A multisite feasibility study of integrated cognitive-behavioral treatment for co-existing nocturia and chronic insomnia.

BACKGROUND: Nocturia (waking from sleep at night to void) and chronic insomnia frequently co-exist in older adults, contributing synergistically to sleep disturbance. Treatments typically target either nocturia or insomnia rather than simultaneously addressing shared mechanisms for these disorders. METHODS: We conducted a multisite feasibility study to: (1) test and refine a protocol for recruitment, randomization, and assessment of older adults with co-existing nocturia and insomnia; and (2) examine preliminary changes in outcome measures to inform a future larger, multisite clinical trial. Participants were men and women aged 60 years and older recruited from outpatient clinics, reporting an average of two or more nocturia episodes per night over the past 4 weeks and meeting diagnostic criteria for chronic insomnia disorder. Participants were randomized to receive either integrated cognitive-behavioral therapy for insomnia and nocturia or a health education control program involving five weekly visits with a trained nurse practitioner interventionist. Outcomes (e.g., nocturia episodes) were measured 1-week post-treatment and 4-month post-randomization. Descriptive statistics examined the feasibility of outcomes to guide preparations for a future efficacy trial. RESULTS: Of 245 adults screened, 55% were ineligible and 25% declined to participate. Sixty-one percent of 49 participants who provided informed consent were randomized. Of the 30 participants randomized (mean age = 70.6 years, 60% White), 14 were assigned to integrated cognitive-behavioral treatment and 16 to the control group. All randomized participants provided 4-month follow-up data. At 4 months, mean nightly nocturia episodes decreased by 0.9 (SD 1.0) in the integrated treatment group and by 0.2 (SD 1.2) in the control group compared with baseline. DISCUSSION: Findings demonstrate the feasibility of recruiting, randomizing, and collecting outcome data from older adults (predominantly male) assigned to an integrated cognitive-behavioral therapy for coexisting insomnia and nocturia or a health education control program.

Masked Taper With Behavioral Intervention for Discontinuation of Benzodiazepine Receptor Agonists: A Randomized Clinical Trial.

Importance: Placebo effects are commonly observed in benzodiazepine receptor agonist hypnotic clinical trials. Clinical guidelines recommend discontinuing benzodiazepine receptor agonist hypnotics (particularly in older adults) and administering cognitive behavioral therapy for insomnia (CBTI) as first-line therapy for insomnia. It is unknown whether a novel intervention that masks the daily dose of benzodiazepine receptor agonist during tapering and augments CBTI with novel cognitive and behavioral exercises targeting placebo effect mechanisms improves benzodiazepine receptor agonist discontinuation. Objective: To compare a masked benzodiazepine receptor agonist taper plus augmented CBTI vs an unmasked taper plus standard CBTI. Design, Setting, and Participants: This randomized clinical trial conducted at an academic medical center and a Department of Veterans Affairs medical center included adults aged 55 years or older who had used lorazepam, alprazolam, clonazepam, temazepam, and/or zolpidem for current or prior insomnia, at doses of less than 8-mg diazepam-equivalent 2 or more nights per week for at least 3 months. Data were collected between December 2018 and November 2023. Data analyses were conducted between November 2023 and July 2024. Interventions: Masked taper plus cognitive behavioral therapy-augmented program (MTcap); standard CBTI plus supervised (unmasked) gradual taper (SGT). Main Outcomes and Measures: The primary efficacy outcome was percentage achieving benzodiazepine receptor agonist discontinuation 6 months after treatment ended (6-month; intention-to-treat) measured with 7-day self-reported medication logs and for a subset, urine tests. Secondary outcomes were Insomnia Severity Index scores at 1 week posttreatment and 6 months posttreatment, percentage of participants that have discontinued benzodiazepine receptor agonist use at 1 week posttreatment, and benzodiazepine receptor agonist dose and the Dysfunctional Beliefs About Sleep-Medication subscale at 1 week and 6 months posttreatment. Results: Of 338 participants who underwent in-depth screening, 188 participants (mean [SD] age, 69.8 [8.3] years, 123 male [65.4%] and 65 female [35.6%]) were randomly assigned to MTcap (n = 92) or SGT (n = 96). Compared with SGT, MTcap resulted in greater benzodiazepine receptor agonist discontinuation at 6 months (MTcap = 64 [73.4%], SGT = 52 [58.6%]; odds ratio [OR], 1.95; 95% CI 1.03-3.70; P = .04) and 1 week posttreatment (MTcap = 76 [88.4%], SGT = 62 [67.4%]; OR, 3.68; 95% CI, 1.67-8.12; P = .001) and reduced frequency of benzodiazepine receptor agonist use (nights/week) at 1 week posttreatment (-1.31; 95% CI, -2.05 to -0.57; P < .001). Insomnia Severity Index improved with no significant between-group difference at follow-up (baseline to 1 week posttreatment, 1.38; P = .16; baseline to 6 months, 0.16; P = .88). Conclusions and Relevance: This randomized clinical trial found that a program combining masked tapering with novel cognitive and behavioral exercises targeting placebo mechanisms improved the percentage of long-term benzodiazepine receptor agonist discontinuation compared with standard CBTI plus an unmasked taper. Trial Registration: ClinicalTrials.gov Identifier: NCT03687086.

