Losing sleep influences dietary intake in children: a longitudinal compositional analysis of a randomised crossover trial.

BACKGROUND: Although inadequate sleep increases the risk of obesity in children, the mechanisms remain unclear. The aims of this study were to assess how sleep loss influenced dietary intake in children while accounting for corresponding changes in sedentary time and physical activity; and to investigate how changes in time use related to dietary intake. METHODS: A randomized crossover trial in 105 healthy children (8-12 years) with normal sleep (~ 8-11 h/night) compared sleep extension (asked to turn lights off one hour earlier than usual for one week) and sleep restriction (turn lights off one hour later) conditions, separated by a washout week. 24-h time-use behaviors (sleep, wake after sleep onset, physical activity, sedentary time) were assessed using waist-worn actigraphy and dietary intake using two multiple-pass diet recalls during each intervention week. Longitudinal compositional analysis was undertaken with mixed effects regression models using isometric log ratios of time use variables as exposures and dietary variables as outcomes, and participant as a random effect. RESULTS: Eighty three children (10.2 years, 53% female, 62% healthy weight) had 47.9 (SD 30.1) minutes less sleep during the restriction week but were also awake for 8.5 (21.4) minutes less at night. They spent this extra time awake in the day being more sedentary (+ 31 min) and more active (+ 21 min light physical activity, + 4 min MVPA). After adjusting for all changes in 24-h time use, losing 48 min of sleep was associated with consuming significantly more energy (262 kJ, 95% CI:55,470), all of which was from non-core foods (314 kJ; 43, 638). Increases in sedentary time were related to increased energy intake from non-core foods (177 kJ; 25, 329) whereas increases in MVPA were associated with higher intake from core foods (72 kJ; 7,136). Changes in diet were greater in female participants. CONCLUSION: Loss of sleep was associated with increased energy intake, especially of non-core foods, independent of changes in sedentary time and physical activity. Interventions focusing on improving sleep may be beneficial for improving dietary intake and weight status in children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ANZCTR ACTRN12618001671257, Registered 10th Oct 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367587&isReview=true.

Impact of text difficulty and visual emphasis on pediatric neuropsychological evaluation reports: The parent's perspective.

Objective: Despite varying opinions, little research has examined how to best write pediatric neuropsychology reports. Method: This study gathered input from 230 parents on how text difficulty (reading level) and visual emphasis (bullets, underline, italics) affect report readability and utility. We focused on the most-read report section: summary/impressions. Each parent rated the readability and usefulness of a generic summary/impressions section written in four different styles. The four styles crossed text difficulty (high school-vs-collegiate) with use of visual emphasis (absent-vs-present). Results: Parents found versions with easier text to be more clearly written, easier to follow, and easier to find information (p<.001). Parents rated those with harder text to be overly detailed, complex, hard to understand, and hard to read (p<.001). Visual emphasis made it easier to find key information and the text easier to follow and understand - but primarily for versions that were written in difficult text (interaction p≤.026). After rating all four styles, parents picked their preference. They most often picked versions written in easier text with visual emphasis (p<.001). Conclusions: Findings support writing styles that use easier text difficulty and visual emphasis.

Treatment of Lateral Epicondylitis: Is Surgery Still an Option?

Background: The prevailing trend for the treatment of lateral epicondylitis (LE) is nonsurgical. Although many providers consider LE surgery controversial, others consider surgical intervention in patients with recalcitrant symptoms. The purpose of this study is to analyze epidemiological changes in LE surgery over a 9-year period prior to the coronavirus pandemic in 2019. Methods: A cross-sectional analysis of the Texas health care database from 2010 to 2018 was performed. We analyzed all procedures performed for LE during the set time period using Current Procedure Terminology (CPT) codes. Statistical analyses included procedures performed, patient demographics, zone of residence, and insurance designation. Results: There were a total of 12802 records of LE with 1 or more associated surgical procedures. Lateral epicondylar debridement (with/without tendon repair) was the most common procedure recorded, followed by arthroscopic procedures and tendon lengthening. Overall incidence remained low and did not significantly change during the studied period; however, surgical case volumes were significantly higher in metropolitan areas and increased at a faster rate when compared with those of more rural regions. Commercial insurance was the most prevailing form of payment. The incidence was significantly higher in the age group between 45 and 64 years old and most commonly performed in Caucasian females. Conclusions: The benefit of surgery for the treatment of LE has yet to be completely elucidated; however, surgical intervention continues to be offered. Although the incidence of surgery for the treatment of LE remained low over the study period, the volume of cases in metropolitan areas increased at a fast rate between 2010 and 2018. The results of this study found that surgery is still a treatment option in some patients despite the controversy. Level of Evidence: Economic/Decision Analysis, Level IV.

