Search

Introduction: Brain computed tomography (CT) is inconsistently recommended worldwide in the investigative algorithm of patients presenting with first episode psychosis (FEP). The objective of this study is to investigate the clinical efficacy of brain CT in patients presenting with FEP without neurological signs in a major metropolitan teaching hospital. Methods: The CT brain scan reports of 237 consecutive patients, for which the imaging requests or reports provided a history of FEP but no focal neurological signs, were retrospectively identified within a 6-year period in a 750-bed tertiary referral teaching hospital using the radiology information system text-search function (170 male, 67 female; mean age, 28.3 years). All reports were authored or approved by consultant radiologist. They were reviewed for the presence of any lesion that could cause psychosis and hence alter clinical management. Minor neuroradiological abnormalities were also noted. Hospital Ethics Committee registration and approval were obtained and patient informed consent was not required. Results: No focal brain lesion potentially responsible for the psychosis or focal lesion requiring surgical intervention was identified in any patient. Findings unable to be directly linked to the psychosis such as evidence of small vessel ischaemic disease, arachnoid cysts, cerebral atrophy, and normal variants were present in 17.6% of patients (45 of 237 studies), none of which led to an alteration of clinical management. Conclusion: The results of this study postulate that brain CT should not be universally performed in the initial assessment of patients with first episode psychosis without neurological signs. [ABSTRACT FROM AUTHOR]

Background: Adequate sleep plays a crucial role in maintaining physical, mental, and emotional health. On average, adults require 7-9 h of sleep per night. However, less than two-thirds of women meet this recommendation. During the coronavirus disease 2019 (COVID-19) pandemic, poor sleep quality and moderate-to-severe stress were highly prevalent among healthcare workers (HCWs), especially women. While some interventions have been proposed to address stress/burnout in HCWs, few have focused specifically on women in healthcare. Therefore, this is a protocol for a study that aims to determine the efficacy of a mind-body intervention (MBI) to improve sleep duration among women HCWs aged 40-60 years using the personalized (N-of-1) trial design., Methods: A personalized (N-of-1) trials model will be employed to evaluate the efficacy of an MBI to improve sleep duration (primary endpoint) and explore its effects on sleep quality, physiological factors, and their relationships with participants' perceived stress, anxiety, and depression. The series of personalized trials (n = 60) will be conducted over 16 weeks. The MBI will include mindfulness, yoga, and guided walking, delivered in two 2-week block sequences for 12 weeks, with two 2-week periods for baseline and follow-up. Participants will watch 30-min videos three times weekly and wear an activity tracker to monitor sleep and activity. They will receive daily text messages with questions about sleep quality and bi-weekly questionnaires about their stress, anxiety and depression scores, fatigue, concentration, confidence, mood, and pain levels., Conclusion: Results from this study will inform the development of N-of-1 methodology for addressing the health and wellness needs of middle-aged women., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Aims: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic., Methods: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs., Results: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs., Conclusions: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs., (© 2024 British Pharmacological Society.)

Background: Determining the maximum tolerated dose (MTD) remains the primary objective for the majority of dose-finding oncology trials. Whilst MTD determination often relies upon clinicians to identify dose-limiting toxicities (DLTs) experienced by patients during the trial, research suggests that clinicians may underreport patient's adverse events. Therefore, contemporary practice may be exposed to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using patient-reported outcomes (PROs) in dose-finding trials., Design: We present Utility-PRO-Continual Reassessment Method (U-PRO-CRM), a novel trial design which simultaneously uses clinician-rated and patient-rated DLTs (Clinician-DLTs and Patient-DLTs, respectively) to make dose (de-)escalation decisions and to recommend an MTD. U-PRO-CRM contains the published PRO-CRM as a special case and provides greater flexibility to trade-off the rate of Patient-DLTs and Clinician-DLTs to find an optimal dose. We present simulation results for U-PRO-CRM., Results: For specified trade-offs between Clinician-DLT and Patient-DLT rate, U-PRO-CRM outperforms the PRO-CRM design by identifying the true MTD more often. In the special case where U-PRO-CRM generalises to PRO-CRM, U-PRO-CRM performs as well as its published counterpart. U-PRO-CRM minimises the number of patients overdosed whilst maintaining a similar proportion of patients allocated to the true MTD., Conclusions: By using a utility-based dose selection approach, U-PRO-CRM offers the flexibility to define a trade-off between the risk of patient-rated and clinician-rated DLTs for an optimal dose. Patient-centric dose-finding strategies, which integrate PROs, are poised to assume an ever more pivotal role in significantly advancing our understanding of treatment tolerability. This bears significant implications in shaping the future landscape of early-phase trials., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