Integrating the Memory Support Intervention into the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C): can improving memory for treatment in midlife and older adults improve patient outcomes? Study protocol for a randomized controlled trial.

BACKGROUND: Poor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments. METHODS: Participants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility. DISCUSSION: This study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

A review of biosimilars in psoriasis: impacts on efficacy, safety, access, and a first-hand look at biosimilar cost savings within the department of veterans affairs.

BACKGROUND: Psoriasis is a chronic immune-mediated systemic disease whose treatment has been revolutionized due to the induction of monoclonal antibody-based biologics. However, access to these drugs has been limited due to their high cost. Biosimilars utilize reverse engineering to create a highly similar product to an originator drug following patent expiration and provide an avenue to reduce costs of biologic treatment. This review seeks to synthesize current knowledge about the development, efficacy, and established benefits of biosimilars, including cost savings and increased access to biologic medicines. RESULTS: In 2023, the Veterans Health Administration (VA) generated a cost avoidance of over 67 million dollars through use of 6 currently adopted biosimilars across all indications. There is an opportunity for further cost avoidance, with the pre-set percent discount of statutory contract prices necessary for the adoption of future biosimilars, including adalimumab and etanercept, set at over 50%. CONCLUSIONS: Biosimilars appear to offer an overall effective, safe, and well-tolerated treatment method for patients with psoriasis and are already providing substantial cost savings within the VA. Additional education is needed to address sources of ambivalence for both patients and providers to assist in further uptake of biosimilars for the treatment of psoriasis.

Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [14C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [14C]-Tirzepatide was prepared by incorporating four 14C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 µCi of [14C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg-1 (133 µCi/kg) of [14C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg-1 (20 µCi/kg) of [14C]-tirzepatide. Following a single SC dose of [14C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, ß-oxidation of the C20 diacid moiety, and amide hydrolysis. ClinicalTrials.gov identifier: NCT 04,311,424.

Strategic Learning Strategies of Doctor of Physical Therapy Students.

