (173/381, 45%). Opioids during hospitalization were significantly more prescribed by intensivists, by providers managing higher numbers of SAH patients, and in Europe. At discharge, opioids were more frequently prescribed in North America. 299/435 (69%) indicated no change in prescription practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers, and inpatient versus discharge were found. Conclusions: Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in utilization and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.

Background: Severe headaches are common after subarachnoid hemorrhage (SAH). Guidelines recommend treatment with acetaminophen and opioids, but patient data show that headaches often persist despite multimodal treatment approaches. Considering an overall slim body of data for a common complaint affecting SAH patients during their intensive care stay, we set out to assess practice patterns in headache management among clinicians who treat patients with SAH.Methods: We conducted an international cross-sectional study through a 37-question web-based survey distributed to members of 5 professional societies relevant to intensive and neurocritical care from 11/2021-1/2022. Responses were characterized through descriptive analyses; Fisher’s exact test was used to test associations.Results: Of 516 responses, 329/497 (66%) were from North America and 121/497 (24%) from Europe. 379/435 (87%) reported headache as major management concern for SAH patients. Intensive-care-teams were primarily responsible for analgesia during hospitalization (249/435, 57%), while responsibility shifted to neurosurgery at discharge (233/501, 47%). Most used medications were acetaminophen (90%), opioids (66%), corticosteroids (28%) and antiseizure medications (28%). Opioids or medication combinations including opioids were most frequently perceived as most effective, by 169/433 (39%, predominantly intensivists), followed by corticosteroids or combinations with corticosteroids (96/433, 22%, predominantly neurologists). Of medications prescribed at discharge, acetaminophen was most common (303/381, 80%), followed by opioids (175/381 [46%]), and antiseizure medications (173/381, 45%). Opioids during hospitalization were significantly more prescribed by intensivists, by providers managing higher numbers of SAH patients, and in Europe. At discharge, opioids were more frequently prescribed in North America. 299/435 (69%) indicated no change in prescription practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers, and inpatient versus discharge were found. Conclusions: Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in utilization and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.

Traumatic brain injury (TBI) is a common source of functional impairment among athletes, military personnel, and the general population. Professional fighters in both boxing and mixed martial arts (MMA) are at particular risk for repetitive TBI and may provide valuable insight into both the pathophysiology of TBI and its consequences. Currently, effects of fighter weight class on brain volumetrics (regional and total) and functional outcomes are unknown. Fifty-three boxers and 103 MMA fighters participating in the Professional Fighters Brain Health Study (PRBHS) underwent volumetric magnetic resonance imaging (MRI) and neuropsychological testing. Fighters were divided into lightweight (≤139.9 lb), middleweight (140.0–178.5 lb), and heavyweight (>178.5 lb). Compared with lightweight fighters, heavyweights displayed greater yearly reductions in regional brain volume (boxers: bilateral thalami; MMA: left thalamus, right putamen) and functional performance (boxers: processing speed, simple and choice reaction; MMA: Trails A and B tests). Lightweights suffered greater reductions in regional brain volume on a per-fight basis (boxers: left thalamus; MMA: right putamen). Heavyweight fighters bore greater yearly burden of regional brain volume and functional decrements, possibly related to differing fight dynamics and force of strikes in this division. Lightweights demonstrated greater volumetric decrements on a per-fight basis. Although more research is needed, greater per-fight decrements in lightweights may be related to practices of weight-cutting, which may increase vulnerability to neurodegeneration post-TBI. Observed decrements associated with weight class may result in progressive impairments in fighter performance, suggesting interventions mitigating the burden of TBI in professional fighters may both improve brain health and increase professional longevity.