With the advent of targeted agents and immunological therapies, the medical research community has become increasingly aware that conventional methods for determining the best dose or schedule of a new agent are inadequate. It has been well established that conventional phase I designs cannot reliably identify safe and effective doses. This problem applies, generally, for cytotoxic agents, radiation therapy, targeted agents, and immunotherapies. To address this, the US Food and Drug Administration's Oncology Center of Excellence initiated Project Optimus, with the goal "to reform the dose optimization and dose selection paradigm in oncology drug development." As a response to Project Optimus, the articles in this special issue of Clinical Trials review recent advances in methods for choosing the dose or schedule of a new agent with an overall objective of informing clinical trialists of these innovative designs. This introductory article briefly reviews problems with conventional methods, the regulatory changes that encourage better dose optimization designs, and provides brief summaries of the articles that follow in this special issue., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This network meta-analysis aimed to estimate the comparative effectiveness of non-pharmacological interventions on sleep in individuals with chronic musculoskeletal pain. Seven databases were systematically searched up to February 2023. A random-effects network meta-analysis in a frequentist framework was performed to synthesize continuous data as standardized mean differences (SMD) along with a 95% confidence interval (95% CI). A total of 15,641 records were identified, and 107 randomized controlled trials involving 8,121 participants were included. Of 14 identified interventions, eight were significantly more effective than passive control in improving sleep quality at immediate post-intervention (SMDs = 0.67-0.74), with cognitive behavioral therapy (CBT) being the most effective treatment (SMD = 0.74, 95% CI: 0.45-1.03). Only CBT demonstrated sustained effects at short-term (SMD = 1.56; 95% CI: 0.62-2.49) and mid-term (SMD = 1.23; 95% CI: 0.44-2.03) follow-ups. Furthermore, CBT significantly improved subjective (SMD = 0.64; 95% CI: 0.25-1.03) and objective (SMD = 0.30; 95% CI: 0.01-0.59) sleep efficiency compared with passive control at immediate post-intervention. Our findings support CBT as the first-line treatment for improving sleep in individuals with chronic musculoskeletal pain, given its superior effectiveness across multiple sleep outcomes and its sustainable effects until mid-term follow-up. However, the certainty of evidence for these interventions in improving sleep quality was very low to low., Competing Interests: Declaration of competing interest There were no financial or competing conflicts of interest in this work. Dr. Sharma is supported by the International Association for the Study of Pain John J. Bonica Postdoctoral Fellowship. The corresponding author had full access to all data in the study and took final responsibility for the decision to submit for publication., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stretchable and curved electronic devices are a promising technology trend due to their remarkable advantages. Many approaches have been developed to manufacture stretchable and curved electronics. Here, to allow such electronics to better serve practical applications, ranging from wearable devices to soft robotics, we propose a novel vertical serpentine conductor (VSC) with superior electrical stability to interconnect functional devices through a silicon-based microfabrication process. Conformal vacuum transfer printing (CVTP) technology was developed to transfer the networked platform onto complex curved surfaces to demonstrate feasibility. The mechanical and electrical performance were investigated numerically and experimentally. The VSC interconnected network provides a new approach for stretchable and curved electronics with high stretchability and reliability., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2023.)