INTRODUCTION: The use of strategic learning strategies has been positively associated with academic performance in several graduate health profession programs. This finding suggests that it may be an important construct to explore in Doctor of Physical Therapy (DPT) education. The Learning and Study Strategies Inventory (LASSI) summarizes a student's perception and use of 10 learning and study strategies. REVIEW OF LITERATURE: Although the LASSI has limited reporting in DPT education, other health care education programs have shown correlation with academic performance. The purpose of this study was to examine DPT students' early perceptions of strategic learning with descriptive summaries of LASSI data and examine correlations between demographic and admissions-related data. SUBJECTS: Matriculated DPT students (n = 294) at a 2-year hybrid program who completed the LASSI at orientation in 2020 and 2021. METHODS: This was a descriptive study that retrospectively analyzed LASSI scores in entry-level DPT students. LASSI score differences among demographic groups and Spearman's rho correlations between the LASSI, Graduate Record Examination (GRE) scores, grade point averages, grit, and emotional intelligence (EI) were explored. RESULTS: LASSI score means were in the 50th-75th percentile (moderate category) suggesting a need for further development in strategic learning. Group differences in LASSI scores were noted for gender identity (male higher Anxiety management, P < .001; female higher Attitude, P < .001, Time Management, P = .003, and Use of Academic Resources, P = .003), racial-ethnic minoritized group (higher Self-regulation, P = .013), first-generation college students (higher Attitude, P = .047), physical therapy assistants (higher Information Processing, P = .047), students with a primary language other than English (higher Time Management, P = .046), and older students (higher Anxiety management, P = .026). Weak but significant correlations were identified between LASSI scale and component scores and several admissions variables. Highest correlations were with grit (Will, ρ = 0.319, P < .001; Concentration, ρ = 0.312, P < .001), EI (Will, ρ = 0.328, P < .001; Attitude, ρ = 0.302, P < .001; Self-regulation, ρ = 0.382, P < .001; Use of Academic Resources ρ = 0.331, P < .001), and quantitative GRE scores (Anxiety management, ρ = 0.341, P < .001). DISCUSSION/CONCLUSION: All LASSI scale scores and components were in the moderate category, potentially indicating a need to coach and develop strategic learning strategies. Group differences in LASSI scores may represent varied student needs. The weak relationship between LASSI scores and admissions variables could suggest that the constructs measured by LASSI are not currently captured through typical DPT admissions practices.

Machine learning approach to investigate pregnancy and childbirth risk factors of sleep problems in early adolescence: Evidence from two cohort studies.

BACKGROUND: This study aimed to predict early adolescent sleep problems using pregnancy and childbirth risk factors through machine learning algorithms, and to evaluate model performance internally and externally. METHODS: Data from the China Jintan Child Cohort study (CJCC; n=848) for model development and the US Healthy Brain and Behavior Study (HBBS; n=454) for external validation were employed. Maternal pregnancy histories, obstetric data, and adolescent sleep problems were collected. Several machine learning techniques were employed, including least absolute shrinkage and selection operator, logistic regression, random forest, naïve bayes, extreme gradient boosting, decision tree, and neural network. The area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, and root mean square of residuals were used to evaluate model performance. RESULTS: Key predictors for CJCC adolescents' sleep problems include gestational age, birthweight, duration of delivery, and maternal happiness during pregnancy. In HBBS adolescents, the duration of postnatal depressive emotions was the primary perinatal predictor. The prediction models developed in the CJCC had good-to-excellent internal validation performance but poor performance in predicting the sleep problems in HBBS adolescents. CONCLUSION: The identification of specific perinatal risk factors associated with adolescent sleep problems can inform targeted interventions during and after pregnancy to mitigate these risks. Health providers should consider integrating these predictive factors into routine pre- and postnatal assessments to identify at-risk populations. The variability in model performance across different cohorts highlights the need for context-specific models and the cautious application of predictive analytics across diverse populations. Future research should focus on refining predictive models to account for such variations, potentially through the incorporation of additional socio-cultural factors and genetic markers. This study emphasizes the importance of personalized and culturally sensitive approaches in the prediction and management of adolescent sleep problems, leveraging advanced computational methods to enhance maternal and child health outcomes.

Insights from user experience and evaluation of a mobile health nutrition intervention for children with autism: A qualitative study.

