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Ali A El-Solh,1– 3 Yolanda Lawson,1 Gregory E Wilding4 1Research Department, VA Western New York Healthcare System, Buffalo, NY, USA; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine; Jacobs School of Medicine, Buffalo, NY, USA; 3Department of Epidemiology and Environmental Health, School of Public Health and Health Professions; University at Buffalo, Buffalo, NY, USA; 4Department of Biostatistics, School of Public Health and Health Professions; University at Buffalo, Buffalo, NY, USACorrespondence: Ali A El-Solh, Research Department, VA Western New York Healthcare System, 3495 Bailey Avenue, Buffalo, NY, 14215, USA, Tel +1 (716) 862-7392, Fax +1 (716) 862-6526, Email solh@buffalo.eduPurpose: Hypnotics are commonly prescribed in patients with COPD to manage insomnia. Given the considerable risks associated with these drugs, the aim of the study was to evaluate the risk of all-cause mortality associated with hypnotics in a cohort of veterans with COPD presenting with insomnia.Methods: We conducted a retrospective cohort study that used Veterans Health Administration Corporate Data Warehouse with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2010 through 2019. The primary outcome was all-cause mortality. Analyses were conducted using propensity score 1:1 matching to balance baseline characteristics.Results: Of the 5759 veterans with COPD (mean [SD] age, 71.7 [11.2]; 92% men), 3585 newly initiated hypnotic agents during the study period. During a mean follow-up of 7.4 (SD, 2.7) years, a total of 2301 deaths occurred, with 65.2 and 48.7 total deaths per 1000 person-years among hypnotic users and nonusers, respectively. After propensity matching, hypnotic use was associated with a 22% increased risk of mortality compared with hypnotic nonusers (hazard ratio [HR] 1.22; 95% confidence interval [CI],1.11– 1.35). The benzodiazepine receptor agonists (BZRAs) group experienced a higher incidence rate of all-cause mortality compared to hypnotic nonusers (Incidence rate ratio [IRR] 1.27; 95% CI, 1.14– 1.43). Conversely, the mortality rate of non-BZRA hypnotics decreased after the first 2 years and was not significantly different for hypnotic nonusers (IRR 1.04; 95% CI, 0.82– 1.11).Conclusion: Among patients with COPD and insomnia, treatment with hypnotics was associated with a higher risk of all-cause mortality. The association was observed in patients prescribed BZRAs. The risk of mortality for non-BZRAs moderated after the first 2 years, indicating a class effect.Keywords: insomnia, chronic obstructive pulmonary disease, mortality, benzodiazepine receptor agonists

Background: Treating the octogenarian and nonagenarian patients who have acute myeloid leukemia (AML) with intensive chemotherapy is controversial. Several models to predict outcome were proposed, including the use of a comorbidity index. However, it is unclear whether the Charlson comorbidity index (CCI) or the hematopoietic cell transplant comorbidity index (HCTCI) is more sensitive.Methods: The authors analyzed their experience with 92 patients aged >or=80 years who had AML. Patients' pretreatment characteristics and their treatment outcomes were recorded.Results: All patients were offered intensive treatment; 59 patients (64%) were treated intensively with a variety of regimens, whereas 33 patients (36%) elected to receive supportive care. The CCI and the HCTCI had similar predictive ability for outcome in both groups. A multivariate analyses of prognostic factors identified near-normal albumin (48% of patients; 1-year survival rate, >27%) as a favorable factor for the whole cohort, age <83 years (47% of patients; 1-year survival rate, >25%) and nonmonocytic morphology (75% of patients; 1-year survival rate, >26%) as favorable factors for the intensively treated cohort, and bone marrow blasts <46% (50% of patients; 1-year survival rate, >19%) as a favorable factor for patients who received supportive care.Conclusions: This retrospective analysis was developed to assist in treatment decisions for octogenarian and nonagenarian patients with AML. The findings will need validation in a prospective study. [ABSTRACT FROM AUTHOR]

Background: In a previous investigation, eighty-two patients with chronic proximal plantar fasciitis for a duration of more than ten months completed a randomized, prospective clinical trial. The patients received instructions for either a plantar fascia-stretching protocol or an Achilles tendon-stretching protocol and were evaluated after eight weeks. Substantial differences were noted in favor of the group managed with the plantar fascia-stretching program. The goal of this two-year follow-up study was to evaluate the long-term outcomes of the plantar fascia-stretching protocol in patients with chronic plantar fasciitis.Methods: Phase one of the clinical trial concluded at eight weeks. At the eight-week follow-up evaluation, all patients were instructed in the plantar fascia-stretching protocol. At the two-year follow-up evaluation, a questionnaire consisting of the pain subscale of the Foot Function Index and an outcome survey related to pain, function, and satisfaction with treatment was mailed to the eighty-two subjects who had completed the initial clinical trial. Data were analyzed with use of a mixed-model analysis of covariance for each outcome of interest.Results: Complete data sets were obtained from sixty-six patients. The two-year follow-up results showed marked improvement for all patients after implementation of the plantar fascia-stretching exercises, with an especially high rate of improvement for those in the original group treated with the Achilles tendon-stretching program. In contrast to the eight-week results, the two-year results showed no significant differences between the groups with regard to the worst pain or pain with first steps in the morning. Descriptive analysis of the data showed that 92% (sixty-one) of the sixty-six patients reported total satisfaction or satisfaction with minor reservations. Fifty-one patients (77%) reported no limitation in recreational activities, and sixty-two (94%) reported a decrease in pain. Only sixteen of the sixty-six patients reported the need to seek treatment by a clinician.Conclusions: This study supports the use of the tissue-specific plantar fascia-stretching protocol as the key component of treatment for chronic plantar fasciitis. Long-term benefits of the stretch include a marked decrease in pain and functional limitations and a high rate of satisfaction. This approach can provide the health-care practitioner with an effective, inexpensive, and straightforward treatment protocol. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of patients with plantar fasciitis have development of persistent and often disabling symptoms. A poor response to treatment may be due, in part, to inappropriate and nonspecific stretching techniques. We hypothesized that patients with chronic plantar fasciitis who are managed with the structure-specific plantar fascia-stretching program for eight weeks have a better functional outcome than do patients managed with a standard Achilles tendon-stretching protocol.Methods: One hundred and one patients who had chronic proximal plantar fasciitis for a duration of at least ten months were randomized into one of two treatment groups. The mean age was forty-six years. All patients received prefabricated soft insoles and a three-week course of celecoxib, and they also viewed an educational video on plantar fasciitis. The patients received instructions for either a plantar fascia tissue-stretching program (Group A) or an Achilles tendon-stretching program (Group B). All patients completed the pain subscale of the Foot Function Index and a subject-relevant outcome survey that incorporated generic and condition-specific outcome measures related to pain, function, and satisfaction with treatment outcome. The patients were reevaluated after eight weeks.Results: Eighty-two patients returned for follow-up evaluation. With the exception of the duration of symptoms (p < 0.01), covariates for baseline measures revealed no significant differences between the groups. The pain subscale scores of the Foot Function Index showed significantly better results for the patients managed with the plantar fascia-stretching program with respect to item 1 (worst pain; p = 0.02) and item 2 (first steps in the morning; p = 0.006). Analysis of the response rates to the outcome measures also revealed significant differences with respect to pain, activity limitations, and patient satisfaction, with greater improvement seen in the group managed with the plantar fascia-stretching program.Conclusions: A program of non-weight-bearing stretching exercises specific to the plantar fascia is superior to the standard program of weight-bearing Achilles tendon-stretching exercises for the treatment of symptoms of proximal plantar fasciitis. These findings provide an alternative option to the present standard of care in the nonoperative treatment of patients with chronic, disabling plantar heel pain. [ABSTRACT FROM AUTHOR]