Objectives: Determine, through video reviews, how often concussions occur in combat sport matches, what influence they have on the outcome, and how well non-physician personnel can be trained to recognize concussions.Methods: This is a retrospective video analysis by an 8-person panel of 60 professional fights (30 boxing and 30 mixed martial arts). Through video review, physician and non-physician personnel recorded details about each probable concussion and determined if and when they would have stopped the fight compared to the official stoppage time.Results: A concussion was recorded in 47/60 fights. The mean number of concussions per minute of fight time was 0.061 (0.047 for boxers and 0.085 for MMA). When stratifying by outcome of the bout, the mean number of concussions per minute for the winner was 0.010 compared to the loser at 0.111 concussions per minute. The fighter that sustained the first concussion ultimately lost 98% of the time. The physician and non-physician raters had high agreement regarding the number of concussions that occurred to each fighter per match. The physician raters judged that 24 of the 60 fights (11 boxing [37%]; 13 MMA [43%]) should have been stopped sooner than what occurred.Conclusion: Recognizing that the concussions often occur in combat sport matches, that the losing fighter almost always is concussed first and tends to sustain more concussions during the fight, along with the demonstration that non-physician personnel can be taught to recognize concussion, may guide policy changes that improve brain health in combat sports.

OBJECTIVE Repetitive head impacts (RHIs) in combat sports are associated with cognitive decline and brain volume reduction. While fighting style differences between boxers, mixed martial artists (MMAs), and martial artists (MAs) have resulted in a broader spectrum of injury, the effects of RHIs on MAs relative to other fighters have not yet been explored. This study aimed to determine a differential effect of fighting style on cognition and brain. SETTING A large outpatient medical center specializing in neurological care. PARTICIPANTS, DESIGN, AND MAIN MEASURES In total, 40 MAs, 188 boxers, and 279 MMAs were compared on baseline measures of subcortical regional brain volumes, after controlling for total brain volumes, and cognitive performance. RESULTS Significant differences between MAs, MMAs, and boxers were observed in subcortical brain structure volumes and cognitive measures. MMAs and MAs consistently had larger volumes and higher scores than boxers. Fighting style significantly moderated the relationship between the number of professional fights and the volumes of various subcortical brain structures and performance on a measure of processing speed at baseline. CONCLUSIONS Differences in RHIs across fighting styles may be of clinical significance. Exploring changes over time within the MA, boxer, and MMA cohorts may provide insight into longer-term discrepancies in subcortical regional brain volumes and cognitive functioning across fighting styles.

Sample size calculation based on normal approximations is often associated with the loss of statistical power for a single-arm trial with a time-to-event endpoint. Recently, Wu (2015) derived the exact variance for the one-sample log-rank test under the alternative and showed that a single-arm one-stage study based on exact variance often has power above the nominal level while the type I error rate is controlled. We extend this approach to a single-arm two-stage design by using exact variances of the one-sample log-rank test for the first stage and the two stages combined. The empirical power of the proposed two-stage optimal designs is often not guaranteed under a two-stage design setting, which could be due to the asymptotic bi-variate normal distribution used to estimate the joint distribution of the test statistics. We adjust the nominal power level in the design search to guarantee the simulated power of the identified optimal design being above the nominal level. The sample size and the study time savings of the proposed two-stage designs are substantial as compared to the one-stage design.

Multidrug-resistantTo assess the efficacy of eravacycline compared with best previously available therapy in adults with difficult-to-treat resistant (DTR)This was a retrospective study of adults hospitalized for pneumonia with DTRNinety-three patients were included, with 27 receiving eravacycline. Eravacycline was associated with higher 30-day mortality (33%Eravacycline-based combination therapy had similar outcomes to best previously available combination therapy for adults with DTR

Adaptive designs are increasingly used in clinical trials to assess the effectiveness of new drugs. For a single-arm study with a binary outcome, several adaptive designs were developed by using numerical search algorithms and the conditional power approach. The design based on numerical search algorithms is able to identify the global optimal design, but the computational intensity limits the usage of these designs. The conditional power approach searches for the optimal design without expensive computing time. In addition, promising zone strategy was proposed to move on drug development to the follow-up stages when the interim results are promising. We propose to develop two adaptive designs: One based on the conditional power approach, and the other based on the promising zone strategy. These two designs preserve types I and II error rates. It is preferable to satisfy the monotonic property for adaptive designs: The second stage sample size decreases as the first stage responses go up. We theoretically prove this important property for the two proposed designs. The proposed designs can be easily applied to real trials with limited computing resources.