Background: Fatigue is one of the most common symptoms treated in primary care and can lead to deficits in mental health and functioning. Light therapy can be an effective treatment for symptoms of fatigue; however, the feasibility, scalability, and individual-level heterogeneity of light therapy for fatigue are unknown., Objective: This study aimed to evaluate the feasibility, acceptability, and effectiveness of a series of personalized (N-of-1) interventions for the virtual delivery of bright light (BL) therapy and dim light (DL) therapy versus usual care (UC) treatment for fatigue in 60 participants., Methods: Participants completed satisfaction surveys comprising the System Usability Scale (SUS) and items assessing satisfaction with the components of the personalized trial. Symptoms of fatigue were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) daily, PROMIS weekly, and ecological momentary assessment (EMA) questionnaires delivered 3 times daily. Comparisons of fatigue between the BL, DL, and UC treatment periods were conducted using generalized linear mixed model analyses between participants and generalized least squares analyses within individual participants., Results: Participants rated the usability of the personalized trial as acceptable (average SUS score=78.9, SD 15.6), and 92% (49/53) of those who completed satisfaction surveys stated that they would recommend the trial to others. The levels of fatigue symptoms measured using the PROMIS daily fatigue measure were lower or improved in the BL (B=-1.63, 95% CI -2.63 to -0.63) and DL (B=-1.44, 95% CI -2.50 to -0.38) periods relative to UC. The treatment effects of BL and DL on the PROMIS daily measure varied among participants. Similar findings were demonstrated for the PROMIS weekly and EMA measures of fatigue symptoms., Conclusions: The participant scores on the SUS and satisfaction surveys suggest that personalized N-of-1 trials of light therapy for fatigue symptoms are both feasible and acceptable. Both interventions produced significant (P<.05) reductions in participant-reported PROMIS and EMA fatigue symptoms relative to UC. However, the heterogeneity of these treatment effects across participants indicated that the effect of light therapy was not uniform. This heterogeneity along with high ratings of usability and satisfaction support the use of personalized N-of-1 research designs in evaluating the effect of light therapy on fatigue for each patient. Furthermore, the results of this trial provide additional support for the use of a series of personalized N-of-1 research trials., Trial Registration: ClinicalTrials.gov NCT04707846; https://clinicaltrials.gov/ct2/show/NCT04707846., (©Mark Butler, Stefani D’Angelo, Heejoon Ahn, Thevaa Chandereng, Danielle Miller, Alexandra Perrin, Anne-Marie N Romain, Ava Scatoni, Ciaran P Friel, Ying-Kuen Cheung, Karina W Davidson. Originally published in JMIR Formative Research (https://formative.jmir.org), 18.09.2023.)