Abstract Background To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC). Methods 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC). Results The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03). Conclusions Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy. Trial Registration Clinical Trials Registration number: CDR0000067865

Importance: Neurologic post-COVID-19 condition (PCC), or long COVID, symptoms of fatigue and cognitive dysfunction continue to affect millions of people who have been infected with SARS-CoV-2. There currently are no effective evidence-based therapies available for treating neurologic PCC., Objective: To assess the effects of lithium aspartate therapy on PCC fatigue and cognitive dysfunction., Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial (RCT) enrolling participants in a neurology clinic from November 28, 2022, to June 29, 2023, with 3 weeks of follow-up, was conducted. Subsequently, an open-label lithium dose-finding study with 6 weeks of follow-up was performed among the same participants enrolled in the RCT. Eligible individuals needed to report new, bothersome fatigue or cognitive dysfunction persisting for more than 4 weeks after a self-reported positive test for COVID-19, Fatigue Severity Scale-7 (FSS-7) or Brain Fog Severity Scale (BFSS) score of 28 or greater, Beck Depression Inventory-II score less than 24, and no history of a condition known to cause fatigue or cognitive dysfunction. All participants in the RCT were eligible for the dose-finding study, except for those who responded to the placebo. Intention-to-treat analysis was used., Intervention: Lithium aspartate, 10 to 15 mg/d, or identically appearing placebo for 3 weeks followed by open-label lithium aspartate, 10 to 15 mg/d, for 2 weeks. In the subsequent dose-finding study, open-label lithium aspartate dosages up to 45 mg/d for 6 weeks were given., Main Outcomes and Measures: Change in sum of FSS-7 and BFSS scores. The scores for each measure range from 7 to 49, with higher scores indicating more severe symptoms. Secondary outcomes included changes from baseline in the scores of additional questionnaires., Results: Fifty-two participants were enrolled (30 [58%] males; mean [SD] age, 58.54 [14.34] years) and 26 were randomized to treatment with lithium aspartate (10 females) and 26 to placebo (12 female). Two participants assigned to lithium aspartate were lost to follow-up and none withdrew. No adverse events were attributable to lithium therapy. There were no significant intergroup differences for the primary outcome (-3.6; 95% CI, -16.6 to 9.5; P = .59) or any secondary outcomes. Among 3 patients completing a subsequent dose-finding study, open-label lithium aspartate, 40 to 45 mg/d, was associated with numerically greater reductions in fatigue and cognitive dysfunction scores than 15 mg/d, particularly in 2 patients with serum lithium levels of 0.18 and 0.49 mEq/L compared with 1 patient with a level of 0.10 mEq/L., Conclusions and Relevance: In this RCT, therapy with lithium aspartate, 10 to 15 mg/d, was ineffective for neurologic PCC fatigue and cognitive dysfunction. Another RCT is required to assess the potential benefits of higher lithium dosages for treating neurologic PCC., Trial Registration: ClinicalTrials.gov Identifier: NCT05618587 and NCT06108297.

Objective: Negative affect and affect variability figure prominently in models of addictive behaviors but are not without controversy. Negative affect variability may better capture a mechanism of behavior change in alcohol use disorder (AUD) treatment because it contains information about affect regulation, a common clinical target. The aims of this study are to examine the change in: (a) trajectory of negative affect variability, (b) association of negative affect variability and abstinence, and (c) association of negative affect variability and heavy drinking during AUD treatment., Method: This article is a secondary analysis of data drawn from a randomized clinical trial. N = 181 participants diagnosed with Diagnostic and Statistical Manual of Mental Disorders, fifth edition AUD ( M age = 50.8, SD age = 10.6; 51.4% female) received 12 sessions of Cognitive Behavioral Coping Skills Therapy for AUD. Participants completed one daily diary prompt per day for 84 consecutive days. Each day, participants reported on negative affect and number of alcoholic drinks consumed the previous day. Time-varying effect models examined changes in negative affect variability and its associations with abstinence and heavy drinking., Results: Negative affect variability decreased throughout treatment. The positive association between negative affect variability and heavy drinking became nonsignificant (decoupled) midway through treatment. The inverse association between negative affect variability and daily abstinence became nonsignificant (decoupled) at approximately day 75 of 84. When mean levels of NA were added as a covariate, the effects were in the same direction but no longer statistically significant., Conclusion: Reductions in negative affect variability may capture an important change mechanism of behavioral treatments for AUD because it contains information about affect regulation as compared with mean levels of negative affect. Negative affect variability warrants further consideration as a mechanism of behavior change. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

With the increasing burden of professional burnout in physicians, attention is being paid to optimizing sleep health, starting in training. The multiple dimensions of physicians' sleep are not well described due to obstacles to easily and reliably measuring sleep. This pilot study tested the feasibility of using commercial wearable devices and completing manual sleep logs to describe sleep patterns of medical students and residents. Prospective pilot study of 50 resident physicians and medical students during a single year of training. Participants completed a manual sleep log while concurrently wearing the Fitbit Inspire device for 14-consecutive days over three clinical rotations of varying work schedules: light, medium, and heavy clinical rotations. Study completion was achieved in 24/50 (48%) participants. Overall correlation coefficients between the sleep log and Fitbit were statistically low; however, the discrepancies were acceptable, i.e., Fitbit underestimated time in bed and total sleep time by 4.3 and 2.7 minutes, respectively. Sleep onset time and waketime were within 8 minutes, with good agreement. Treatment of sleep episodes during the day led to variance in the data. Average missingness of collected data did not vary between medical students or residents or by rotation type. When comparing the light to heavy rotations, hours slept went from 7.7 (±0.64) to 6.7 (±0.88), quality-of-life and sleep health decreased and stress, burnout, and medical errors increased. Burnout was significantly associated with worse sleep health, hours worked, and quality-of-life. Prospective data collection of sleep patterns using both sleep logs and commercial wearable devices is burdensome for physicians-in-training. Using commercial wearable devices may increase study success as long as attention is paid to daytime sleep. In future studies investigating the sleep of physicians, the timing of data collection should account for rotation type., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hassinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The National Institute on Alcohol Abuse and Alcoholism's (NIAAA) definition of alcohol use disorder (AUD) recovery stipulates two criteria: remission from DSM-5 AUD and cessation of heavy drinking. Importantly, these criteria allow for consideration of nonabstinent alcohol treatment outcomes. However, researchers have yet to assess potential predictors of the NIAAA recovery outcome. The current study examined associations between mental health and coping predictors of NIAAA recovery status in an AUD treatment sample. At baseline (BL) and end-of-treatment (EOT) research interviews in a clinical trial, participants ( N = 118) completed questionnaires assessing alcohol dependence, mental health, and confidence levels in reducing heavy drinking, as well as alcohol use and DSM-5 AUD symptom endorsement. Logistic regression models tested the associations between chosen predictors and the odds of achieving NIAAA recovery. Twenty-four percent of individuals ( n = 28) met both criteria for NIAAA recovery at EOT. Higher levels of BL state anxiety and anxiety sensitivity predicted lower odds of achieving NIAAA recovery, while greater confidence to reduce heavy drinking predicted increased odds of NIAAA recovery. Social workers are encouraged to continue assessing and addressing mental health in AUD treatment to help individuals with alcohol problems achieve their AUD recovery goals., (© 2024 National Association of Social Workers.)