Background Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE. Methods This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics. Perspective Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547.

Repeated data are increasingly collected in studies to investigate the trajectory of change in measurements over time. Determining a link between one repeated measurement with another that is considered as the biomarker for disease progression, may provide a new target for drug development. When a third variable is associated with one of the two measurements, partial correlation after eliminating the effect of that variable is able to provide reliable estimate for association as compared to the existing raw correlation for repeated data. We propose using linear regression models to compute residuals by modeling a relationship between each measurement and a third variable. The computed residuals are then used in a linear mixed model (implemented by SAS Proc Mixed) to compute partial correlation for repeated data. Alternatively, the partial correlation may be computed as the average of partial correlations at each visit. We provide two real examples to illustrate the application of the proposed partial correlation, and conduct extensive numerical studies to compare the proposed partial correlation coefficients.

Purpose Pharmacists report high levels of burnout. Mindfulness approaches have been demonstrated to have positive results in the general population and in other healthcare professions. However, limited studies have been performed evaluating mindfulness approaches in student pharmacists. The aim of this study was to evaluate the effectiveness of daily use of a mindfulness mobile application in improving student pharmacists’ perceived stress, burnout, and mindfulness. Methods This study was a randomized, longitudinal, waitlist-controlled trial. The intervention group was asked to meditate using the mindfulness application Headspace daily for at least 6 weeks. The waitlist control group was asked to abstain from using the application for the entire study. Stress, burnout, and mindfulness were assessed using validated survey instruments at baseline, 6 weeks, and 10 weeks. A secondary outcome was to assess the persistence of application use after the intervention period. Results Fifty-six participants completed the study. The intervention group reported significantly lower scores on stress and burnout at 6 weeks compared to the control group. The intervention group also reported significantly higher scores on mindfulness. The differences in stress, burnout, and mindfulness persisted at follow-up. The mean percentage of students in the intervention group who used the application each day was 90% over the intervention period and 62% over the follow-up period. Conclusion A mindfulness mobile application significantly improved student pharmacists’ stress, burnout, and mindfulness with daily use. Most participants continued to use the application for 4 weeks after the end of the intervention. Positive effects on stress and mindfulness persisted even with decreased use.

Objective Acute care physical therapists recommend discharge locations and services in part to help prevent falls during post-discharge recovery. Therapists may use standardized tests to inform their recommendation decisions, but evidence linking test scores with fall risk after discharge is lacking. The primary purpose of this study was to explore the associations between Tinetti Performance-Oriented Mobility Assessment (POMA) and Activity Measure for Post-Acute Care Inpatient Mobility Short Form (AM-PAC IMSF) scores and falls in the first 30 days after hospital discharge. Anticipating that agreement between therapist recommendations and discharge locations and services (discharge agreement), age, and sex could impact those associations, these factors were included in this investigation. Methods In this observational cohort study, 258 hospitalized patients consented to medical record data extraction and answered a phone survey 30 days after discharge to report whether they had experienced a fall since leaving the hospital. POMA and AM-PAC IMSF tests were administered for every patient. Participants’ age, sex, diagnosis, last POMA score, last AM-PAC IMSF score, physical therapist discharge recommendations, actual discharge location and services, discharge date, and phone number were collected from their medical records. Results When analyzed alone, higher POMA scores were associated with lower odds of falling, but the association was not significant after adjustment for other factors. Neither AM-PAC IMSF scores, age, nor sex were associated with falls. Discharge agreement, however, was associated with 59% lower odds of falling after adjustment for other factors. Conclusion Participants, who were discharged to the location with the services recommended by their physical therapist, were less likely to fall. Tinetti POMA and AM-PAC IMSF scores did not discriminate well participants who would fall. Impact Findings in this study inform those involved in discharge planning on the value of implementing physical therapist recommendations in reducing fall risk after hospital discharge. Lay Summary If physical therapist discharge recommendations are implemented, patients are less likely to fall during the month after hospital discharge. Balance and mobility test scores may provide therapists valuable information, but they are limited in their ability to identify who will fall after discharge.