Background: In the USA, the primary cause of death and morbidity continues to be cardiovascular disease (CVD). Numerous trials have shown that statin medication reduces the likelihood of CVD events; it is a cornerstone of CVD prevention. However, studies have also indicated that up to 60% of the estimated 26.8 million Americans prescribed primary prevention statin treatment are nonadherent during the first year. Multi-component behavioral change technique (BCT) therapies have shown moderate promise in improving medication adherence as well as other positive health behaviors (such as physical activity). However, no research has looked at the duration of multi-component BCT intervention needed to result in a clinically significant improvement in statin adherence behaviors. This study aims to determine the necessary dose of a multi-component BCT intervention (defined as duration in weeks) to promote adherence to statin medication among those on primary prevention statin treatment by utilizing the modified time-to-event continuous reassessment method (TiTE-CRM)., Methods and Design: The study will utilize the modified TiTE-CRM in 42 participants, recruited in 14 cohorts of 3 participants each. The goal of this analysis is to identify the minimum effective dose (MED) of a multi-behavior change technique (BCT) intervention required to increase adherence to statins by 20% between baseline and follow-up periods. Using the TiTE-CRM method, the dose of the behavior intervention in weeks will be assigned to each cohort based on the performance of the prior cohort. At the end of the study, the intervention dose that has been found to be associated with a 20% increase in statin adherence among 80% of participants assigned to that dose will be identified as the MED., Discussion: If successful, the current trial will provide additional guidance to researchers and clinicians seeking to increase statin medication adherence using a BCT intervention by identifying the dose (i.e., the duration) of an intervention required to meaningfully increase adherence., Trial Registration: ClinicalTrials.gov NCT05273736. Registered on March 10, 2022. https://www., Clinicaltrials: gov/ct2/show/NCT05273736., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Poor sleep, defined as short-duration or poor-quality sleep, is a frequently reported condition with many deleterious effects including poorer cognitive functioning, increased accidents, and poorer health. Melatonin has been shown to be an efficacious treatment to manage symptoms of poor sleep. However, the treatment effects of melatonin on sleep can vary greatly between participants. Personalized, or N-of-1, trial designs represent a method for identifying the best treatment for individual participants. Although using N-of-1 trials of melatonin to treat poor sleep is possible, the feasibility, acceptability, and effectiveness of N-of-1 trials using melatonin are unknown. Using the National Institutes of Health Stage Model for Behavioral Intervention Development, a stage IB (intervention refinement, modification, and adaptation and pilot testing) design appeared to be needed to address these feasibility questions., Objective: This trial series evaluates the feasibility, acceptability, and effectiveness of a series of personalized interventions for remote delivery of melatonin dose (3 and 0.5 mg) versus placebo supplements for self-reported poor sleep among 60 participants. The goal of this study is to provide valuable information about implementing remote N-of-1 randomized controlled trials to improve poor sleep., Methods: Participants will complete a 2-week baseline followed by six 2-week alternating intervention periods of 3 mg of melatonin, 0.5 mg of melatonin, and placebo. Participants will be randomly assigned to 2 intervention orders. The feasibility and acceptability of the personalized trial approach will be determined with participants' ratings of usability and satisfaction with the remote, personalized intervention delivery system. The effectiveness of the intervention will be measured using participants' self-reported sleep quality and duration and Fitbit tracker-measured sleep duration and efficiency. Additional measures will include ecological momentary assessment measures of fatigue, stress, pain, mood, concentration, and confidence as well as measures of participant adherence to the intervention, use of the Fitbit tracker, and survey data collection., Results: As of the submission of this protocol, recruitment for this National Institutes of Health stage IB personalized trial series is approximately 78.3% complete (47/60). We expect recruitment and data collection to be finalized by June 2023., Conclusions: Evaluating the feasibility, acceptability, and effectiveness of a series of personalized interventions of melatonin will address the longer term aim of this program of research-is integrating N-of-1 trials useful patient care? The personalized trial series results will be published in a peer-reviewed journal and will follow the CONSORT (Consolidated Standards of Reporting Trials) extension for N-of-1 trials (CENT 2015) reporting guidelines. This trial series was approved by the Northwell Health institutional review board., Trial Registration: ClinicalTrials.gov NCT05349188; https://www.clinicaltrials.gov/study/NCT05349188., International Registered Report Identifier (irrid): DERR1-10.2196/45313., (©Mark Butler, Stefani D’Angelo, Alexandra Perrin, Jordyn Rodillas, Danielle Miller, Lindsay Arader, Thevaa Chandereng, Ying Kuen Cheung, Ari Shechter, Karina W Davidson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 03.08.2023.)

Background: Statin therapy is a mainstay of cardiovascular disease (CVD) prevention, but research shows that statin therapy alone is insufficient for preventing incident CVD and mortality. Combining statin medication with increased physical activity (PA) can lower mortality risk more than either statin or PA alone. However, PA levels often remain the same and may even decline following statin prescription. Additional information is needed to identify how to increase PA among statin users and determine the minimal length of an intervention (i.e., intervention dose) necessary to increase PA., Objective: The study aims to identify the required dose of a behavior change technique (BCT) intervention to increase PA among individuals on primary prevention statin therapy who have an elevated risk for cardiovascular disease (CVD)., Methods: The study will utilize the modified time-to-event continual reassessment method (TiTE-CRM) in 42 participants. We expect insights relating to dose-efficacy models and BCTs (Behavior Change Techniques) to improve PA in adults at risk for CVD. This trial will also examine potential mechanisms of action (MoAs) for interventions to increase PA, identify any effect a PA intervention may have on medication adherence, and determine whether participants respond uniformly to their respective behavioral interventions., Ethics and Dissemination: This trial was approved by the Northwell Health Institutional Review Board (IRB) and all participants will complete informed consent. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalized trials will follow the CONSORT reporting guidelines., Registration Details: This trial is registered on www., Clinicaltrials: gov (Number NCT05273723)., 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 © 2023 Elsevier Inc. All rights reserved.)