BACKGROUND: Children with autism spectrum disorder (ASD) experience high rates of atypical eating behaviours, such as food neophobia. Mobile health (mHealth) interventions have been found to improve communication, behaviour and social skills for children with ASD. However, there is limited evidence examining mHealth nutrition interventions among children with ASD. METHODS: The present study comprised a qualitative descriptive study that used qualitative content analysis to explore parent and child experiences with a novel mHealth nutrition intervention. Ten parent-child dyads provided user feedback and evaluation of the intervention. Data collection tools included a semistructured interview guide and a quantitative questionnaire with open-ended questions. Data analysis of the interview transcripts and open-ended questionnaire responses was an iterative process that continued until saturation was achieved. Descriptive statistics were used to analyse quantitative questionnaire data. RESULTS: Analysis of the qualitative semistructured interviews led to emergence of three themes: (1) positive intervention outcomes; (2) parent suggestions for improvement; and (3) barriers to engagement. Each theme included subthemes. Questionnaire data revealed the ability to pick rewards and the virtual character that reinforced dietary goals ("Nutrition Ninja") were the most liked components of the application. Sending messages within the application and the Nutrition Ninja game were the least liked components of the application. CONCLUSIONS: Collectively, findings indicated that the app served as an interactive tool prompting dietary change and conversations within families. Yet, for some families, the intervention design, resistance to change or child disinterest hindered use and implementation of the intervention.

Temazepam or Melatonin Versus Placebo for the Treatment of Insomnia in Advanced Cancer: A Three-Arm, Double-Blind, Phase III, Multicenter, Randomized Clinical Trial.

Background: Sleep disturbance has a prevalence of 30-78% in patients with advanced cancer. While pharmacotherapy is common, randomized controlled studies (RCTs) investigating available agents are limited. This study examines the efficacy and safety of temazepam or melatonin versus placebo for sleep in advanced cancer. Methods: This is a multicenter, randomized, double-blind, placebo-controlled study of temazepam, melatonin prolonged release (PR) or placebo for insomnia in patients with advanced cancer, and an insomnia severity index (ISI) score of >11. Results: Twenty-one participants were randomized: nine to temazepam, eight to melatonin, and four to placebo. Baseline characteristics between groups were similar. The adjusted mean difference in day 8 ISI score versus placebo was -9.1 (95% confidence interval [CI] -17.5, 0.7, p = 0.04) for temazepam and -9.6 (95% CI -18,-1.2, p = 0.03) for melatonin PR. There was no improvement in global quality of life. Both agents were well tolerated. Conclusion: Temazepam and melatonin PR were associated with a clinically significant improvement in patient-reported insomnia severity compared with placebo. Findings need confirmation with larger patient numbers.

RECOMED: A comprehensive pharmaceutical recommendation system.

OBJECTIVES: To build datasets containing useful information from drug databases and recommend a list of drugs to physicians and patients with high accuracy by considering a wide range of features of people, diseases, and chemicals. METHODS: A comprehensive pharmaceutical recommendation system was designed based on the features of people, diseases, and medicines extracted from two major drug databases and the created datasets of patients and drug information. Then, the recommendation was given based on recommender system algorithms using patient and caregiver ratings and the knowledge obtained from drug specifications and interactions. Sentiment analysis was employed by natural language processing approaches in pre-processing, along with neural network-based methods and recommender system algorithms for modelling the system. Patient conditions and medicine features were used to make two models based on matrix factorization. Then, we used drug interaction criteria to filter drugs with severe or mild interactions with other drugs. We developed a deep learning model for recommending drugs using data from 2304 patients as a training set and 660 patients as our validation set. We used knowledge from drug information and combined the model's outcome into a knowledge-based system with the rules obtained from constraints on taking medicine. RESULTS: Our recommendation system can recommend an acceptable combination of medicines similar to the existing prescriptions available in real life. Compared with conventional matrix factorization, our proposed model improves the accuracy, sensitivity, and hit rate by 26 %, 34 %, and 40 %, respectively. In addition, it improves the accuracy, sensitivity, and hit rate by an average of 31 %, 29 %, and 28 % compared to other machine learning methods. We have open-sourced our implementation in Python. CONCLUSION: Compared to conventional machine learning approaches, we obtained average accuracy, sensitivity, and hit rates of 31 %, 29 %, and 28 %, respectively. Compared to conventional matrix factorisation our proposed method improved the accuracy, sensitivity, and hit rate by 26 %, 34 %, and 40 %, respectively. However, it is acknowledged that this is not the same as clinical accuracy or sensitivity, and more accurate results can be obtained by gathering larger datasets.