The search for disease modifying therapies in Alzheimers disease (AD) has recently led to promising results but also revealed design issues in clinical trials themselves. Of particular importance is the potential statistical challenges that can arise when dosages change after an interim analysis, which is not uncommon in contemporary AD trials. Following the recent Aducanumab trials, we sought to study the implications of dose changes on the statistical power of an AD trial. We conducted extensive simulations to calculate statistical power when the relationship between treatment effect size and time is linear or non-linear, and the investigated drug has delayed treatment effect or not. Statistical power depends on many design factors including the dose change time, correlation, population homogeneity, and treatment effect time. We recommend that researchers conduct simulation studies at the interim analysis to justify the modified sample size and/or follow-up time modification meanwhile the type I and II error rates are controlled.

In contemporary clinical trials, often evaluated simultaneously are multiple new treatments or the same treatment at multiple dose levels. These treatments are first compared with a control, and the best candidate with sufficient activity is then picked for the following trial for further investigation. When the primary outcome is binary, several testing procedures including Dunnett's test, have been proposed for the assessment of hypotheses. The sample size of each group is predetermined; thus, an unconditional exact approach is aligned with the study design. The exact unconditional approach based on maximization has been studied for comparing multiple treatments with a control. The newly developed exact unconditional approach based on estimation and maximization could possibly increase the effectiveness of exact approaches by smoothing the tail probability surface. We compare these 2 exact unconditional approaches based on 3 commonly used test statistics under various design settings. Based on results from numerical studies, we provide recommendations on the usage of these exact approaches. A real clinical trial to treat psoriasis is used to illustrate the application of the considered exact approaches.

Objective:To evaluate the sex differences in cognitive course over 4 years in Parkinson’s disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls.Methods:Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson’s Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared.Results:Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period).Conclusions:Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

It has long been established that fighting sports such as boxing and mixed martial arts can lead to head injury. Prior work from this group on the Professional Fighters Brain Health Study found that exposure to repetitive head impacts is associated with lower brain volumes and decreased processing speed in fighters. Current and previously licensed professional fighters were recruited, divided into active and retired cohorts, and matched with a control group that had no prior experience in sports with likely head trauma. This study examined the relationship between age of first exposure (AFE) to fighting sports and brain structure (MRI regional volume), cognitive performance (CNS Vital Signs, iComet C3), and clinical neuropsychiatric symptoms (PHQ-9, Barratt Impulsiveness Scale). Brain MRI data showed significant correlations between earlier AFE and smaller bilateral hippocampal and posterior corpus callosum volumes for both retired and active fighters. Earlier AFE in active fighters was correlated with decreased processing speed and decreased psychomotor speed. Retired fighters showed a correlation between earlier AFE and higher measures of depression and impulsivity. Overall, the results help to inform clinicians, governing bodies, parents, and athletes of the risks associated with beginning to compete in fighting sports at a young age.

Bilateral data are frequently occur in medical research. Asymptotic approaches are traditionally used to construct confidence intervals for proportion difference. However, they are often have unsatisfactory performance with regards to coverage, with the actual coverage below the nominal level or being too conservative. For these reasons, we propose developing exact one-sided limits for proportion difference in a parallel study with bilateral data to guarantee the coverage probability when sample size is small to medium. A statistical quantity has to be used for sample space ordering in the exact limit calculation. Four asymptotic limits are utilized as statistical quantities: the Wald limits under the independence or dependence assumptions for variance estimates, the Wald limits with the difference estimate under the dependence assumption, and the bootstrap percentile limits. We compare the performance of these exact limits with regards to average length and the limits of all possible samples. A real example from a randomized clinical trial in otolaryngology is used to illustrate the application of the proposed exact limits.