Existing evidence linking insomnia to all-cause mortality in older individuals remains inconclusive. We conducted a retrospective study of a large cohort of veterans aged 65-80 years old identified from the Corporate Data Warehouse, a large data repository derived from the Veterans Health Administration integrated medical records. Veterans' enrollees with and without International Classification of Diseases, Ninth and Tenth Revision, codes corresponding to insomnia diagnosis between 1 January 2010 and 30 March 2019 were assessed for eligibility. The primary outcome was all-cause mortality. A total of 36,269 veterans, 9584 with insomnia and 26,685 without insomnia, were included in the analysis. Baseline mean (SD) age was 72.6 (4.2) years. During a mean follow-up of 6.0 (2.9) years of the propensity score matched sample, the mortality rate was 34.8 [95% confidence interval: 33.2-36.6] deaths per 1000 person-years among patients with insomnia compared with 27.8 [95% confidence interval: 26.6-29.1] among patients without insomnia. In a Cox proportional hazards model, insomnia was significantly associated with higher mortality (hazard ratio: 1.39; [95% confidence interval: 1.27-1.52]). Patients with insomnia also had a higher risk of non-fatal cardiovascular events (hazard ratio: 1.21; [95% confidence interval: 1.06-1.37]). Secondary stratified analyses by sex, race, ethnicity and hypertension showed no evidence of effect modification. A higher risk of mortality (hazard ratio: 1.51; [95% confidence interval: 1.33-1.71]) was observed when depression was present compared with absent (hazard ratio: 1.26; [95% confidence interval: 1.12-1.44]; p = 0.02). In this cohort study, insomnia was associated with increased risk-adjusted mortality and non-fatal cardiovascular events in older individuals., (© 2024 European Sleep Research Society.)

Objectives: To explore and characterize predisposing, precipitating, and perpetuating factors of subthreshold, moderate, and severe insomnia in cancer survivors., Sample & Setting: 135 cancer survivors who self-reported symptom severity on the Insomnia Severity Index during the baseline phase of a randomized clinical trial on insomnia treatment., Methods & Variables: Participants completed measures assessing predisposing factors (age, sex, race and ethnicity, body mass index), precipitating factors (number of years since cancer diagnosis, depression and anxiety symptoms, health-related quality of life), and perpetuating factors (frequency of consuming alcoholic and caffeinated beverages, napping behavior, dysfunctional beliefs about sleep)., Results: In the multivariate model, being female was protective against insomnia, and being a person of color, having higher anxiety, having more depression symptoms, and having stronger dysfunctional beliefs about sleep were significantly associated with greater insomnia severity., Implications for Nursing: By fostering interprofessional collaboration and implementing evidence-based interventions, nurses can contribute to the well-being of cancer survivors and address their sleep-related challenges. This study underscores the importance of regular insomnia screenings for cancer survivors, with nurses as essential facilitators.

Study Objectives: Reduced sleep duration and work hour variability contribute to medical error and physician burnout. This study assesses the relationships between physician performance, burnout, and the dimensions of sleep beyond hours slept., Methods: This was an ancillary analysis of 3 years of data from an international prospective cohort study: the Intern Health Study. Actigraphy data from 3,654 intern physicians capturing sleep timing, regularity, efficiency, and duration were used individually and combined as a composite sleep health index to measure the association of multidimensional sleep patterns on self-reported medical errors and burnout., Results: From 2017-2019, interns' work hours decreased by 4 hours per week and total sleep time also decreased (6.7 to 5.99 hours), and sleep efficiency, timing, and regularity all worsened (all P < .05). In the 21.2% of participants who committed an error, there was no difference in sleep duration, timing, or regularity. Lower sleep efficiency was associated with higher odds of committing an error ( P = .003) and higher burnout scores ( P < .001). Although overall sleep quality was poor in the entire cohort, interns in the lowest quintile of sleep duration, regularity, and efficiency had higher burnout scores than those in the best quintile., Conclusions: Sleep efficiency, not duration, was associated with increased self-reported medical errors and burnout in intern physicians. Overall sleep quality and duration worsened despite fewer hours worked. Future studies on physician burnout should measure all aspects of sleep health., Citation: Hassinger AB, Velez C, Wang J, Mador MJ, Wilding GE, Mishra A. Association between sleep health and rates of self-reported medical errors in intern physicians: an ancillary analysis of the Intern Health Study. J Clin Sleep Med . 2024;20(2):221-227., (© 2024 American Academy of Sleep Medicine.)