Using online methods to recruit participants into mental health clinical trials: considerations and recommendations from the RE-MIND study.

BACKGROUND: Ensuring diversity in clinical trials can be a challenge, which may be exacerbated when recruiting vulnerable populations, such as participants with mental health illness. As recruitment continues to be the major cause of trial delays, researchers are turning to online recruitment strategies, e.g. social media, to reach a wider population and reduce recruitment time and costs. There is mixed evidence for the use of online recruitment strategies; therefore, the REcruitment in Mental health trials: broadening the 'net', opportunities for INclusivity through online methoDs (RE-MIND) study aimed to identify evidence and provide guidance for use of online strategies in recruitment to mental health trials, with a focus on whether online strategies can enhance inclusivity. This commentary, as part of the RE-MIND study, focusses on providing recommendations for recruitment strategy selection in future research with the aim to improve trial efficiency. A mixed-methods approach was employed involving three work packages: (I) an evidence review of a cohort of 97 recently published randomised controlled trials/feasibility or pilot studies in mental health to assess the impact of online versus offline recruitment; (II) a qualitative study investigating the experiences of n = 23 key stakeholders on use of an online recruitment approach in mental health clinical trials; (III) combining the results of WP1 and WP2 to produce recommendations on the use of an online recruitment strategy in mental health clinical trials. The findings from WP1 and 2 have been published elsewhere; this commentary represents the results of the third work package. CONCLUSION: For external validity, clinical trial participants should reflect the populations that will ultimately receive the interventions being tested, if proven effective. To guide researchers on their options for inclusive recruitment strategies, we have developed a list of considerations and practical recommendations on how to maximise the use of online recruitment methods.

Measuring Cognitive Function In-Person and Remotely in Round 4 of the National Social Life, Health, and Aging Project (NSHAP).

OBJECTIVES: This paper describes the changes made to the collection of cognitive measures when the National Social Life, Health, and Aging Project (NSHAP) introduced remote modes of data collection. METHODS: In Round 4 (2021-23), the longitudinal study transitioned from being conducted in-person to collecting data via multiple modes including in-person and remote modes: web, phone, and paper-and-pencil. The team began with the measures used in Rounds 2 and 3 of NSHAP-the survey-adapted Montreal Cognitive Assessment (MoCA-SA)-and evaluated which measures could be administered remotely, introducing new measures for each cognitive subdomain, as needed, to compensate for items that could not be administered remotely. RESULTS: Cognitive items used in Rounds 2 and 3 that could not be administered remotely were dropped from the respective modes, and items selected from the Rush Alzheimer's Disease Center's (RADC) global cognition battery were added as substitutes. For comparison, the RADC substitute items were added to the in-person mode making it longer in R4. DISCUSSION: The changes in cognitive measures resulted in different numbers of cognitive items across the four modes of survey administration in Round 4. Analysts should be aware of these changes when creating a single global cognition score for the entire NSHAP sample in Round 4, and aware that there may be mode effects that could impact cognition scores.

Adaptive Pressure Control-Continuous Mandatory Ventilation Versus Volume Control-Continuous Mandatory Ventilation: Factors Associated With Initiation, Maintenance, and Adjustment.