More than half of the patients with Alzheimer’s disease (AD) have comorbidities including TDP-43 and Lewy bodies, which are also associated with frontotemporal lobar degeneration and dementia with Lewy bodies, respectively. These comorbidities may help explain the overlapping neuropsychiatric symptoms between AD and other dementias. Data on 221 AD patients with Neuropsychiatric Inventory-Questionnaire were obtained from the National Alzheimer’s Coordinating Center. TDP-43 was associated with aberrant motor activity, whereas Lewy bodies were associated with anxiety, irritability, sleep behavior, and appetite problems. The associations between these comorbidities and neuropsychiatric symptoms were more significant for patients with sparse diffuse plaques.

To estimate the disease prevalence, a gold standard test is the best choice for accurate estimation. The gold standard could be very expensive or time consuming for use in practice. For this reason...

In a parallel group study comparing a new treatment with a standard of care, missing data often occur for various reasons. When the outcome is binary, the data from such studies can be summarized into a 2 × 3 contingency table, with the missing observations in the last column. When the missingness is neither related to the outcome of interest nor related to other outcomes from the study but it is covariate dependent with the sole covariate being treatment, this type of missing data mechanism is considered as missing at random. In 2016, Tian et al. proposed three statistics to test the hypothesis that the response rate is equivalent for a parallel group study with missing data. The asymptotic limiting distributions of these test statistics were used for statistical inference. However, asymptotic approaches for testing proportions generally do not have satisfactory performance with regard to type I error rate control for a clinical trial with the sample size from small to medium. For this reason, we consider an exact approach based on maximization to provide valid and efficient statistical inference for a parallel group study with missing data. Exact approaches can guarantee the type I error rate and they are computationally feasible in this setting. We conduct extensive numerical studies to compare the performance of the exact approach based on the three statistics for a one-sided hypothesis testing problem. We conclude that the exact approach based on the likelihood ratio statistic is more powerful than the exact approach based on the other two statistics. Two real clinical trial data sets are used to illustrate the application of the proposed exact approach.

Adaptive designs play an important role in contemporary clinical trials to make designs flexible and efficient. In cancer clinical trials, given a relatively small sample size, it is important to o...

Background: There is a current lack of any composite measure for the effective tracking and monitoring of clinical change in individuals exposed to repetitive head impacts (RHI). The aim of this study is to create a composite instrument for the purposes of detecting change over time in cognitive and behavioral function in individuals exposed to RHI.Methods: The data to derive the composite instrument came from the Professional Fighters Brain Health Study (PFBHS), a longitudinal study of active and retired professional fighters [boxers and mixed martial arts (MMA) fighters] and healthy controls. Participants in the PFBHS underwent assessment on an annual basis that included computerized cognitive testing and behavioral questionnaires. Multivariate logistic regression models were employed to compare active fighters (n = 117) with controls (n = 22), and retired fighters (n = 26) with controls to identify the predictors that could be used to differentiate the groups over time. In a second step, linear discriminant analysis was performed to derive the linear discriminant coefficients for the three groups by using the predictors from the two separate logistic regression models.Results: The composite scale is a weighted linear value of 12 standardized scores consisting of both current and yearly change scores in domains including: processing speed, choice reaction time, semantic fluency, letter fluency, and Barrett Impulsiveness Scale. Because the weighting of values differed between active and retired fighters, two versions emerged. The mean and standard deviation ratio (MSDR) showed that the new index had better sensitivity compared to the individual measures, with the ratio of MSDR of the new index to that of the existing measures of at least 1.84.Conclusion: With the increasing need for tools to follow individuals exposed to RHI and the potential of clinical trials on the horizon for CTE, the RHICI is poised to serve as an initial approach to a composite clinical measure.

Gallbladder cancer (GBC) is a rare, poor-prognosis cancer with unique demographics, comorbidities and a paucity of research. This study investigated inpatient palliative care and its associations with demographics, comorbidities (e.g., obesity), length of stay and hospital charges in GBC in US hospitals (2007-2016).Data were extracted from the National Inpatient Sample (NIS) database that contains deidentified clinical and nonclinical information for each hospitalisation. Inpatient palliative care utilisation was identified using the International Classification of Diseases (ICD-9 and ICD-10) codes (V66.7 and Z51.5). Generalised regression analysis was conducted with adjustment for variations in predictors.Of the 4921 reported GBC hospitalizations, only 10.3% encountered palliative care. Palliative care was associated with reduced hospital charges by $12,405 per hospitalisation (P 0.0001) with no change in length of stay. Palliative care utilisation increased over time (P = 0.004). It was associated with age80 years, with more severe disease, and in-hospital death (P 0.0001). Obesity had a negative association with palliative care utilisation (P = 0.0029).Our novel study found that obese people were less likely to use palliative care services in GBC. Interventions are needed to increase palliative care consultation in GBC patients, particularly in obese patients.