Objective: To better understand the timing and unique contribution of four potential mechanisms of behavior change (MOBC) during alcohol use disorder (AUD) treatment (negative affect, positive affect, alcohol craving, and adaptive alcohol coping), we used a time-varying effect modeling analytic approach to examine the change trajectories of alcohol abstinence, heavy drinking, the hypothesized MOBCs, and the time-varying associations between the MOBCs and alcohol outcomes., Method: Participants ( N = 181; M age = 50.8 years, SD = 10.6; 51% women; 93.5% Caucasian) were enrolled in a 12-week randomized clinical trial of cognitive behavioral outpatient treatment program for AUD. For 84 consecutive days, participants provided self-reports of positive and negative affect, craving, alcohol use, and adaptive alcohol coping strategies employed., Results: Throughout the 84-day treatment window, higher daily average craving levels were associated with both decreased likelihood of alcohol abstinence and increased odds of heavy drinking, whereas higher adaptive alcohol coping was associated with increased odds of abstinence and decreased odds of heavy drinking. Higher negative affect was associated with decreased odds of abstinence in the first 10 days of treatment and increased odds of heavy drinking before Day 4 or Day 5. Higher positive affect was associated with decreased odds of heavy drinking during the first 4 or 5 days., Conclusions: The differential time-varying associations between negative affect, positive affect, alcohol craving, adaptive alcohol coping, and alcohol use provide insights into how and when each of the MOBCs is active during AUD treatment. These findings can help optimize the efficacy of future AUD treatments. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Emotion differentiation refers to cognitively distinguishing among discrete, same-valenced emotions. Negative emotion differentiation (NED) is a transdiagnostic indicator of emotional functioning. The role of positive emotion differentiation (PED) in clinical disorders, including alcohol use disorder (AUD), is less understood. Further, despite consensus that emotions are highly variable, little is known about within-person fluctuations in NED/PED. The current study leveraged 84 consecutive daily smartphone surveys from participants (N = 181) in a clinical trial of cognitive behavioral therapy for AUD to investigate whether between-person differences in overall NED/PED, or within-person variability in daily NED/PED, were associated with affect intensity, craving, drinking, and heavy drinking in daily life. Subsequent analyses explored whether associations were moderated by baseline alexithymia. At the between-persons level, greater average PED, but not NED, was associated with lower heavy drinking odds. At the within-persons level, higher-than-usual PED was associated with lower negative affect and odds of any drinking. Individuals with baseline alexithymia had stronger negative within-person associations between daily NED and both any and heavy drinking. PED is a skill linked to less alcohol use between- and within-persons irrespective of baseline alexithymia, whereas greater daily NED appears especially important for reduced alcohol use among individuals with co-morbid AUD and alexithymia., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the discrepancy and correlation between sleep-wake measures (i.e., time in bed (TIB), total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), and sleep efficiency (SE%)) reported on sleep diary and measured by actigraphy among cancer survivors with insomnia symptoms; and examine the influences of sociodemographic and clinical variables on these measurement differences., Methods: A heterogenous sample of cancer survivors with insomnia symptoms (n = 120; M age = 63.7 ± 10.1; female = 58.3%) was included. Seven consecutive days of sleep diary and actigraphic data were obtained along with information on demographic, sleep, and mental health symptoms. Bland-Altman plot, Pearson correlation coefficient, concordance correlation coefficient, and mixed linear model approach were used to conduct the analysis., Results: Self-reported TIB, SOL, and WASO were longer than measured by actigraphy (TIB: 8.6 min. (95% CI, 3.7, 13.5; p < .001); SOL: 14.8 min. (95% CI, 9.4, 20.2; p < .0001); and WASO: 20.7 min. (95% CI, 9.4, 20.2; p < .0001), respectively); and self-reported TST and SE% were shorter than measured by actigraphy (TST: 6.8 min. (95% CI, -18.7, 5.13); and SE%: 0.7% (95%CI, -3.0, 2.0), respectively), but were not statistically significant. Sex, higher insomnia severity, and poor sleep quality were associated with discrepancy between several sleep-wake measures., Conclusion: Subjective and objective sleep-wake measures may present discrepant finding among cancer survivors with symptoms of insomnia. Future research is needed to validate appropriate sleep-wake assessment, and better understand factors that influence the discrepancy that exists between measures among this population., Clinical Trial Registration: Clinical trials identifier: NCT03810365. Date of registration: January 14, 2019., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Primary care pharmacists are uniquely positioned to improve care quality by intervening within care transitions in the postdischarge period. However, additional evidence is required to demonstrate that pharmacist-led interventions can reduce health care utilization in a cost-effective manner. The study's objective was to evaluate the clinical and economic effectiveness of a pharmacy-led transition of care (TOC) program within a primary care setting., Methods: This cluster randomized trial was conducted between 2019 and 2021 and included three primary care practices. Eligible patients were ≥18 years of age and at high risk of readmission. The multifaceted pharmacy intervention included medication reconciliation, comprehensive medication review, and patient and provider follow-up. The primary composite endpoint included hospital readmissions and emergency department (ED) visits within 30 days of discharge. Differences in outcomes were modeled using a generalized estimated equations approach and outcomes were assumed to be distributed as a Poisson random variable. A cost-benefit analysis was embedded within the study and estimated economic outcomes from a provider group/health system perspective. Cost measures included: net benefit, benefit to cost ratio (BCR), and return on investment (ROI)., Results: Of 300 eligible patients, 36 were in the intervention group and 264 in the control group. The intervention significantly reduced the primary composite outcome of all-cause readmissions and ED visits within 30 days (adjusted incidence rate ratio [aIRR], 0.54; 95% CI, 0.44-0.66; P < 0.001). There were significant reductions in both 30-day all-cause readmissions (aIRR, 0.64; 95% CI, 0.60-0.67; P < 0.001) and ED visits (aIRR, 0.25; 95% CI, 0.20, 0.31; P < 0.001) between groups. The net benefit of the intervention was $9,078, with a BCR of 2.11 and a ROI of 111%. Sensitivity analyses were robust to changes in economic inputs., Conclusion: This care transition program had positive clinical and economic benefits, providing further support for the essential role pharmacists demonstrate in providing TOC services., Competing Interests: Disclosure DMJ is supported by the National Institutes of Health/National Heart, Lung, and Blood Institute under award number K23HL153582. This research reported in this publication was supported by the National Center for Advancing Translational Sciences and ULTR001412 to the University at Buffalo. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine whether hypnotic use in patients with insomnia reduces major adverse cardiovascular events, including all-cause mortality and nonfatal major adverse cardiovascular events., Methods: Using the Veterans Affairs Corporate Data Warehouse, we conducted a retrospective cohort study of 16,064 patients who were newly diagnosed with insomnia between January 1, 2010, and December 31, 2019. A pair of 3912 hypnotic users and nonusers were selected based on a 1:1 propensity score methodology. The primary outcome was extended major adverse cardiovascular events, a composite of the first occurrence of all-cause mortality or nonfatal major adverse cardiovascular events., Results: During the median follow-up of 4.8 years, a total of 2791 composite events occurred, including 2033 deaths and 762 nonfatal major adverse cardiovascular events. Although the incidence rates of major adverse cardiovascular events were comparable between hypnotic users and nonusers in the propensity-matched cohort, users of benzodiazepines and Z-drugs had a higher risk of all-cause mortality (hazard ratio 1.47 [95% CI, 1.17-1.88] and 1.20 [95% CI, 1.03-1.39], respectively), while serotonin antagonist and reuptake inhibitors users had a survival advantage (hazard ratio 0.79 [95% CI, 0.69-0.91]) compared with nonusers. There were no differences in the risk of nonfatal major adverse cardiovascular events between all classes of hypnotics. Male patients and those aged 60 years or younger who were using benzodiazepines or Z-drugs experienced higher major adverse cardiovascular events than their counterparts., Conclusions: In patients with newly diagnosed insomnia, treatment with hypnotics resulted in higher extended major adverse cardiovascular events but not nonfatal major adverse cardiovascular events with benzodiazepine and Z-drug users compared with nonusers. The use of serotonin antagonist and reuptake inhibitors agents had a protective effect against major adverse cardiovascular events warranting further investigation., Competing Interests: Declaration of Conflict of Interest The authors report no conflicts of interest., (Published by Elsevier Inc.)