Trajectory of Sleep, Depression, and Quality of Life in Pediatric HSCT Recipients.

Disrupted sleep is commonly reported during hematopoietic stem cell transplant. In this study, we use actigraphy to measure sleep parameters, and qualitative measures of quality of life, depression, and sleep in pediatric and young adult transplant recipients to describe their time course through transplant. Eight patients had evaluable actigraphy data, and 10 patients completed the surveys. The median age of the 6 male and 7 female participants was 13.94 years old. Sleep duration and efficiency measured by actigraphy were suboptimal prior to transplant, then declined to a nadir between Day +7 to +14. Self-reported sleep quality, depression, and quality of life were worst at Day +14 to +30 but improved by Day +100. Findings support efforts to improve sleep, which may improve recovery, mental health and quality of life.

A big step for MYC-targeted therapies.

The MYC proto-oncogene encodes a master transcriptional regulator that is frequently dysregulated in human cancer. Decades of efforts have failed to identify a MYC-targeted therapeutic, and this is still considered to be a holy grail in drug development. We highlight a recent report by Garralda et al. of a Phase 1 clinical trial of OMO-103 in patients with solid malignancies.

Impact of age on NIS2+™ and other non-invasive blood tests for the evaluation of liver disease and detection of at-risk MASH.

Background & Aims: Robust performance of non-invasive tests (NITs) across ages is critical to assess liver disease among patients with metabolic dysfunction-associated liver disease (MASLD). We evaluated the impact of age on the performance of NIS2+™ vs. other NITs. Methods: An analysis cohort (N = 1,926) with biopsy-proven MASLD was selected among individuals screened for the phase III RESOLVE-IT clinical trial and divided into ≤45, 46-55, 56-64, and ≥65 years groups. To avoid potential confounding effects, a well-balanced cohort (n = 708; n = 177/age group) was obtained by applying a propensity score-matching algorithm to the analysis cohort. Baseline values of biomarkers and NITs were compared across age groups using one-way ANOVA, and the impact of age and histology were compared through three-way ANOVA. The impact of age on NIT performance for the detection of at-risk metabolic dysfunction-associated steatohepatitis (MASH; MASLD activity score [MAS] ≥4 and fibrosis stage [F] ≥2) was also evaluated. Results: Age did not affect the distributions of NIS2+™ and APRI (aspartate aminotransferase-to-platelet ratio index), but significantly (p <0.0001) impacted those of NFS (NAFLD fibrosis score), FIB-4 (Fibrosis-4 index), and Enhanced Liver Fibrosis (ELF™) score. NIS2+™ was the only NIT on which fibrosis and MAS exerted a moderate to large effect. While the impact of fibrosis on APRI was moderate, that of MAS was low. The impact of age on FIB-4 and NFS was larger than that of fibrosis. NIS2+™ exhibited the highest AUROC values for detecting at-risk MASH across age groups, with stable performances irrespective of cut-offs. Conclusions: NIS2+™ was not significantly impacted by age and was sensitive to both fibrosis and MAS grade, demonstrating a robust performance to rule in/out at-risk MASH with fixed cut-offs. Impact and Implications: While metabolic dysfunction-associated steatotic liver disease (MASLD) can affect individuals of all ages, patient age could represent an important confounding factor when interpreting non-invasive test (NIT) results, highlighting the need for reliable and efficient NITs that are not impacted by age and that could be interpreted with fixed cut-offs, irrespective of patient age. We report the impact of age on different well-established NITs - among those tested, only two panels, NIS2+™ and APRI, were not impacted by age and can be used and interpreted independently of patient age. NIS2+™ was also sensitive to both fibrosis and MAS, further confirming its efficiency for the detection of the composite endpoint of at-risk MASH and its potential as a valuable candidate for large-scale implementation in clinical practice and clinical trials.

Which adolescents are more likely to complete home-based sleep manipulation trials?