An N-of-1 trial is a multi-period crossover trial performed in a single individual, with a primary goal to estimate treatment effect on the individual instead of population-level mean responses. As in a conventional crossover trial, it is critical to understand carryover effects of the treatment in an N-of-1 trial, especially when no washout periods between treatment periods are instituted to reduce trial duration. To deal with this issue in situations where a high volume of measurements are made during the study, we introduce a novel Bayesian distributed lag model that facilitates the estimation of carryover effects, while accounting for temporal correlations using an autoregressive model. Specifically, we propose a prior variance-covariance structure on the lag coefficients to address collinearity caused by the fact that treatment exposures are typically identical on successive days. A connection between the proposed Bayesian model and penalized regression is noted. Simulation results demonstrate that the proposed model substantially reduces the root mean squared error in the estimation of carryover effects and immediate effects when compared to other existing methods, while being comparable in the estimation of the total effects. We also apply the proposed method to assess the extent of carryover effects of light therapies in relieving depressive symptoms in cancer survivors., (© 2023 John Wiley & Sons Ltd.)

Purpose: Sedentary time is ubiquitous in developed nations and is associated with deleterious health outcomes. Physical activity guidelines recommend reductions in sedentary time; however, quantitative guidelines that inform how often and how long sedentary time should be interrupted have not been provided. The purpose of this study was to examine the acute effects of multiple doses of a sedentary break intervention on cardiometabolic risk factors, concurrently evaluating efficacy of varying frequencies and durations of sedentary breaks., Methods: In a randomized crossover study, middle- and older-age adults ( n = 11) completed the following 8-h conditions on five separate days: 1 uninterrupted sedentary (control) condition and four acute (experimental) trials that entailed different sedentary break frequency/duration combinations: every 30 min for 1 min, every 30 min for 5 min, every 60 min for 1 min, and every 60 min for 5 min. Sedentary breaks entailed light-intensity walking. Glucose and blood pressure (BP) were measured every 15 and 60 min, respectively., Results: Compared with control, glucose incremental area under the curve was significantly attenuated only for the every 30 min for 5-min dose (-11.8[4.7]; P = 0.017). All sedentary break doses yielded significant net decreases in systolic BP from baseline compared with control ( P < 0.05). The largest reductions in systolic BP were observed for the every 60 min for 1 min (-5.2 [1.4] mm Hg) and every 30 min for 5 min (-4.3[1.4] mm Hg) doses., Conclusions: The present study provides important information concerning efficacious sedentary break doses. Higher-frequency and longer-duration breaks (every 30 min for 5 min) should be considered when targeting glycemic responses, whereas lower doses may be sufficient for BP lowering., (Copyright © 2023 by the American College of Sports Medicine.)

We formulate the estimation of monotone response surface of multiple factors as the inverse of an iteration of partially ordered classifier ensembles. Each ensemble (called PIPE-classifiers) is a projection of Bayes classifiers on the constrained space. We prove the inverse of PIPE-classifiers (iPIPE) exists, and propose algorithms to efficiently compute iPIPE by reducing the space over which optimisation is conducted. The methods are applied in analysis and simulation settings where the surface dimension is higher than what the isotonic regression literature typically considers. Simulation shows iPIPE-based credible intervals achieve nominal coverage probability and are more precise compared to unconstrained estimation., Competing Interests: conflict of interest The authors have no conflicts of interest to disclose.

A β-galactosidase-responsive photosensitiser has been designed and synthesised. It contains a galactosyl substrate, a boron dipyrromethene-based photosensitising unit and a black hole quencher 2 connected via an AB 2 -type self-immolative linker. This novel photosensitiser can be selectively activated by the senescence-associated β-galactosidase in senescent cells, leading to restoration in fluorescence emission and effective killing of the cells via photodynamic action.