Introduction: Predictors for successful aerosolized surfactant treatment are not well defined., Objective: To identify predictors for successful treatment in the AERO-02 trial and the AERO-03 expanded access program., Methods: Neonates receiving nasal continuous positive airway pressure (NCPAP) at the time of first aerosolized calfactant administration were included in this analysis. Associations between demographic and clinical predictors to need for intubation were examined using univariate testing and multivariate logistic regression analyses., Results: Three hundred and eighty infants were included in the study. Overall, 24% required rescue by intubation. Multivariate modeling revealed that the predictors of successful treatment were a gestational age ≥31 weeks, a respiratory severity score (RSS) of <1.9, and <2 previous aerosol treatments., Conclusion: Gestational age, number of aerosols, and RSS are predictive of successful treatment. These criteria will help select patients most likely to benefit from aerosolized surfactant., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recently released a new definition of recovery from alcohol use disorder (AUD). A patient is considered recovered if they are remitted from DSM-5 AUD and report cessation of heavy drinking. The NIAAA has also recently proposed the Addictions Neuroclinical Assessment (ANA) to guide treatment research. Negative emotionality is one of three domains of the ANA and theory proposes that AUD is maintained by negative reinforcement via the relief of negative affect. The purpose of the current study was to examine: (1) the relationship of end-of-treatment negative emotionality and NIAAA recovery, and (2) the ability of NIAAA recovery at the end of treatment to predict three- and six-month drinking outcomes., Method: At baseline and end-of-treatment, women and men (n = 181) in treatment for AUD completed measures of negative emotionality, drinking, and were assessed for DSM-5 AUD diagnostic criteria. At three- and six-months post-treatment, drinking was re-assessed., Results: 22.5% (n = 24) of participants met full criteria for NIAAA recovery at end-of-treatment. Lower levels of end of treatment negative emotionality were associated with increased odds of achieving NIAAA recovery. Meeting NIAAA recovery predicted greater percent days abstinent (PDA) and lower percent heavy drinking days (PHDD) at 3-months, but not at 6-months post-treatment., Conclusions: This study is among the first to report a relationship between the negative emotionality domain of the ANA and NIAAA recovery. Results underscore the importance of addressing negative emotionality in treatment. Findings also suggest that NIAAA recovery predicts positive short term drinking outcomes., Competing Interests: Conflict of interest All authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: The Symbol Digit Modalities Test (SDMT), the most reliable and sensitive measure of cognition in people with multiple sclerosis (PwMS), is increasingly used in clinical trials and care., Objectives: We aimed to establish how SDMT performance is influenced by repeating forms and frequency of use in PwMS., Methods: A retrospective analysis was completed on a large database of PwMS (n = 740) with multiple SDMT administrations. Change in SDMT performance was analyzed, accounting for frequency of tests and utilization of alternate- versus same-form conditions., Results: SDMT administrations ranged from 2 to 14 per subject over a mean (SD) of 5.9 (4.5) years. Accounting for demographics, the mixed effects model revealed a significant main effect of SDMT exposures (1.8 point improvement per repetition, p = 0.001) and an interaction between time since previous SDMT and whether the same test form was administered in the previous administration (estimate=-1.1, p = 0.037). As well, SDMT decline is observed when testing intervals exceed two years (F = 9.69, p<0.001)., Conclusion: Improvements in SDMT performance with repeated exposure, likely reflecting practice effects, were greatest when repeating the same SDMT form over briefer intervals. We recommend the use of alternate forms or analogous versions of timed symbol-digit coding particularly where samples are saturated with many administrations., Competing Interests: Declaration of Conflicting Interests R.H.B.B received honoraria, speaking, or consulting fees from Biogen, BMS, Celgene, EMD Serono, Genentech, Medday, Merck, Novartis, Roche, and Sanofi, and has received research support from Biogen, BMS, Genentech, Genzyme, and Novartis. He has received royalties from Psychological Assessment resources, Inc. B.W.G. has participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon. She has also received grant/ research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. T.A.F., G.W., J.G., M.J., and M.Y. have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Insomnia has been frequently reported as one of the most burdensome symptoms among cancer survivors. To date, little research exists on strategies to effectively reduce insomnia in cancer survivors, especially in the application of cognitive behavioral therapy for insomnia (CBTI) at the bedside by nurses. The current objective is to determine efficacy and durability of a streamlined, individually delivered version of CBTI, specifically Brief Behavioral Therapy for Insomnia (BBTI) versus a healthy eating attention control, using a large heterogeneous sample of 158 cancer survivors. Study participants will be adults ≥18 years of age; ≥1 month from treatment (except hormones and targeted therapies are acceptable) for stages I through III breast, colorectal, lung or prostate cancers; meet criteria for insomnia defined by Insomnia Severity Index (ISI) >7; screen negative for obstructive sleep apnea <15 events/h; and ability to complete data collection instruments in English. Baseline, and then 1-, 3-, and 12-month objective (i.e., actigraphy) and subjective sleep, mood, and quality of life assessments after the interventions are planned. The primary outcome will be measured with the ISI, a psychometrically-sound instrument used to measure perceived insomnia severity. The results of this trial will demonstrate the application of BBTI in a larger heterogenous sample of cancer survivors for the first time and may lead to implementation strategies that will promote the dissemination and sustainability of this intervention. Clinical trials identifier: http://ClinicalTrials.gov, NCT03810365., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Brain iron homeostasis is necessary for healthy brain function. MRI and histological studies have shown altered brain iron levels in the brains of patients with multiple sclerosis (MS), particularly in the deep gray matter (DGM). Previous studies were able to only partially separate iron-modifying effects because of incomplete knowledge of iron-modifying processes and influencing factors. It is therefore unclear to what extent and at which stages of the disease different processes contribute to brain iron changes. We postulate that spatially covarying magnetic susceptibility networks determined with Independent Component Analysis (ICA) reflect, and allow for the study of, independent processes regulating iron levels. We applied ICA to quantitative susceptibility maps for 170 individuals aged 9-81 years without neurological disease ("Healthy Aging" (HA) cohort), and for a cohort of 120 patients with MS and 120 age- and sex-matched healthy controls (HC; together the "MS/HC" cohort). Two DGM-associated "susceptibility networks" identified in the HA cohort (the Dorsal Striatum and Globus Pallidus Interna Networks) were highly internally reproducible (i.e. "robust") across multiple ICA repetitions on cohort subsets. DGM areas overlapping both robust networks had higher susceptibility levels than DGM areas overlapping only a single robust network, suggesting that these networks were caused by independent processes of increasing iron concentration. Because MS is thought to accelerate brain aging, we hypothesized that associations between age and the two robust DGM-associated networks would be enhanced in patients with MS. However, only one of these networks was altered in patients with MS, and it had a null age association in patients with MS rather than a stronger association. Further analysis of the MS/HC cohort revealed three additional disease-related networks (the Pulvinar, Mesencephalon, and Caudate Networks) that were differentially altered between patients with MS and HCs and between MS subtypes. Exploratory regression analyses of the disease-related networks revealed differential associations with disease duration and T2 lesion volume. Finally, analysis of ROI-based disease effects in the MS/HC cohort revealed an effect of disease status only in the putamen ROI and exploratory regression analysis did not show associations between the caudate and pulvinar ROIs and disease duration or T2 lesion volume, showing the ICA-based approach was more sensitive to disease effects. These results suggest that the ICA network framework increases sensitivity for studying patterns of brain iron change, opening a new avenue for understanding brain iron physiology under normal and disease conditions., Competing Interests: Declaration of competing interests Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Keystone Heart, Protembis, and Novartis for speaking and consultant fees and has received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical. Bianca Weinstock-Guttman has participated in speakers bureaus for, served as a consultant for, and/or received research support from Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi & Genzyme, Janssen, Horizon, Bayer, and LabCorp. Dr. Weinstock-Guttman also serves on the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology., (Copyright © 2022. Published by Elsevier Inc.)

Rationale: Patient-centered outcomes are increasingly sought to evaluate social interactions and healthcare interventions in patients with sleep disorders. Yet, measures to assess quality of life (QoL) are lacking for those who experience nightmares., Objective: The aim of the study is to describe the development and validation of a new health-related quality of life (HRQoL) instrument for patients with nightmares., Methods: Attributes obtained from a focus group of patients (n = 113) with established nightmares were analyzed using exploratory factor analysis to elicit salient QoL themes for the new instrument. A validation cohort (n = 34) was used to determine the psychometric performance of the 16-item questionnaire including item-scaling, concurrent validity, and test-retest reliability tested four weeks apart., Results: Four factors (sleep health, emotional and psychological well-being, social interaction, and motivation) explained 53.9% of the total variance. The Nightmare Quality of Life (NQoL) showed good internal consistency (Cronbach's alpha 0.85) and test-retest reliability (ICC = 0.89). Concurrent validity was evidenced by a strong correlation with the Nightmare Distress Questionnaire (r = 0.87; p < .001) and more modest associations with the Nightmare Frequency Questionnaire (r = , 0.69; p < .001), SF-36 (r = -0.68; p < .001), and PSQI (r = 0.45; p = .007)., Conclusions: The NQoL has demonstrable construct validity and reliability and represents a promising multi-dimensional instrument to assess outcome measures for quality of life in patients with nightmares.

