Subject Burden Research Articles

Assessing how individuals conceptualize numeric pain ratings: validity and reliability of the Pain Schema Inventory (PSI-6) Short Form.

While numeric scales to represent pain intensity have been well validated, individuals use various conceptualizations when assigning a number to pain intensity, referred to as pain rating schema. The 18-item Pain Schema Inventory (PSI-18) quantifies pain rating schema by asking for numeric values for multiple mild, moderate or severe pain conditions. This study aimed to assess the validity and reliability of a shortened form of the PSI, using only 6 items (PSI-6). A secondary analysis was performed on two existing datasets. The first (n = 641) involved a community-based population that completed the PSI-18. The second (n = 182) included participants with chronic pain who completed the PSI-6 twice, one week apart. We assessed face validity, convergent validity, offset biases, test-retest reliability, and internal consistency of the PSI-6 compared to the PSI-18. Both the PSI-18 and PSI-6 demonstrated excellent face validity. The PSI-6 demonstrated excellent convergent validity relative to the PSI-18, with correlations from r = 0.88 to 0.92. Bland-Altman plots revealed offset biases near zero (< 0.22 on 0-10 scale) across all categories of mild, moderate, severe and average pain. Internal consistency was excellent, with Cronbach's Alpha = 0.91 and 0.80, for PSI-18 and PSI-6 respectively. Test-retest reliability of the PSI-6 was high with correlations from r = 0.70-0.76. The PSI-6 is a valid and reliable tool to assess pain rating schema with reduced subject burden, to better interpret individuals' pain ratings and adjust for inter-individual variability.

Wearable sensor and machine learning estimate tendon load and walking speed during immobilizing boot ambulation

The purpose of this study is to develop a wearable paradigm to accurately monitor Achilles tendon loading and walking speed using wearable sensors that reduce subject burden. Ten healthy adults walked in an immobilizing boot under various heel wedge conditions (30°, 5°, 0°) and walking speeds. Three-dimensional motion capture, ground reaction force, and 6-axis inertial measurement unit (IMU) signals were collected. We used a Least Absolute Shrinkage and Selection Operator (LASSO) regression to predict peak Achilles tendon load and walking speed. The effects of altering sensor parameters were also explored. Walking speed models (mean absolute percentage error (MAPE): 8.81 ± 4.29%) outperformed tendon load models (MAPE: 34.93 ± 26.3%). Models trained with subject-specific data performed better than models trained without subject-specific data. Removing the gyroscope, decreasing the sampling frequency, and using combinations of sensors did not change the usability of the models, having inconsequential effects on model performance. We developed a simple monitoring paradigm that uses LASSO regression and wearable sensors to accurately predict (MAPE ≤ 12.6%) Achilles tendon loading and walking speed while ambulating in an immobilizing boot. This paradigm provides a clinically implementable strategy to longitudinally monitor patient loading and activity while recovering from Achilles tendon injuries.

Multitissue responses to exercise: a MoTrPAC feasibility study.

We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25 ± 2 yr, 12 M, 8 W) completed an endurance exercise bout (n = 8, 40 min cycling at 70% V̇o2max), a resistance exercise bout (n = 6, ∼45 min, 3 sets of ∼10 repetition maximum, 8 exercises), or a resting control period (n = 6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2 h, and 3.5 h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (periumbilical) biopsies were taken before and ∼4 h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) was reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, whereas skeletal muscle was transcriptionally more responsive than adipose 4 h postexercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.NEW & NOTEWORTHY This study highlights the feasibility of key aspects of the MoTrPAC adult human clinical protocols. This initial preview of what can be expected from acute exercise trial data from MoTrPAC provides an impetus for scientists to design exercise studies to interlace with the rich phenotypic and -omics data that will populate the MoTrPAC DataHub at the completion of the parent protocol.

Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes

Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10−4), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10−3), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10−8; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.

Anticipatory Anxiety, Familiarization, and Performance: Finding the Sweet Spot to Optimize High-Quality Data Collection and Minimize Subject Burden.