Executive function is a cognitive domain with sizable heritability representing higher-order cognitive abilities. Genome-wide association studies (GWAS) of executive function are sparse, particularly in populations underrepresented in medical research. We performed a GWAS on a composite measure of executive function that included measures of mental flexibility and reasoning using data from the Northern Manhattan Study, a racially and ethnically diverse cohort (N = 1077, 69% Hispanic, 17% non-Hispanic Black and 14% non-Hispanic White). Four SNPs located in the long intergenic non-protein coding RNA 1362 gene, LINC01362, on chromosome 1p31.1, were significantly associated with the composite measure of executive function in this cohort (top SNP rs2788328, ß = 0.22, p = 3.1 × 10 -10 ). The associated SNPs have been shown to influence expression of the tubulin tyrosine ligase like 7 gene, TTLL7 and the protein kinase CAMP-activated catalytic subunit beta gene, PRKACB, in several regions of the brain involved in executive function. Together, these findings present new insight into the genetic underpinnings of executive function in an understudied population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Owing to the complication in organisation, the dangerous job nature and the rise of demonstrations and protests across the world in the past decade, police work-related stress has become a topic of global concern. This review aimed to provide an understanding of predictors, mediators and moderators of police work-related stress from a multi-level perspective. Using a scoping review approach underpinned by the six-stage methodological framework, studies were found from six electronic databases (MEDLINE, Web of Science, Sociological Abstracts, Scopus, PsycINFO and PsychiatryOnline) and grey literature sources. Thirty studies were yielded across 35,446 participants from 12 locations. This review contributes to a systematic understanding of the factors affecting police work-related stress by identifying six predictors, four mediators and three moderators. It then discusses limitations and future research.

Background: Although protective in secondary stroke prevention of intracranial arterial stenosis (ICAS), it is uncertain if the benefits of leisure time physical activity (LTPA) extend to asymptomatic ICAS or extracranial carotid stenosis (ECAS). Therefore, we sought to determine LTPA's relationship with ECAS and ICAS in a stroke-free, race-ethnically diverse cohort., Methods: This cross-sectional study included participants from the magnetic resonance imaging substudy of the Northern Manhattan Study, of whom 1274 had LTPA assessments at enrollment. LTPA was represented continuously as metabolic equivalent score (MET-score) and ordinally as model-based cluster analysis (LTPA-cluster), both based on the same LTPA assessments. We evaluated ECAS sonographically using carotid intima-media thickening and number of carotid plaques. ICAS was assessed with time-of-flight magnetic resonance angiograph and defined as ≥50% or ≥70% stenosis. We applied regression analyses to evaluate the association between LTPA with ECAS and ICAS, adjusting for confounders., Results: Of 1274 included participants (mean age 71±9 years; 60% women; 65% Hispanic), the mean MET-score was 10±16 and 60% were in a LTPA-cluster with any activity. Among those with carotid ultrasound (n=1234), the mean carotid intima-media thickening was 0.97±0.09 mm, and 56% of participants had at least one carotid plaque identified. Among those with magnetic resonance angiograph (n=1211), 8% had ≥50% ICAS and 5% had ≥70% ICAS. For ICAS, MET-score was associated with ≥70% ICAS (adjusted odds ratio per unit increase in MET-score [95% CI, 0.97 [0.94-0.99]) but not with ECAS measures (carotid intima-media thickening, adjusted β-estimate per unit increase in MET-score [95% CI], 0.002 [-0.003 to 0.006] or number of plaques, adjusted β-estimate [95% CI], 0.0001 [-0.0001 to 0.0003]). Substituting MET-score with LTPA-clusters replicated the association between ≥70% ICAS and LTPA (adjusted odds ratio per each increased LTPA-cluster [95% CI], 0.83 [0.70-0.99])., Conclusions: In this diverse stroke-free population, we found LTPA most strongly associated with asymptomatic ≥70% ICAS. Given the high-risk nature of ≥70% ICAS, these findings may emphasize the role of LTPA in people at risk for ICAS.