Repeated measures designs are widely used in practice to increase power, reduce sample size, and increase efficiency in data collection. Correlation between repeated measurements is one of the first research questions that needs to be addressed in a repeated-measure study. In addition to an estimate for correlation, confidence interval should be computed and reported for statistical inference. The asymptotic interval based on the delta method is traditionally calculated due to its simplicity. However, this interval is often criticized for its unsatisfactory performance with regards to coverage and interval width. Bootstrap could be utilized to reduce the interval width, and the widely used bootstrap intervals include the percentile interval, the bias-corrected interval, and the bias-corrected with acceleration interval. Wilcox (Comput Stat Data Anal 22:89–98,1996) suggested a modified percentile interval with the interval levels adjusted by sample size to have the coverage probability close to the nominal level. For a study with repeated measures, more parameters in addition to sample size would affect the coverage probability. For these reasons, we propose modifying the percentiles in the percentile interval to guarantee the coverage probability based on simulation studies. We analyze the correlation between imaging volumes and memory scores from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study to illustrate the application of the considered intervals. The proposed interval is exact with the coverage probability guaranteed, and is recommended for use in practice.

Purpose To examine the financial impact of automatic formulary substitution of nebulization solutions for pressurized metered dose inhalers and dry powder inhalers and the effect of the automatic substitution initiative on respiratory care practitioner (RCP) workload at a community hospital. Methods A retrospective observational study was conducted in a 326-bed nonacademic community hospital. Adult patients who received respiratory medications and had an inpatient stay, were admitted for observation, or had an emergency room visit from December 2016 through February 2017 (the control group) or from December 2017 through February 2018 (the study group) were included in the analysis. The primary outcomes were the cost of respiratory medications per hospital stay and the number of RCP visits per hospital stay. The secondary outcome was the cost of wasted doses per hospital stay. Results A total of 3,766 patients were included in the study: 2,030 in the study group and 1,736 in the control group. The mean cost of respiratory medications per hospital stay was significantly lower in the study group vs the control group ($13.29 vs $36.48, P < 0.001). The mean number of RCP visits per hospital stay was also statistically lower in the study group vs the control group (11.6 vs 12.9, P = 0.04). The mean cost of wasted doses was significantly lower in study group vs the control group ($0.25 vs $22.91, P < 0.001). Conclusion Automatic formulary substitution of nebulization solutions for inhaler medications significantly decreased medication costs without increasing the average number of RCP visits per hospital stay.

Background Guidelines for pneumonia recommend empiric dual antipseudomonal therapy in patients with specific risk factors. However, there is lack of consensus on when to use dual antipseudomonal therapy as the recommendations are rated as weak, based on low-quality evidence. Objectives The objectives of this study were to develop combination antibiograms to assess the susceptibility of Pseudomonas aeruginosa (P. aeruginosa) in respiratory cultures to combinations of empiric antibiotics and to use combination antibiograms to delineate the impact of specific risk factors for which guidelines recommend dual antipseudomonal therapy. Methods A retrospective cohort study was conducted of adults hospitalized with pneumonia with positive respiratory cultures for P. aeruginosa between September 2014 and September 2018. Data collected included demographics, antimicrobial susceptibility results, and risk factors for which guidelines recommend dual antipseudomonal therapy. Combination antibiograms were developed and logistic regression was performed to identify risk factors for nonsusceptibility to beta-lactams. Results Eight hundred nineteen patients were included and 72% received antibiotics. Beta-lactam susceptibility ranged from 58% to 69% and addition of a fluoroquinolone or aminoglycoside resulted in statistically significant increases in susceptibility. However, only addition of tobramycin or amikacin provided susceptibility rates approaching or exceeding 90% stratified by pneumonia type and risk factors. Presence of guideline-based risk factors generally resulted in reduced susceptibility rates. Logistic regression identified three risk factors associated with nonsusceptibility to beta-lactams: intravenous antibiotics in the previous 90 days, nursing home residence, and mechanical ventilation at onset. The cumulative presence of each additional risk factor affected beta-lactam susceptibility rates, which were 93% in the absence of any risk factors and 39% when all three risk factors co-existed. Conclusions Risk factors necessitating dual antipseudomonal therapy for pneumonia should be locally validated. When dual antipseudomonal therapy is indicated, tobramycin or amikacin have the best likelihood of providing adequate in vitro activity.