Accurate baseline data are essential for researchers to determine an intervention’s effects yet may be affected by anticipatory anxiety and assessment familiarity. Familiarization sessions help establish accurate baseline data. High-intensity functional training (HIFT) elicits performance outcomes based on constantly varied workouts. It is unclear how familiarization affects anticipatory anxiety and workout performance among HIFT novices. Familiarization was hypothesized to decrease anxiety and improve workout performance. Sixteen college-aged subjects (62.5% women, 20.2 ± 1.14 years) completed one introductory and four sessions of the same workout. All subjects were recreationally trained with no HIFT experience. State and trait anxiety were assessed at the first session. During the workout sessions, state anxiety (SQALS) was assessed upon arrival at the gym (SQALS 1), after learning the workout protocol (SQALS 2), and when the workout concluded (SQALS 3). A significant main effect of the number of previous sessions on workout performance was observed (p = 0.011). A repeated-measures ANOVA showed a main effect of time on SQALS 1 (p < 0.001), SQALS 2 (p < 0.001), and SQALS 3 (p < 0.001). Our results suggest implementing two familiarization sessions for our HIFT-based workout was sufficient to decrease anxiety and establish a baseline measurement. Future research should examine if this remains true for other types of HIFT-based workouts.

A Protocol to Assess Adult Outcomes at 30 Years Following Preterm Birth.

Among the most intense adversity experiences for infants is premature birth. Early birth marks the beginning of a life course that broadly affects families, healthcare, education, social systems, and the survivors themselves. For many, the transition to adulthood is challenging and often hampered by cognitive, physical and mental health, and motor and independence difficulties. The aim of this study was to share a comprehensive protocol of a 10th follow-up study of premature infants in their 30s. The protocol accounts for stress during the neonatal period, the cumulative context (risk and protection) of development, biological and epigenetic mechanisms, and individual resilience. The prospective, five-group longitudinal design includes 215 term-born and preterm-born individuals with various neonatal morbidities at ages 30-35 years. Adult outcomes include health, adaptive, executive function, work, and social competence. Novel measures are four system indicators of allostatic load (AL) and epigenetics. Contextual measures include socioeconomic risk and individual resilience. All measures were selected based on coherence with constructs of the scientific aims, strong psychometrics, continuity for repeated measures, and minimal subject burden. Objective assessments include body composition imaging, exercise testing, blood and saliva collection, and actigraphy. The two-phase protocol takes approximately 8 hours. After an 11-month COVID-19 pause, participant response has been strong. As of May 2022, 75 participants have completed the full protocol, and 99 have consented to participate. When socioeconomic risk is controlled, we hypothesize that life course trajectories in physical and psychological health, adaptive function, and executive function will differ between term and preterm neonatal morbidity groups. AL will vary across groups and contribute to outcomes. We expect proximal protection and resilience to mediate the cumulative medical and socioeconomic risk and AL. Epigenome-wide DNA methylation, with estimates of age acceleration, will be examined across groups and explored in longitudinal associations with medical risk, socioeconomic status, and protection. To our knowledge, this is the only U.S. study of premature infants aged 30-35 years. With millions of preterm-born individuals reaching adulthood, the protocol incorporates molecular and genetic biomarkers in a life course developmental examination to inform the timing and content of interventions.

Increasing the Cognitive Screening Efficiency of Global Phase III Trials in Early Alzheimer Disease: The Cognitive Task Force.

A Cognitive Task Force (CTF) was established for the MissionAD program with the aim of reducing the screen failure (SF) rate to ∼30% and thereby reduce unnecessary subject burden, site burden, and excess trial costs. The MissionAD program consisted of 2 global phase 3 studies evaluating the BACE inhibitor elenbecestat in subjects with early Alzheimer disease. The CTF monitored and engaged with MissionAD clinical sites to provide support through collegial discussions to maximize the efficiency of the preconsent recruitment phase. The CTF significantly improved cognitive screening efficiency in the MissionAD program, with a 24% decline in cognitive SF rate for the sites that the CTF contacted. The study-wide 11.5% reduction in cognitive SF rates were likely further driven by wider country-level initiatives in which CTF members held CTF-specific Investigator meetings with the recruitment staff, speaking to all sites on a country level regardless of their recruitment performance. The establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment.