Background: Screening for lung cancer is an evidence-based but underutilized measure to reduce the burden of lung cancer mortality. Lack of adequate data on geographic availability of lung cancer screening inhibits the ability of healthcare providers to help patients with decision-making and impedes equity-focused implementation of screening-supportive services., Objectives: This analysis used data from the 2012-2016 Surveillance, Epidemiology, and End Results (SEER) Program, the Behavioral Risk Factor Surveillance System, and the county health ranking to examine (a) which cancer resources and county-level factors are associated with late-stage lung cancer at diagnosis and (b) associations between county rurality and lung cancer incidence/mortality rates., Methods: Using the New York state SEER data, we identified 68,990 lung cancer patients aged 20-112 years; 48.3% had late-stage lung cancers, and the average lung cancer incidence and mortality rates were 70.7 and 46.2 per 100,000, respectively. There were 144 American College of Radiology-designated lung cancer screening centers and 376 Federally Qualified Health Centers identified in New York state. County rurality was associated with a higher proportion of late-stage lung cancers and higher lung cancer mortality rates., Discussion: Visual geomapping showed the scarcity of rural counties' healthcare resources. County rurality is a significant factor in differences in lung cancer screening resources and patient outcomes. Use of publicly available data with geospatial methods provides ways to identify areas for improvement, populations at risk, and additional infrastructure needs., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Administration of liquid surfactant through an endotracheal tube for the treatment of respiratory distress syndrome has been the standard of care for decades. Surfactant administration through laryngeal or supraglottic airways (SALSA) is a simplified procedure for delivery of surfactant that is less invasive and better tolerated. The Al Bashir Maternity and Children’s Hospital NICU in Amman, Jordan, implemented SALSA as a potentially better practice in 2019 with the objective to effectively and efficiently deliver surfactant in a minimally invasive way and to decrease the adverse events associated with intubation−surfactant−extubation (InSurE) and laryngoscopy. The quality improvement initiative was conducted from March 2019 to December 2019. All infants who weighed 750 g or more who required surfactant were eligible. As physicians were trained in the technique and use expanded, we were able to use plan−do−study−act cycles to observe differences between SALSA and InSurE. The primary aim was the optimization of non-invasive ventilation by the effective and efficient delivery of surfactant. Balancing measures included episodes of bradycardia while receiving surfactant or the need for a second dose of surfactant. We evaluated 220 infants who received surfactant by SALSA or InSurE with a mean gestational age of 32 weeks and a mean birth weight of 1.8 kg. The Respiratory Severity Score (RSS) prior to surfactant administration was 2.7 in the SALSA group compared to 2.9 in the InSurE group (p = 0.024). Those in the InSurE group had a lower mean heart rate during the procedure (p =< 0.0001) and were more likely to need a second dose of surfactant (p = 0.026) or require intubation for mechanical ventilation (p = 0.022). Both groups were effectively delivered surfactant as evidenced by improvement in their RSS over an 8 h period. SALSA was a more time efficient surfactant delivery method (93 vs. 111 secs, p =< 0.0001). Implementation of SALSA into the Al Bashir NICU was successful. We found that it was equally effective to InSurE, but was a more efficient method of delivery. Infants who received surfactant by this method tolerated it well.

Objective: To test the feasibility and effectiveness of a multifaceted intervention administered through school-based health centers (SBHCs) to improve asthma control for children in high-poverty schools with not well controlled asthma., Methods: Students 4-14 years old with persistent asthma were enrolled from three SBHCs. The centers' advanced practice providers received training on evidence-based asthma guidelines. Students randomized to the intervention received directly observed therapy of their asthma controller medication, medication adjustments as needed by the centers' providers, and daily self-management support. Students randomized to usual care were referred back to their primary care provider (PCP) for routine asthma care., Results: We enrolled 29 students. Students in the intervention group received their controller medication 92% of days they were in school. Ninety-four percent of follow-up assessments were completed. During the study, 11 of 12 intervention students had a step-up in medication; 2 of 15 usual care students were stepped up by their PCP. Asthma Control Test scores did not differ between groups, although there were significant improvements from baseline to the 7 month follow-up within each group (both p  < .01). Both FEV 1 % predicted and FEV 1 /FVC ratio significantly worsened in the usual care group (both p  = .001), but did not change in the intervention group ( p  = .76 and .28 respectively)., Conclusions: Our pilot data suggest that a multifaceted intervention can be feasibly administered through SBHCs in communities with health disparities. Despite the small sample size, spirometry detected advantages in the intervention group. Further study is needed to optimize the intervention and evaluate outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT03032744.

Study Objective: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients., Design and Setting: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC 0-12 ), AUC 0-4 , 12-h troughs (C 12 h ), maximum concentrations (C max ), oral clearance (Cl), with dose-normalized AUC 0-12 , troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms., Patients: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated., Measurements and Main Results: Black recipients exhibited higher tacrolimus AUC 0-12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC 0-12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC 0-12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%-19% of tacrolimus variability in dose (p = 0.002); AUC 0-12 h * (p < 0.001), and Cl (p < 0.001)., Conclusions: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC 0-12 h ., (© 2022 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Purpose: Cancer patients experience significant distress and burden of decision-making throughout treatment and beyond. These stressors can interfere with their ability to make reasoned and timely decisions about their care and lead to low physical and social functioning and poor survival. This pilot study examined the impact of offering Problem-Solving Skills Training (PSST) to adult cancer survivors to help them and their caregivers cope more successfully with post-treatment decision-making burden and distress., Patients and Methods: Fifty patients who completed their definitive treatment for colorectal, breast or prostate cancer within the last 6 months and reported distress (level > 2 on the National Comprehensive Cancer Network distress thermometer) were randomly assigned to either care as usual (CAU) or 8 weekly PSST sessions. Patients were invited to include a supportive other (n = 17). Patient and caregiver assessments at baseline (T1), end of intervention or 3 months (T2), and at 6 months (T3) focused on problem-solving skills, anxiety/depression, quality of life and healthcare utilization. We compared outcomes by study arm and interviewed participants about PSST burden and skill maintenance., Results: Trial participation rate was 60%; 76% of the participants successfully completed PSST training. PSST patients reported reduction in anxiety/depression, improvement in QoL (p < 0.05) and lower use of hospital and emergency department services compared to CAU patients (p = 0.04)., Conclusions: The evidence from this pilot study indicates that a remotely delivered PSST is a feasible and potentially effective strategy to improve mood and self-management in cancer survivors in community oncology settings., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC 0-12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC 0-12h . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC 0-12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC 0-12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment., (© 2021, The American College of Clinical Pharmacology.)