The elastic network models (ENMs) are known as representative coarse-grained models to capture essential dynamics of proteins. Due to simple designs of the force constants as a decay with spatial distances of residue pairs in many previous studies, there is still much room for the improvement of ENMs. In this article, we directly computed the force constants with the inverse covariance estimation using a ridge-type operater for the precision matrix estimation (ROPE) on a large-scale set of NMR ensembles. Distance-dependent statistical analyses on the force constants were further comprehensively performed in terms of several paired types of sequence and structural information, including secondary structure, relative solvent accessibility, sequence distance and terminal. Various distinguished distributions of the mean force constants highlight the structural and sequential characteristics coupled with the inter-residue cooperativity beyond the spatial distances. We finally integrated these structural and sequential characteristics to build novel ENM variations using the particle swarm optimization for the parameter estimation. The outstanding improvements on the correlation coefficient of the mean-square fluctuation and the mode overlap were achieved by the proposed variations when compared with traditional ENMs. This study opens a novel way to develop more accurate elastic network models for protein dynamics.

ObjectiveIncidence of concussions and report of symptoms are greater amongst women across sports. While structural brain changes and cognitive declines are associated with repetitive head impact (RHI), the role of sex is not well understood. This study aimed to determine if there is a moderating effect of sex on the relationship number of professional fights has with cognitive functioning and regional brain volumes in a cohort of boxers, mixed martial artists, and martial artists.Methods55 women were matched with 55 men based on age, years of education, ethnicity, and fighting style. Cognition was assessed via CNS Vital Signs computerized cognitive battery and supplemental measures. Structural brain scans, demographic data, and number of professional fights (NoPF) were also considered. Matched pairs were compared via analysis of covariance, accounting for total brain volume. Within-subject moderation models were utilized to assess the moderating effect of sex on the relationship between NoPF and brain volumes and cognitive performance.ResultsMen were observed to have poorer performance on measures of psychomotor speed when compared to women. On a series of analyses assessing the role of sex as a moderator of the relationship between NoPF and regional brain volumes/cognitive performance, a significant moderation effect was observed across multiple measures of cognitive functioning, such that men had poorer performance. Differences in numerous regional brain volumes were also observed, such that the relationship between NoPF and brain volumes was steeper amongst men.ConclusionSex was observed to be an important moderator in the relationship between NoPF, aspects of cognitive functioning, and volumes of numerous brain regions, suggesting that sex differences in neuroanatomic and cognitive response to RHI deserve further attention.

Background The etiology of freezing of gait in Parkinson’s disease (PD) is yet to be clarified. Non-motor risk factors including cognitive impairment, sleep disturbance and mood disorders have been shown in freezing of gait. Research question We aimed to determine the predictive value of non-motor features in freezing of gait development. Methods Data were obtained from the Parkinson’s Progression Markers Initiative. Fifty PD patients with self-reported freezing of gait, and 50 PD patients without freezing of gait at the fourth year visit were included. Groups were matched for Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part III scores. Several cognitive and non-cognitive tests were used for non-motor features at baseline and over time. Executive function, visuospatial function, processing speed, learning and memory tests were used for cognition. Non-cognitive tests included sleepiness, REM sleep behavior disorder, depression and anxiety scales. Results Patients with freezing of gait had higher scores on sleepiness, REM sleep behavior disorder, depression and anxiety scales. However, predictor model analysis revealed that baseline processing speed, learning and sleepiness scores were predictive of self-reported freezing of gait development over time. Significance Our findings suggest that specific cognitive deficits and sleep disorders are predictive of future freezing of gait. These features may be helpful in identifying underlying networks in freezing of gait and should be further investigated with neuroimaging studies.