Impact of a Family-Based Educational Intervention on Knowledge, Attitudes, and Burden of Alzheimer's Caregivers

Background: Family caregivers always encounter high levels of psychological distress and physical strain when caring for a person with dementia. Family-based intervention is an important option for providing effective and practical support. The study aimed to examine the effects of a specific educational intervention on improving Alzheimer's caregivers' knowledge and attitudes and explore how it reduces their subjective burdens. Material and Methods: A quasi-experimental research design was used with a purposive sample of 80 Alzheimer caregivers recruited conveniently from the Geriatric Society Association located at Almontazahat District, Jeddah, Saudi Arabia. To achieve the objectives of the current study 4 tools were used including demographic and personal data, Alzheimer's Disease Knowledge Scale (ADKS), The Dementia Attitudes Scale, and the burden scale of caregivers. Validity and reliability of the tools were confirmed and Cronbach's alpha of the Dementia Attitudes Scale was 0.87 and Cronbach's alpha of the burden scale of caregivers 0.941. Results: the age of the studied subjects ranged from 20 to 60 years with a mean of 35.6±12.2 years. the studied subject's knowledge level and attitudes were improved post-intervention than before. These differences were statistically significant (t: 108.008, P:&lt;0.001). While, the studied subject's disease burden level was decreased post-intervention than before These differences were statistically significant (t: 8.378, P:&lt;0.001). There is a weak positive significant relation between the studied subject's knowledge level and attitude regarding dementia (r:0.286, P:0.010). Whereas there is no correlation noted between knowledge level and caregiver burden with no statistical significance (r: -.048, P: 0.674). Conclusion and recommendation: the findings concluded that the studied subject's knowledge, attitude, and burden level were improved post-intervention than before with statistically significant differences. Therefore, it is recommended to develop a well-planned and structured educational program should be undertaken to improve the level of awareness and contribute to a better understanding of AD and dementia. Keywords: Alzheimer's burden, caregivers' attitudes, families, intervention, knowledge.

Test of Reliability and Validity of Impulsiveness Scale Among Married Chinese.

IntroductionThe Brief Barratt Impulsiveness Scale (BBIS) can be used in large scale rapid assessments and improves data quality while reducing subject response burden. It has been verified to have good reliability and cross-cultural consistency in multiple countries. However, there are no tests of impulsivity for the Chinese married population.AimTo investigate the applicability of the BBIS among the Chinese married population.MethodsThe BBIS was administered to 664 married middle-aged adults (sample 1) for item analysis and exploratory factor analysis (EFA), and to 758 married middle-aged adults (sample 2) for confirmatory factor analysis (CFA). At the same time, the trait anger scale (TAS), the quality marriage index (QMI) and the emotion reactivity scale (ERS) are selected as the calibration standards to test the correlation validity of the calibration standards.ResultsBBIS includes 8 items, which are composed of two dimensions of poor self-control and behavioral impulsivity; the two dimensions explained 68.10% of the total variance. CFA demonstrated that the fit index of the two-factor structure of the scale was good (χ2/df=2.315, RMSEA=0.042, RFI=0.971, CFI=0.989, NFI=0.982, IFI=0.990). The internal consistency reliability of each dimension and total scores were 0.824, 0.826 and 0.787, respectively. Total BBIS scores were significantly positively correlated with trait anger and emotional reactivity, and showed a significant negative correlation with marital quality. The Chinese version of BBIS had measurement equivalence between men and women.ConclusionThe BBIS has good reliability and validity in the Chinese married population, and the measurement results can be compared across groups between different genders, which can be used as a suitable tool for impulse related research.

Early Stopping in Experimentation With Real-Time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test.

Introduction: Functional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed.Methods: Voxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on target statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR).Results: Use of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 min on a 12 min scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters.Conclusion: A systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects.