OBJECTIVES: Attrition and nonadherence are common concerns that can distort findings in clinical trials. This study examines the potential for systematic attrition in the largest sample to date of adolescents undergoing sleep manipulation. METHODS: Using pooled data across two trials involving 242 adolescents, a cumulative logistic regression tested whether demographics and baseline sleep predicted study completion/adherence. RESULTS: Race, a composite measure of socioeconomic status, and its elements (e.g., income, education) individually predicted completion/adherence. When entered concurrently into a multivariate predictive model, only socioeconomic status and study (trial A vs. B) were significant. Adolescents from households with higher socioeconomic status were more likely to complete or adhere to the protocol than those from households with lower socioeconomic status, p < .001. CONCLUSIONS: Systematic attrition in sleep manipulation research could distort conclusions about under-resourced groups. Future sleep trials should intentionally measure systemic/structural factors and adopt strategies to recruit and retain participants from various backgrounds.

Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms.

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

Dorsal-to-palmar branch neuroanastomosis in horses undergoing palmar digital neurectomy does not reduce neuroma formation or improve outcome.

OBJECTIVE: Chronic foot pain, a common cause of forelimb lameness, can be treated by palmar digital neurectomy (PDN). Complications include neuroma formation and lameness recurrence. In humans, neuroanastomoses are performed to prevent neuroma formation. The aim of the study was to evaluate the outcome of horses undergoing dorsal-to-palmar branch neuroanastomosis following PDN. STUDY DESIGN: Retrospective case series. ANIMALS: Eighty-five horses with PDN and dorsal-to-palmar branch neuroanastomosis. METHODS: Medical records for horses undergoing this procedure at two hospitals between 2015 and 2020 were reviewed. Palmar and dorsal nerve branches of the PDN were transected and end-to-end neuroanastomosis was performed by apposition of the perineurium. Follow-up was obtained from medical records and telephone interviews. Success was defined as resolution of lameness for at least one year. RESULTS: Lameness resolved following surgery in 81/85 (95%) horses with 57/84 (68%) sound at one year. Postoperative complications occurred in 19/85 (22%) cases. The main limitations of the study were an incomplete data set, inaccurate owner recall, and variations in procedure. CONCLUSION: Compared to previous studies, this technique resulted in similar numbers of horses sound immediately after surgery, a comparable rate of postoperative neuroma formation but a higher recurrence of lameness rate at 1 year postoperatively. CLINICAL SIGNIFICANCE: End-to-end neuroanastomosis of the dorsal and palmar branches of the PDN does not reduce the rate of neuroma formation in horses. Long-term outcome was less favorable compared to previously reported PDN techniques.

Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma.

The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

Prospective, longitudinal assessment of subchondral bone morphology and pathology using standing, cone-beam computed tomography in fetlock joints of 2-year-old Thoroughbred racehorses in their first year of training.

BACKGROUND: Catastrophic injuries of the fetlock joints occur in Thoroughbred racehorses and are preceded by stress-induced bone injury. Early detection of subchondral bone injury is essential to prevent irreversible damage or bone failure. OBJECTIVES: To investigate the use of standing, robotic cone-beam computed tomography (CBCT) for assessing longitudinal changes in subchondral bone morphology and pathology of the fetlock joints associated with race training in young Thoroughbreds. STUDY DESIGN: Observational cohort study. METHODS: Forty-one 2-year-old Thoroughbred racehorses were recruited prior to the start of race training. Standing CBCT and radiographs of all 4 metacarpo-/metatarsophalangeal (MCP/MTP) joints were obtained at 0, 6 and 12 months. Hyperdensity, as an estimate of subchondral bone sclerosis, was measured in the distal third metacarpal (MC3)/metatarsal (MT3) bone and proximal phalanx (P1) at each time point on computed tomography. CBCTs were examined for subchondral bone pathology consisting of areas of hypodensity within regions of hyperdensity. RESULTS: Subchondral bone sclerosis increased significantly over time in the medial and lateral MC3/MT3 condyles and in the medial and lateral parasagittal grooves of MC3/MT3. The presence of subchondral bone pathology increased significantly over time in the medial and lateral palmar condyles of MC3/MT3, the lateral parasagittal groove, the medial dorsal condyle and the medial and lateral ridges of P1. MAIN LIMITATIONS: There was attrition of horses due to relocation, change in ownership, and retirement from racing. Husbandry, training regimens and racing schedules were not controlled for in the study. CONCLUSIONS: Standing CBCT is an efficient and effective screening tool for assessing subchondral bone morphology and identifying pathology of the fetlock joint in young Thoroughbred racehorses. CBCT may facilitate early detection of bone pathology allowing for timely intervention and prevention of more serious injuries.