Background Meta-analysis provides a useful statistical tool to effectively estimate treatment effect from multiple studies. When the outcome is binary and it is rare (e.g., safety data in clinical trials), the traditionally used methods may have unsatisfactory performance. Methods We propose using importance sampling to compute confidence intervals for risk difference in meta-analysis with rare events. The proposed intervals are not exact, but they often have the coverage probabilities close to the nominal level. We compare the proposed accurate intervals with the existing intervals from the fixed- or random-effects models and the interval by Tian et al. (2009). Results We conduct extensive simulation studies to compare them with regards to coverage probability and average length, when data are simulated under the homogeneity or heterogeneity assumption of study effects. Conclusions The proposed accurate interval based on the random-effects model for sample space ordering generally has satisfactory performance under the heterogeneity assumption, while the traditionally used interval based on the fixed-effects model works well when the studies are homogeneous.

Clustered binary data are commonly encountered in many medical research studies with several binary outcomes from each cluster. Asymptotic methods are traditionally used for confidence interval calculations. However, these intervals often have unsatisfactory performance with regards to coverage for a study with a small sample size or the actual proportion near the boundary. To improve the coverage probability, exact Buehler’s one-sided intervals may be utilized, but they are computationally intensive in this setting. Therefore, we propose using importance sampling to calculate confidence intervals that almost always guarantee the coverage. We conduct extensive simulation studies to compare the performance of the existing asymptotic intervals and the new accurate intervals using importance sampling. The new intervals based on the asymptotic Wilson score for sample space ordering perform better than others, and they are recommended for use in practice.

The aim of this study is to evaluate longitudinal change in plasma neurofilament light (NF-L) and tau levels in relationship to clinical and radiological measures in professional fighters. Participants (active and retired professional fighters and control group) underwent annual blood sampling, 3-Tesla magnetic resonance imaging (MRI) brain imaging, computerized cognitive testing, and assessment of exposure to traumatic brain injury. Plasma tau and NF-L concentrations were measured using Simoa assays. Multiple linear regression models were used to compare the difference across groups in regard to baseline measurements, whereas mixed linear models was used for the longitudinal data with multiple measurements for each participant. Plasma samples were available on 471 participants. Baseline NF-L measures differed across groups (F3,393 = 6.99; p = 0.0001), with the active boxers having the highest levels. Higher NF-L levels at baseline were correlated with lower baseline MRI regional volumes and lower cognitive scores. The number of sparring rounds completed by the active fighters was correlated with NF-L (95% confidence interval, 0.0116-0.4053; p = 0.0381), but not tau, levels. Among 126 subjects having multiple yearly samples, there was a significant difference in average yearly percentage change in tau across groups (F3,83 = 3.87; p = 0.0121). We conclude that plasma NF-L and tau behave differently in a group of active and retired fighters; NF-L better reflects acute exposure whereas the role of plasma tau levels in signifying chronic change in brain structure over time requires further study.

In addition to point estimate for the probability of response in a two-stage design (e.g., Simon’s two-stage design for a Phase II clinical trial with binary endpoints), confidence limits should be Cute the confidence interval does not guarantee coverage probability in a two-stage setting. The existing exact approach to calculate one-sided limits is based on the overall number of responses to order the sample space. This approach could be conservative because many sample points have the same limits. We propose a new exact one-sided interval based on p-value for the sample space ordering. Exact intervals are computed by using binomial distributions directly, instead of a normal approximation. Both exact intervals preserve the nominal confidence level. The proposed exact interval based on the p-value generally performs better than the other exact interval with regard to expected length and simple average length of confidence intervals. Therefore, the new interval calculation based on p-value is recommended for use in practice.