A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation

BackgroundIn the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aβ) levels consistent with the presence of Alzheimer’s disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs.MethodsHealthy elderly subjects (n = 200; age 65–70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aβ1-42 concentrations, plasma Aβ1-40, Aβ1-42, neurofilament light, and total Tau concentrations were measured. Aβ1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier.ResultsTwo hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65–86) years. Twenty-four (27.3%) were Aβ positive for AD (age 65–83). The results of the logistic regression classifier showed that predictive features for Aβ positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10).ConclusionThis algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aβ levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs.Trial registrationISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).

Sleep pattern gender differences and fragmentation in postpartum parents of twins.

ObjectiveParents of newborn twins are at risk for both shortened sleep duration and sleep discontinuity. The purpose of this study was to characterize weekday and weekend sleep duration, sleep continuity, and awakenings in both mothers and fathers of newborn twins during the first 3 months at home.Material and MethodsSleep-wake parameters were assessed at two time points using self-report diaries and actigraphy in 75 families with newborn twins. To assess sleep on weekdays and weekends with minimal subject burden, actigraphy recordings of both parents commenced at 9:00 p.m. Saturday and terminated at 9:00 p.m. Tuesday.ResultsMean sleep duration over 24 hours for parents of twins ranged between 6.7 and 7.5 hours during the first 3 months postpartum and did not significantly differ on weekdays or weekends for mothers. Weekend sleep was more fragmented for fathers at both one month and three months with more awakenings, compared to weekday sleep. Mothers had more fragmented night sleep compared to fathers at one month. In contrast, at three months postpartum fathers had shorter total sleep time and night sleep time, but fewer night awakenings on weekdays than mothers. No differences were observed in weekend sleep duration or sleep patterns between mothers and fathers at three months.DiscussionConsolidated sleep periods for both parents averages three hours or less during the first three months postpartum and sleep for both parents is fragmented. In families with newborn twins, the extent of sleep disruption for mothers and fathers is similar.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AimsHTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).MethodsPart A was a four‐treatment open label sequential study in healthy elderly investigating 10–83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five‐treatment randomized, double‐blind, placebo and physostigmine controlled cross‐over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.ResultsPharmacokinetics of HTL0009936 showed dose‐proportional increases in exposure with a mean half‐life of 2.4 hours. HTL0009936 was well‐tolerated with transient dose‐related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99–10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18–7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.ConclusionsHTL0009936 showed well‐characterized pharmacokinetics and single doses were safe and generally well‐tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Predictive value of carotid artery ultrasonography for the risk of coronary artery disease.

To assess carotid intima-media thickness (IMT), carotid plaques, and cardiovascular risk factors in patients with suspected coronary artery disease (CHD) to determine their association and predictive value for CHD. We performed duplex Doppler ultrasonography of the carotid arteries and coronary angiography or CT in 480 patients with suspected CHD, and investigated their personal and medical histories. Patients were then assigned to the CHD or the control group depending on the presence of coronary lesions. Ultrasonography was performed the morning after admission prior to any treatment, coronary angiography, or CT. Carotid plaques were mainly distributed in the common carotid artery bifurcation, with a significant difference between the CHD and control groups. Plaque incidence (80%) and IMT were significantly higher (P < .001 and P = .012, respectively) in the CHD (80% and 0.84 ± 0.21 mm) than in the control group (49% and 0.76 ± 0.18 mm). The factors significantly associated with CHD were introduced into a multivariate regression model. Male subject (OR = 1.569, 95%CI 1.004-2.453; P = .048) and plaque burden (OR = 0.457, 95%CI 0.210-0.993; P = .048) were significant predictors for CHD occurrence. The presence of carotid plaques performed significantly better than IMT and the Framingham risk score for predicting CHD lesions (P < .001 for both). CHD patients showed higher percentage of clinical (plaques) or subclinical (IMT) carotid artery wall change, and the presence of carotid plaques showed better predictive value than IMT and Framingham risk score for the presence of coronary artery lesions.

Considerations for Measurement of Sodium Intake.