High levels of sleep disturbance across early childhood increases cardiometabolic disease risk index in early adolescence: longitudinal sleep analysis using the Health Outcomes and Measures of the Environment study.

STUDY OBJECTIVES: This study examines the impact of sleep duration, bedtime, and sleep disturbance during early childhood on the risk of cardiometabolic disorder (CMD) in early adolescence. METHODS: Within the Health Outcomes and Measures of Environment Study, we examined sleep patterns of 330 children from ages 2 to 8 years and the relationship of these sleep patterns with cardiometabolic risk measures at age 12 (N = 220). We used a group-based semi-parametric mixture model to identify distinct trajectories in sleep duration, bedtime timing, and sleep disturbance for the entire sample. We then examined the associations between sleep trajectories and CMD risk measures using general linear models using both an unadjusted model (no covariates) and an adjusted model (adjusting for child pubertal stage, child sex, duration of breastfeeding, household income, maternal education, and maternal serum cotinine). RESULTS: In the unadjusted and adjusted models, we found significant differences in CMD risk scores by trajectories of sleep disturbance. Children in the "high" disturbance trajectory had higher CMD risk scores than those in the 'low' disturbance trajectory (p's = 0.002 and 0.039, respectively). No significant differences in CMD risk were observed for bedtime timing or total sleep time trajectories in the unadjusted or adjusted models. CONCLUSIONS: In this cohort, caregiver-reported sleep disturbance in early childhood was associated with more adverse cardiometabolic profiles in early adolescence. Our findings suggest that trials to reduce CMD risk via sleep interventions-which have been conducted in adolescents and adults-may be implemented too late.

Association of Systemic Lupus Erythematosus Disease Activity With Choroidal Thickness.

OBJECTIVE: To determine the association between disease activity and choroidal thickness in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a cohort study of 24 SLE patients and 13 healthy controls recruited at Washington University School of Medicine between June 2019 and November 2021. SLE disease activity was assessed using the SLE Disease Activity Index-2000 Responder Index-50 (S2K RI-50). Patients were divided into four groups: high disease activity/no lupus nephritis (HDA/no LN; S2K RI-50 > 4), HDA/active LN (HDA/active LN; S2K RI-50 > 4), low disease activity/inactive LN (LDA/inactive LN; S2K RI-50 ≤ 4), and LDA/no LN (LDA/no LN; S2K RI-50 ≤ 4). LDA/no LN patients were age-, sex-, and race-matched to healthy controls and patients in other SLE groups. Choroidal thickness of the right eye was measured blinded to disease activity on a horizontal section through the fovea on optical coherence tomography images taken within a week of disease assessment. RESULTS: Patients with HDA had choroidal thickening compared with matched patients with LDA. After controlling for multiplicity, choroidal thinning remained statistically significant at 1000 µm nasal to the fovea (308 ± 68 vs 228 ± 64 µm, p = 0.001). Choroidal thickness was not different between LDA/no LN and LDA/inactive LN or healthy controls. CONCLUSION: HDA in patient with SLE is associated with increased choroidal thickness whereas comorbid inactive LN did not affect choroidal thickness. Additional studies in a larger longitudinal cohort are needed to study whether choroidal thickness may be used as a noninvasive, adjunctive measure for disease activity in SLE.

Altered neuronal response to visual food stimuli in adolescents undergoing chronic sleep restriction.