Background: Under a master protocol, open platform trials allow new experimental treatments to enter an existing clinical trial. Whether late-entry experimental treatments should be compared to all available or concurrently randomized controls is not well established. Using all available data can increase power and precision; however, drift in population parameters can yield biased estimates and impact type I error rate., Methods: We explored the application of methods developed to incorporate historical controls in two-arm trials to the analysis of a late-entry arm in a simulated open platform trial under varying scenarios of parameter drift. Methods explored include test-then-pool, fixed power prior, dynamic power prior, and multi-source exchangeability model approaches., Results/conclusions: Simulated trial results confirm that in the presence of no drift, naively pooling all controls increases power and produces more precise, unbiased estimates when compared to using concurrent controls only. However, under drift, pooling can result in type I error rate inflation or deflation and biased estimates. In the presence of parameter drift, methods that partially borrow non-concurrent data, either through a static weighting mechanism or through methods that allow the heterogeneity between non-concurrent and concurrent data to determine the degree of borrowing, are superior to naively pooling the data. However, compared to using concurrent controls only, these approaches cannot guarantee type I error control or unbiased estimates. Thus, concurrent controls should be used as comparators in confirmatory studies., 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.)

Introduction: Fatigue is one of the most commonly recorded patient symptoms that can result in deficits in aspects of psychomotor functioning, cognition, work performance and mood. Research shows that bright light and dim light therapy may be an efficacious way to reduce symptoms of fatigue. Still, the feasibility, scalability, individual treatment effects and adverse event heterogeneity of these treatments are unknown., Methods and Analysis: The current study evaluates the feasibility, acceptability and effectiveness of a series of personalised (N-of-1) interventions for virtual delivery of bright light therapy and dim light therapy versus usual care treatment for fatigue in 60 participants. We hypothesise that this study will provide valuable information about implementing virtual, N-of-1 randomised controlled trials (RCTs) for fatigue. It will also offer results about determining participants' ratings of usability and satisfaction with the virtual, personalised intervention delivery system; evaluating participants' improvement of fatigue symptoms; and, in the long term, identify ways to integrate N-of-1 light therapy trials into patient care., Ethics and Dissemination: This trial was approved by the Northwell Health Institutional Review Board. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalised trials will follow the Consolidated Standards of Reporting Trials extension for N-of-1 trials CENT 2015 reporting guidelines., Registration Details: This trial is registered in www., Clinicaltrials: gov (number NCT04707846)., Trial Registration Number: NCT04707846., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although work stress, turnover intention, and work-family conflicts among police officers have been extensively investigated, no studies have explored these issues simultaneously under the context of the coronavirus pandemic. Clearly, both work and family domains have been drastically affected by this global health crisis, and it is likely that each domain has a distinctive impact on work outcomes. Using survey data based on a representative random sample of 335 police officers in Hong Kong, this study examines the impacts of resource losses and gains across family and work domains on occupational stress and turnover intention amid the pandemic. A multiple regression indicates that both family-to-work and work-to-family conflicts lead to work stress and turnover intention among police officers. Among officers, supervisory support is negatively associated with turnover intention and moderates the impact of work-to-family conflicts on turnover intention. Finally, measures to mitigate work stress during public health disasters are discussed., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

In this article we address the problem of estimating minimum effective doses in dose-finding clinical trials of multidimensional treatment. We are motivated by a behavioral intervention trial where we introduce sedentary breaks to subjects with a goal to reduce their glucose level monitored over 8 hours. Each sedentary break regimen is defined by two elements: break frequency and break duration. The trial aims to identify minimum combinations of frequency and duration that shift mean glucose, that is, the minimum effective dose (MED) combinations. The means of glucose reduction associated with the dose combinations are only partially ordered. To circumvent constrained estimation due to partial ordering, we propose estimating the MED by maximizing a weighted product of combinationwise posterior gains. The estimation adopts an asymmetric gain function, indexed by a decision parameter ϵ , which defines the relative gains of a true negative decision and a true positive decision. We also introduce an adaptive ϵ -tapering algorithm to be used in conjunction with the estimation method. Simulation studies show that using asymmetric gain with a carefully chosen ϵ is critical to keeping false discoveries low, while ϵ -tapering adds to the probability of identifying truly effective doses (i.e., true positives). Under an ensemble of scenarios for the sedentary break study, ϵ -tapering yields consistently high true positive rates across scenarios and achieves about 90% true positive rate, compared to 68% by a nonadaptive design with comparable false discovery rate.