BACKGROUND: Adaptive pressure control-continuous mandatory ventilation (APC-CMV) is a frequently utilized ventilator mode in ICU settings. This analysis compared APC-CMV and traditional volume control-continuous mandatory ventilation (VC-CMV) mode, describing factors associated with initiation, maintenance, and changes in settings of each mode. METHODS: We analyzed ventilator data from a retrospective electronic health record data set collected as part of a quality improvement project in a single academic ICU. The majority ventilator mode was defined as the mode comprising the highest proportion of mechanical ventilation time. Multivariable logistic regression was used to identify variables associated with initial and majority APC-CMV or VC-CMV modes. Wilcoxon rank-sum tests were used to compare ventilator setting changes/d and sedation as a function of APC-CMV and VC-CMV majority modes. RESULTS: Among 1,213 subjects initiated on mechanical ventilation from January 2013-March 2017, 68% and 24% were initiated on APC-CMV and VC-CMV, respectively, which composed 62% and 21% of the majority ventilator modes. Age, sex, race, and ethnicity were not associated with the initial or majority APC-CMV or VC-CMV modes. Subjects initiated on APC-CMV spent 88% of the mechanical ventilation time on APC-CMV mode. Compared to VC-CMV, subjects with APC-CMV majority mode experienced more ventilator setting changes/d (1.1 vs 0.8, P < .001). There were no significant differences in sedative medications when comparing subjects receiving APC-CMV versus VC-CMV majority modes. CONCLUSIONS: APC-CMV was highly utilized in the medical ICU. Subjects on APC-CMV had more ventilator setting changes/d than those on VC-CMV. APC-CMV offered no advantage of reduced setting adjustments or less sedation compared to VC-CMV.

Poor sleep and inflammatory gene expression among care partners of persons living with dementia: a pilot trial of a behavioral sleep intervention.

Objective: Poor sleep is associated with increased inflammation, thereby increasing the risk of chronic diseases and mortality. However, the effects of behavioral sleep interventions on the upstream inflammatory system are unknown among family care partners (CP). The present study explored the role of a behavioral sleep intervention program on inflammatory gene expression. Methods: This was part of a randomized controlled trial of a sleep intervention for dementia care dyads with sleep problems. Thirty dyads were randomized to sleep intervention or control groups. Sleep outcomes for CP were assessed with 1 week of actigraphy and sleep diary, and the Pittsburgh Sleep Quality Index. Other information included CP demographics, body mass index, and intensity of caregiving tasks. All outcomes were collected at baseline, post-treatment, and 3-month follow-up. Results: Neither group showed any significant differential changes in gene expression from baseline to post-treatment or 3-month follow-up. A decrease in inflammatory gene expression was significantly associated with more nights of good sleep (i.e. nights without trouble falling or staying asleep at night). This finding remained significant after controlling for group (intervention/control), timepoint (baseline, post-treatment, and 3-month follow-up), and CP characteristics (e.g. age and ethnicity). Conclusions: Although better sleep was associated with decreased inflammatory gene expression, this study did not demonstrate any benefits of a behavioral sleep intervention over control, most likely due to a small sample. Studies with larger sample sizes are needed to test the specific aspects of disturbed sleep that relate to inflammatory biology among CP of persons living with dementia.

Comparison between a single- and a multi-point calibration method using LC-MS/MS for measurement of 5-fluorouracil in human plasma.