Introduction: The benefits of minimally invasive surgery are numerous; however, considerable variability exists in its application and there is a lack of standardized training for important advanced skills. Our goal was to determine whether participation in an advanced laparoscopic curriculum (ALC) results in improved laparoscopic suturing skills., Methods and Procedures: Study design was a prospective, randomized controlled trial. Surgery novices and trainees underwent baseline FLS training and were pre-tested on bench models. Participants were stratified by pre-test score and randomized to undergo either further FLS training (control group) or ALC training (intervention group). All were post-tested on the same bench model. Tests for differences between post-test scores of cohorts were performed using least squared means. Multivariable regression identified predictors of post-test score, and Wilcoxon rank sum test assessed for differences in confidence improvement in laparoscopic suturing ability between groups., Results: Between November 2018 and May 2019, 25 participants completed the study (16 females; 9 males). After adjustment for relevant variables, participants randomized to the ALC group had significantly higher post-test scores than those undergoing FLS training alone (mean score 90.50 versus 82.99, p = 0.001). The only demographic or other variables found to predict post-test score include level of training (p = 0.049) and reported years of video gaming (p = 0.034). There was no difference in confidence improvement between groups., Conclusions: Training using the ALC as opposed to basic laparoscopic skills training only is associated with superior advanced laparoscopic suturing performance without affecting improvement in reported confidence levels. Performance on advanced laparoscopic suturing tasks may be predicted by lifetime cumulative video gaming history and year of training but does not appear to be associated with other factors previously studied in relation to basic laparoscopic skills, such as surgical career aspiration or musical ability., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Measuring the effectiveness of interprofessional education (IPE) experiences is essential but challenging. Surveying learners before (pretest) and after (posttest) an IPE experience may result in minimal change due to response shift bias. Retrospective pretest/posttest assessment may ameliorate response shift bias but may also result in inflated change scores due to social desirability bias. We studied a cohort of 675 students from 12 health professions who completed the Interprofessional Attitudes Scale (IPAS) within the 4 weeks before (pretest) and the 3 weeks after (posttest) an IPE forum and completed the Interprofessional Collaborative Competency Attainment Survey (ICCAS) within the 3 weeks after the forum as a retrospective pretest/posttest. We found higher scores on the pretest IPAS than the retrospective pretest ICCAS and greater change in scores on the ICCAS than the IPAS, indicating potential response shift and social desirability biases. Furthermore, we found few significant correlations between change scores in subscales of the two tests, but a high number of strong and significant correlation among the ICCAS subscale change scores. Our results indicate the timing of pretest administration may impact change scores or that subscales of IPAS may be more unique than those of ICCAS. These findings suggest that educators should consider the potential impact of response shift and social desirability biases when interpreting results of the IPAS and ICCAS in response to an IPE learning experience.

Purpose: We sought to determine the prevalence of low arousal threshold (LAT) in veterans with post-traumatic stress disorder (PTSD) and whether or not LAT is associated with decreased use of continuous positive airway pressure (CPAP)., Methods: We conducted a retrospective study of all veterans with documented PTSD who had an apnea hypopnea index > 5/h over a 27-month period. Demographic, clinical characteristics, and CPAP usage were extracted from the medical records. A multivariate analysis was conducted to assess predictors of CPAP use at 3 months in patients with LAT after adjusting for severity of PTSD., Results: LAT was identified in 55% of 119 patients with PTSD and newly diagnosed OSA. LAT was associated with younger age (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.86-0.95), lower BMI (OR 0.82; 95% CI 0.73-0.91), presence of insomnia (OR 1.34; 95% CI 1.19-1.81), and use of antidepressant (OR 1.14; 95% CI 1.09-2.01). PTSD severity, REM rebound, and the presence of baseline comorbid insomnia were each associated with CPAP use at 3 months. Neither daytime sleepiness, body mass index (BMI), nor LAT endotype was correlated with CPAP utilization. Insomnia was the only factor associated with decreased CPAP use in patients with PTSD and LAT (P = 0.04)., Conclusion: The LAT endotype is common among veterans with PTSD. An improved understanding of how insomnia in this population affects CPAP utilization would be instrumental in designing targeted therapy to improve sleep quality.

Purpose: The purpose of this study is to determine factors associated with prolonged intubation after inguinal herniorrhaphy in neonates., Methods: Retrospective, single institution review of neonates undergoing inguinal herniorrhaphy between 2010 and 2018. Variables recorded included demographics, comorbidities, ventilation status at time of hernia repair, and anesthetic technique., Results: We identified 97 neonates (median corrected gestational age 39.9 weeks, IQR 6.6). The majority (87.6%) received general anesthesia (GA); the remainder received caudal anesthesia (CA). Among the GA subjects, 25.8% remained intubated for at least 6 h after surgery, whereas none of the CA patients required intubation postoperatively (p = 0.03). Two risk factors associated with prolonged postoperative intubation: a history of intubation before surgery (p = 0.04) and a diagnosis of bronchopulmonary dysplasia (p = 0.03)., Conclusions: Neonates undergoing inguinal herniorrhaphy under GA have a greater rate of prolonged postoperative intubation compared with those undergoing CA. A history of previous intubation and bronchopulmonary dysplasia were significant risk factors for prolonged postoperative intubation.

In diabetic kidney disease (DKD), podocyte depletion, and the subsequent migration of parietal epithelial cells (PECs) to the tuft, is a precursor to progressive glomerular damage, but the limitations of brightfield microscopy currently preclude direct pathological quantitation of these cells. Here we present an automated approach to podocyte and PEC detection developed using kidney sections from mouse model emulating DKD, stained first for Wilms' Tumor 1 (WT1) (podocyte and PEC marker) by immunofluorescence, then post-stained with periodic acid-Schiff (PAS). A generative adversarial network (GAN)-based pipeline was used to translate these PAS-stained sections into WT1-labeled IF images, enabling in silico label-free podocyte and PEC identification in brightfield images. Our method detected WT1-positive cells with high sensitivity/specificity (0.87/0.92). Additionally, our algorithm performed with a higher Cohen's kappa (0.85) than the average manual identification by three renal pathologists (0.78). We propose that this pipeline will enable accurate detection of WT1-positive cells in research applications.