This paper presents the principle, design, fabrication, and characterization of Molecular Electronic Transducer (MET) dual-axis tilt sensors. The proposed sensor has a 3D-printed cylindrical channel inserted with four double-band electrodes and partially filled with a liquid electrolyte. The double-band electrodes were fabricated by wire winding with a ~0.1 mm anode-cathode distance under controlled tension. It allows the electrode to become any 3D coil rather than a 2D structure by microfabrication and exhibits good repeatability (±10%). The tilting changes the electrolyte level and electrode-electrolyte contact area, resulting in Faradaic current changes. The x -axis and the y -axis sensitivity reach 0.121 V/° and 0.154 V/°, respectively.

An extension of quantile regression is proposed to model zero-inflated outcomes, which have become increasingly common in biomedical studies. The method is flexible enough to depict complex and nonlinear associations between the covariates and the quantiles of the outcome. We establish the theoretical properties of the estimated quantiles, and develop inference tools to assess the quantile effects. Extensive simulation studies indicate that the novel method generally outperforms existing zero-inflated approaches and the direct quantile regression in terms of the estimation and inference of the heterogeneous effect of the covariates. The approach is applied to data from the Northern Manhattan Study to identify risk factors for carotid atherosclerosis, measured by the ultrasound carotid plaque burden.

Background: Intracranial stenosis is one of the most common causes of stroke worldwide. Several single nucleotide polymorphisms have been associated with intracranial atherosclerosis, which is inferred to be the most common underlying cause of intracranial large artery stenosis (ILAS). We previously reviewed known genetic variants related to ILAS in predominantly Asian cohorts, but their prevalence and role in ILAS among western multiethnic populations are uncertain., Methods: We leveraged existing imaging and genetic data from the Northern Manhattan Study, a multiethnic prospective cohort study. Based on literature review, we selected adiponectin Q (ADIPOQ) rs2241767 and rs182052, ring finger protein 213 (RNF213) rs112735431, apolipoprotein E (APOE) rs429358, phosphodiesterase 4D (PDE4D) rs2910829, lipoprotein lipase (LPL) rs320, and aldosterone synthase (CYP11B2) rs1799998 variants as candidates to explore. We defined ILAS as luminal stenosis >50% in any intracranial large artery using time-of-flight magnetic resonance angiography (MRA)., Results: We included 1109 participants (mean age 70 ± 9 years, 70% Hispanic, 60% women) in this study. ILAS was identified in 81 (7%) NOMAS participants. Logistic regression analyses adjusted for age, sex, principal components, and vascular risk factors showed ILAS prevalence associated with CYP11B2 rs1799998 under the dominant model (OR = 0.56, 95%CI: 0.35-0.89) and LPL rs320 heterozygote genotype (OR = 1.68, 95%CI: 1.05-2.71). The genotype distributions of ADIPOQ rs2241767 and rs182052, APOE rs429358 and CYP11B2 rs1799998 variants were significantly different among non-Hispanic white and Black, and Hispanic groups. When participants were further stratified by race/ethnicity, the estimates were consistent for CYP11B2 rs1799998 across race/ethnic groups but not for LPL rs320., Conclusion: The CYP11B2 rs1799998 variant may be a protective genetic factor for ILAS across race/ethnic groups, but the risk of ILAS associated with LPL rs320 varies by race/ethnic group. Further functional studies may help elucidate the role that these variants play in the pathophysiology of ILAS., (Copyright © 2022 Elsevier B.V. All rights reserved.)