When quantifying therapeutic drugs using LC-MS/MS instrumentation in clinical laboratories, batch-mode analysis with a calibration curve consisting of 6-10 concentrations for each analyte is the most widely used approach. However, this is an inefficient use of this technology since it increases cost, delays result availability and precludes random instrument access. Various alternative methods to reduce the calibrator use and improve efficiency without compromising analytical quality have been investigated, and a single-point calibration has been reported to be the simplest, least expensive and the quickest approach. This study compares a single and a multi-point calibration method using LC-MS/MS with 5-fluorouracil (5-FU) as a model drug. The method was validated for quantitative analysis of 5-FU over a concentration range of 0.05-50 mg/L. Patients undergoing cancer treatment with intravenous 5-FU had plasma 5-FU concentrations measured, and their dose adjusted in real time based on the calculated area under the time-concentration curve (AUC). Subsequently, a single point calibration method using a concentration at 0.5 mg/L was compared to the multi-point calibration method in terms of accuracy and precision. A Bland-Altman bias plot and a Passing-Bablok regression analysis showed a good agreement between the two methods (mean difference = -1.87 %, slope = 1.002, respectively) when comparing patient plasma 5-FU concentrations. The calibration method did not impact the AUC results nor the decision on 5-FU dose adjustments. Our study demonstrated that a single point calibration method produced analytically and clinically comparable results to those produced by a multi-point method when quantifying 5-FU and is feasible to be used clinically.

Spanish Translation and Cultural Adaptation of the Intensive Care Unit Delirium Playbook.

Background: A lack of high-quality provider education hinders the delivery of standard-of-care delirium detection and prevention practices in the intensive care unit (ICU). To fill this gap, we developed and validated an e-learning ICU Delirium Playbook consisting of eight videos and a 44-question knowledge assessment quiz. Given the increasing Spanish-speaking population worldwide, we translated and cross-culturally adapted the playbook from English into Spanish. Objective: To translate and culturally adapt the ICU Delirium Playbook into Spanish, the second most common native language worldwide. Methods: The translation and cross-cultural adaptation process included double forward and back translations and harmonization by a 14-person interdisciplinary team of ICU nurses and physicians, delirium experts, methodologists, medical interpreters, and bilingual professionals representing many Spanish-speaking global regions. After a preeducation quiz, a nurse focus group completed the playbook videos and posteducation quiz, followed by a semistructured interview. Results: The ICU Delirium Playbook: Spanish Version maintained conceptual equivalence to the English version. Focus group participants posted mean (standard deviation) pre- and post-playbook scores of 63% (10%) and 78% (12%), with a 15% (11%) pre-post improvement (P = 0.01). Participants reported improved perceived competency in performing the Confusion Assessment Method for the ICU and provided positive feedback regarding the playbook. Conclusion: After translation and cultural adaptation, the ICU Delirium Playbook: Spanish Version yielded significant knowledge assessment improvements and positive feedback. The Spanish playbook is now available for public dissemination.

Sleep and Daytime Function in People with Spinal Cord Injury.

Study Design: Cross-sectional cohort study. Objectives: To determine the role of sleep-disordered breathing (SDB), insomnia symptoms and sleep quality in the daytime function and quality of life of veterans with spinal cord injury (SCI). Setting: A Veterans Administration (VA) medical center in the Midwestern US. Methods: Thirty-eight male veterans with SCI (22 cervical, 16 thoracic; mean [SD] age = 62.9[9.5] years) completed baseline assessments within a larger clinical trial. Measures assessed sleep apnea severity (apnea-hypopnea index, AHI), insomnia symptoms (Insomnia Severity Index, ISI), self-reported sleep quality (Pittsburg Sleep Quality Index, PSQI), daytime sleepiness (Epworth Sleepiness Scale, ESS), fatigue (Flinders Fatigue Scale, FFS), depression (Patient Health Questionnaire-9 item, PHQ-9 excluding sleep item), functioning (Spinal Cord Independence Measure, SCIM), and quality of life (World Health Organization Quality of Life, WHOQOL-BREF). Bivariate correlations (alpha p<.05) were used to assess relationships between sleep (AHI, ISI, PSQI, ESS) and function (FFS, PHQ-9, SCIM, WHOQOL-BREF). Results: Mean AHI was 29.9(26.6), mean ISI was 9.38(6.2), mean PSQI was 9.0(4.6), and mean ESS was 7.0(5.2). There were no significant relationships between AHI and function measures. Significant relationships emerged between ISI and PHQ-9, some WHOQOL-BREF subscales, and SCIM as well as between PSQI and FFS, PHQ-9, and some WHOQOL-BREF subscales. Conclusions: Among Veterans with SCI, insomnia symptom severity and poor sleep quality were associated with worse functioning, whereas SDB severity was not. Insomnia and poor sleep quality represent modifiable contributors to poor daytime function. Research evaluating the impact of evidence-based insomnia treatments among individuals living with SCI is warranted.