Background: To study the clinical and radiologic factors predicting the need for surgical intervention after blunt abdominal trauma (BAT) in children with equivocal computed tomography (CT) scan findings., Methods: We performed a retrospective review of the trauma database at our level I pediatric trauma center between 2011 and 2019. We selected patients with BAT and equivocal findings for surgical intervention on CT scan. We studied five factors: abdominal wall bruising (AWB), abdominal pain/tenderness (APT), thoracolumbar fracture, the presence of free fluid (FF), and the presence of solid organ injury, all previously reported in the literature to predict the need for operative intervention. We used t-test, the Kruskal-Wallis test and logistic regression to study the association of these factors with the need for operation in our pediatric cohort., Results: Of 3044 blunt trauma patients, 288 had abdominal CT scans with 61 patients demonstrating equivocal findings. Operation was performed for 12 patients (19.7%) confirming surgically correctable traumatic injuries. The need for surgical intervention was significantly associated with the age of the patients (P = 0.03), the presence of APT (P = 0.001), AWB (P = 0.01), and FF (P = 0.04). The presence of thoracolumbar fracture and solid organ injury were not significantly associated with the need for operation. For the subset of 37 patients who were injured in a motor vehicle crash, five (13.5%) required surgical intervention, which was significantly associated with the presence of AWB (P = 0.04), APT (P = 0.01), and FF (P = 0.03). A predictive model that used these factors produced a receiver operating characteristic curve of 0.86., Conclusions: In cases of equivocal abdominal CT scan findings to evaluate BAT in children, the presence of abdominal wall tenderness, AWB, or FF may be significant factors predicting more accurately the need for operative intervention. A predictive model using the combination of clinical and image findings might determine with more certainty, the need for surgical intervention in children with BAT and equivocal CT findings. Validation on a larger multi-institutional data set should be done., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Exogenous surfactants to treat respiratory distress syndrome (RDS) are approved for tracheal instillation only; this requires intubation, often followed by positive pressure ventilation to promote distribution. Aerosol delivery offers a safer alternative, but clinical studies have had mixed results. We hypothesized that efficient aerosolization of a surfactant with low viscosity, early in the course of RDS, could reduce the need for intubation and instillation of liquid surfactant., Methods: A prospective, multicenter, randomized, unblinded comparison trial of aerosolized calfactant (Infasurf) in newborns with signs of RDS that required noninvasive respiratory support. Calfactant was aerosolized by using a Solarys nebulizer modified with a pacifier adapter; 6 mL/kg (210 mg phospholipid/kg body weight) were delivered directly into the mouth. Infants in the aerosol group received up to 3 treatments, at least 4 hours apart. Infants in the control group received usual care, determined by providers. Infants were intubated and given instilled surfactant for persistent or worsening respiratory distress, at their providers' discretion., Results: Among 22 NICUs, 457 infants were enrolled; gestation 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The rates of intubation for surfactant instillation were 26% in the aerosol group and 50% in the usual care group ( P < .0001). Respiratory outcomes up to 28 days of age were no different., Conclusions: In newborns with early, mild to moderate respiratory distress, aerosolized calfactant at a dose of 210 mg phospholipid/kg body weight reduced intubation and surfactant instillation by nearly one-half., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Drs Cummings and Wilding are contracted consultants to ONY Biotech. Dr Egan is chief medical officer of ONY Biotech; the other authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Purpose: To examine the relationship between state school vision screening requirements and the likelihood that children 3-5 years of age receive vision testing., Methods: We obtained nationally representative data from the 2016 National Survey of Children's Health on children ages 3-5 (n = 7,567) and used available sources to compile state policies that mandate childhood vision testing. We calculated the rates of parent-reported vision testing for each state and fit logistic regression models using survey-based estimation methods with nationally representative weights. Our models controlled for factors such as age, sex, race/ethnicity, and insurance coverage. Additional analyses added comorbidities that may lead to an eye care provider referral., Results: Parent-reported vision testing rates by state ranged from 41% to 84%. A significant association was found between the presence of state-level vision screening requirements and parent-reported vision testing, which remained after controlling for comorbidities (aOR = 1.374; P = 0.016). Of these comorbidities, arthritis, blindness, and very low birth weight were associated with a higher rate of vision screening (all P < 0.05)., Conclusions: The presence of a state-level school vision screening requirement is associated with increased parent-reported vision testing in children 3-5 years of age. This suggests that state policy may ensure timely screening for amblyopia and other sight-threatening complications., (Published by Elsevier Inc.)

Objective: This study compares the effect of partially hydrolyzed formula (PHF) and standard formula (SF) on the severity and short-term outcomes of neonatal abstinence syndrome (NAS)., Study Design: We performed a retrospective chart review of 124 opioid-dependent mothers and their term or near-term infants. Infants were categorized according to the predominant type of formula consumed during the hospital stay. Finnegan's scale was used to assess symptoms of withdrawal., Results: A total of 110 infants met our inclusion criteria. Thirty-four (31%) infants were fed predominantly PHF, 60 (54%) infants were fed SF, and 16 (15%) infants were fed maternal breast milk. There was no difference between the infants in the PHF and SF groups with respect to requirement of morphine (MSO 4 ) therapy, maximum dose of MSO 4 used, duration of MSO 4 treatment or length of hospital stay after performing multivariate analyses to control for type of drug used by the mother, maternal smoking, regular prenatal care, inborn status, and maximum Finnegan score prior to MSO 4 treatment., Conclusion: Use of PHF failed to impact short-term outcomes in infants treated for NAS including maximum MSO 4 dose, duration of MSO 4 treatment, and length of hospital stay. A prospective randomized controlled trial may be indicated to confirm this finding., Competing Interests: None declared., (Thieme. All rights reserved.)

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1 . Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗ 3 (rs776746), ∗ 6 (10264272), and ∗ 7(41303343 ), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642) . Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance ( P < 0.001) with 50% lower AUC ∗ ( P < 0.001) than Poor metabolizers. No differences in C 12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose ( P = 0.03), CL ( P = 0.023), CL/LBW ( P = 0.022), and AUC ∗ ( P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5 ∗ 3 ∗ 4 ∗ 5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks., (Copyright © 2020 Brazeau, Attwood, Meaney, Wilding, Consiglio, Chang, Gundroo, Venuto, Cooper and Tornatore.)

With recent developments in computer power the application of exact inferential methods has become more feasible which has resulted in increasing popularity of these approaches. However, there is a lack of such methodology for populations with more complex structure, such as finite populations. When a small sample is drawn from a finite population, the number of individuals with a specific characteristic of interest follows hypergeometric distribution. In order to test for the comparison of two proportions in finite populations we develop an exact unconditional test. We utilize the information gained from the sample to restrict our search for the maximum p -value. Our proposed test has power equal to its competitors while maintains the pre-specified nominal significance level., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 Informa UK Limited, trading as Taylor & Francis Group.)

The Ki-67 index is an established prognostic factor in gastrointestinal neuroendocrine tumors (GI-NETs) and defines tumor grade. It is currently estimated by microscopically examining tumor tissue single-immunostained (SS) for Ki-67 and counting the number of Ki-67-positive and Ki-67-negative tumor cells within a subjectively picked hot-spot. Intraobserver variability in this procedure as well as difficulty in distinguishing tumor from non-tumor cells can lead to inaccurate Ki-67 indices and possibly incorrect tumor grades. We introduce two computational tools that utilize Ki-67 and synaptophysin double-immunostained (DS) slides to improve the accuracy of Ki-67 index quantitation in GI-NETs: (1) Synaptophysin-KI-Estimator (SKIE), a pipeline automating Ki-67 index quantitation via whole-slide image (WSI) analysis and (2) deep-SKIE, a deep learner-based approach where a Ki-67 index heatmap is generated throughout the tumor. Ki-67 indices for 50 GI-NETs were quantitated using SKIE and compared with DS slide assessments by three pathologists using a microscope and a fourth pathologist via manually ticking off each cell, the latter of which was deemed the gold standard (GS). Compared to the GS, SKIE achieved a grading accuracy of 90% and substantial agreement (linear-weighted Cohen's kappa 0.62). Using DS WSIs, deep-SKIE displayed a training, validation, and testing accuracy of 98.4%, 90.9%, and 91.0%, respectively, significantly higher than using SS WSIs. Since DS slides are not standard clinical practice, we also integrated a cycle generative adversarial network into our pipeline to transform SS into DS WSIs. The proposed methods can improve accuracy and potentially save a significant amount of time if implemented into clinical practice.