Current salt consumption is the major risk factor for hypertension and consequently cardiovascular disease (CVD). Accurate measurement of Na intake is an important component of developing dietary interventions to treat hypertension and lower CVD risk. Given that existing methods have a large subject burden, quick and practical ways to assess Na intake in individuals, particularly in hypertensive subjects, are needed. Such tools may be used for motivation to quantify salt intake and to set targets for lifestyle changes for prevention of CVD within a clinic setting. Patients at high risk of development of CVD may be identified and targeted for motivational interviewing. They may also be used as part of cardiac rehabilitation programs and will allow individuals to measure their own intake and to see the results of their individual action.

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 μg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.

Machine learning-based cognitive impairment classification with optimal combination of neuropsychological tests.

IntroductionAn extensive battery of neuropsychological tests is currently used to classify individuals as healthy (HV), mild cognitively impaired (MCI), and with Alzheimer's disease (AD). We used machine learning models for effective cognitive impairment classification and optimized the number of tests for expeditious and inexpensive implementation.MethodsUsing random forests (RF) and support vector machine, we classified cognitive impairment in multi‐class data sets from Rush Religious Orders Study Memory and Aging Project, and National Alzheimer's Coordinating Center. We applied Fisher's linear discrimination and assessed importance of each test iteratively for feature selection.ResultsRF has best accuracy with increased sensitivity, specificity in this first ever multi‐class classification of HV, MCI, and AD. Moreover, a subset of six to eight tests shows equivalent classification accuracy as an entire battery of tests.DiscussionsFully automated feature selection approach reveals six to eight tests comprising episodic, semantic memory, perceptual orientation, and executive functioning can accurately classify the cognitive status, ensuring minimal subject burden.

Family caregivers of children and adolescents with rare diseases: a novel palliative care intervention

ObjectiveTo develop and pilot test a palliative care intervention for family caregivers of children with rare diseases (FAmily-CEntered pediatric Advance Care Planning-Rare (FACE-Rare)).MethodsFACE-Rare development involved an iterative, family-guided process including...

Perceived Burden of Completion of Patient-Reported Outcome Measures in Clinical Trials:: Results of a Preliminary Study.

Understanding the perceived burden of clinical trial participation is an important element of patient-centric trial design and conduct. We report the results of a study to gain preliminary insights into the perceived burden associated with patient-reported outcome (PRO) data collection among a sample (n = 61) of volunteers from the general population including people with various health conditions resulting in chronic pain. Participants identified morning completion as more burdensome than completion of PRO measures in the evening. Weekly completion was perceived as less burdensome than daily, and twice-a-day more burdensome than once-a-day. Our results, while not generalizable in isolation, provide a valuable starting point to understand the complex construct of subject burden. This preliminary work is intended to be a catalyst for more in-depth research to better understand and predict burden and acceptable burden thresholds in clinical trials. Understanding subject burden is a vital component of human subject research that will be valuable in helping to inform future clinical trial designs.

A text message delivered smoking cessation intervention: Design and rationale of the Text My Quit Study

IntroductionSmoking cessation interventions delivered through mobile technologies offer promise as an effective intervention tool. However, most existing programs have not been empirically tested, were not developed with end-user participation, and/or do not address evidence-based cognitive and behavioral variables shown to enhance smoking cessation in clinical trials. In addition, many programs tested in research trials have required users to access the internet and/or a smartphone app to access all program features, limiting the potential reach of those programs. Methods/designThis study is a randomized controlled trial testing the efficacy of the TMQ intervention for smoking cessation. All participants are randomly assigned to receive 12 weeks of either; (1) a tailored smoking-cessation intervention delivered 100% through text messaging (TMQ), or (2) non-smoking-related text messages serving as a control for contact and subject burden (Mojo). Assessments are conducted at baseline, 3- and 6-month follow-up. The primary outcome is prolonged abstinence using an intent-to-treat approach. To understand why TMQ may be more effective than Mojo, we will test several posited mechanisms of action (i.e., mediators) that may underlie intervention efficacy and will examine use of the TMQ integrated social support (ISS) network. At the end of treatment, semi-structured interviews will be conducted with TMQ participants. ConclusionsThis study will provide a rigorous test of an innovative smoking cessation program delivered 100% through text messages. Use of mixed methodologies will provide the opportunity to enhance our understanding of the user's experience with TMQ and identify areas for future enhancement and/or expansion.