Has the human biological interaction with SARS-CoV2 variants entered a pliant "Faustian bargain"?

We hypothesize that a "Faustian bargain"-the trading of increased SARS-CoV2 viral infection with a concurrent potential for prevention of life-threatening lower lung infection explains the previous and future morbidity and mortality from COVID-19. Further, this trade-off is made feasible by fundamental principles of thermodynamics and receptor affinity.

A Novel Role for the Histone Demethylase JMJD3 in Mediating Heroin-Induced Relapse-Like Behaviors.

BACKGROUND: Epigenetic changes that lead to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration. METHODS: Male Sprague Dawley rats were trained to self-administer heroin. Western blotting and quantitative polymerase chain reaction were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc (n = 7-11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9-11/group). The RiboTag capture method (n = 3-5/group) and viral vectors (n = 7-8/group) were used in male transgenic rats to identify the contributions of D1- and D2-expressing medium spiny neurons in the NAc. Drug seeking was tested by cue-induced response previously paired with drug infusion. RESULTS: Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and H3K27me3 levels. JMJD3 bidirectionally affected seeking: expression of the wild-type increased cue-induced seeking whereas expression of a catalytic dead mutant decreased it. JMJD3 expression was increased in D2+ but not D1+ medium spiny neurons. Expression of the mutant JMJD3 in D2+ neurons was sufficient to decrease cue-induced heroin seeking. CONCLUSIONS: JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway.

Comparative efficacy of later-line therapies for metastatic colorectal cancer: a network meta-analysis of survival curves.

INTRODUCTION: We evaluated the comparative efficacy of six later-line (≥3) therapies for metastatic colorectal cancer (mCRC) over placebo. We applied a novel statistical method of reconstructing pseudo-patient-level data (pseudo-IPD) to inform a network meta-analysis of survival curves that considers shape in addition to scale parameters. METHODS: A literature search yielded 10 phase II/III trials. We digitized all survival curves and applied a novel method incorporating curve coordinates, patients-at-risk, and events reported to generate pseudo-IPD. Using fitted random effects lognormal distributions, we estimated the survival proportions and HRs (95CrI) of progression-free (PFS) and overall survival (OS) over 12 months of follow-up. RESULTS: Compared to placebo, in ascending order, 12-month OS HRs were 0.50 (95% CrI = 0.35, 0.69; PFS = 0.11 (95% CrI = 0.06, 0.14)) for TAS+bevacizumab; 0.71 (95% CrI = 0.51, 0.97; PFS = 0.26 (95% CrI = 0.16, 0.41)) for regorafenib; 0.75 (95% CrI = 0.61, 0.91; (PFS = 0.24 (95% CrI = 0.17, 0.31)) for TAS-102; 0.80 (95% CrI = 0.79, 0.90; PFS = 0.18 (95% CrI = 0.13, 0.24)) for fruquintinib; 0.83 (95% CrI = 0.50, 0.99; PFS = 0.42 (95% CrI = 0.20, 0.75)) for atezolizumab+cobimetinib; and 1.03 (95% CrI = 0.55, 1.65; PFS = 0.67 (95% CrI = 0.29, 1.01)) for atezolizumab. CONCLUSION: In this independent NMA of survival data, all later-line mCRC therapies but atezolizumab monotherapy exhibited superiority in 12-month PFS and OS over placebo. TAS+bevacizumab emerged as the most dominant option and may be the preferred choice, with fruquintinib, regorafenib, and TAS-102 monotherapy showing statistically significant but lower PFS and OS benefits. REGISTRATION: PROSPERO: CRD42022371953.