STUDY OBJECTIVES: Poor sleep in adolescents can increase the risk of obesity, possibly due to changes in dietary patterns. Prior neuroimaging evidence, mostly in adults, suggests that lacking sleep results in increased response to food cues in reward-processing brain regions. Needed is a clarification of the mechanisms by which food reward processing is altered by the kind of chronic sleep restriction (SR) typically experienced by adolescents. This study aimed to elucidate the impact of sleep duration on response to visual food stimuli in healthy adolescents using functional neuroimaging, hypothesizing increased reward processing response after SR compared to a well-rested condition. METHODS: Thirty-nine healthy adolescents, 14-17 years old, completed a 3-week protocol: (1) sleep phase stabilization; (2) SR (~6.5 h nightly); and (3) healthy sleep (HS) duration (~9 h nightly). Participants underwent functional MRI while performing a visual food paradigm. Contrasts of food versus nonfood responses were compared within-subject between conditions of SR and HS. RESULTS: Under SR, there was a greater response to food stimuli compared to HS in a voxel cluster including the left ventral tegmental area and substantia nigra. No change in food appeal rating due to the sleep manipulation was detected. CONCLUSIONS: Outcomes of this study suggest that SR, as commonly experienced by healthy adolescents, results in the elevated dopaminergic drive of the reward network that may augment motivation to seek food in the context of individual food appeal and inhibitory profiles. Countermeasures that reduce food salience could include promoting consistent HS habits.

Sleep and circadian disruptors: Unhealthy noise and light levels for hospitalized pediatric patients.

Noise and light levels during hospitalizations can disrupt sleep and circadian health, resulting in worsened health outcomes. This study describes patterns of noise and light for inpatient children undergoing stem cell transplants. Objective meters tracked noise and light levels every minute for 6 months. Median overnight sound was 55 dB (equivalent to conversational speech). There were 3.4 loud noises (>80 dB) per night on average. Children spent 62% of the 24-h cycle in nonoptimal lighting, with daytime light dimmer than recommended 98% of the time. Over the 6-month period, the lowest overnight noise level recorded exceeded World Health Organization recommendations for sleep, with frequent spikes into ranges known to cause wakings. During the day, children were rarely exposed to light sufficient to preserve healthy circadian rhythms. Hospitals should address systematic environmental and workflow disruptors to improve the sleep and circadian health of patients, particularly those already at elevated risk for health morbidities.

Comparing the Driving Skills of Adolescents with Obstructive Sleep Apnea to Healthy Controls: The Results of a Case-Controlled Observational Study.

Auto crashes are a leading cause of death and injury among adolescents. Untreated obstructive sleep apnea (OSA) can cause sleepiness and inattention, which could negatively impact novice drivers, but OSA-related studies have focused on older drivers. This study used a driving simulator to examine whether licensed 16-19-year-old adolescents with OSA have diminished driving skills. Twenty-one adolescents with OSA and twenty-eight without OSA (both confirmed using polysomnography) completed two randomly ordered driving trials in a simulator (with induced distractions versus without). A mixed ANOVA examined the between-subjects effect of the OSA group, the within-subjects effect of the distraction condition, and the group-by-condition interaction effect on the ability to maintain lane position and the frequency of extended eye glances away from the roadway. T-tests were also used to examine group differences in reported sleepiness and inattention during daily life. The distraction task increased extended off-road glances and difficulties maintaining lane position (p < 0.001). However, adolescents with OSA did not display worse eye glance or lane position than controls and there were no significant group-by-condition interactions. Although the groups differed on polysomonographic features, there were also no significant differences in reported sleepiness or inattention. The distraction task negatively impacted both groups of adolescent drivers, but those with OSA did not fare differentially worse. Most adolescents in our study had mild OSA (median obstructive apnea-hypopnea index = 4.4), the most common form in the community. It remains possible that youth with more severe OSA would show increased driving impairment.

Combination Treatment to Improve Mucociliary Transport of Pseudomonas aeruginosa Biofilms.

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

Retention of Study Partners in Longitudinal Studies of Alzheimer Disease.

BACKGROUND: Study partners are required for all participants at Alzheimer's Disease Research Centers (ADRCs). Study partners' attitudes and beliefs may contribute to missed visits and negatively impact retention of participants in longitudinal AD studies. OBJECTIVE: Study partners (N = 212) of participants (Clinical Dementia Rating® [CDR]≤2) at four ADRCs were randomly surveyed to examine their facilitators and barriers to continued participation in AD studies. METHODS: Reasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models. Open-ended responses were characterized with a Latent Dirichlet Allocation topic model. RESULTS: Study partners participated for personal benefit and altruism. They emphasized personal benefits more when their participants had a CDR > 0 than when they had a CDR = 0. This difference declined with participant age. The majority of study partners rated their ADRC participation as positive and meeting their goals. Although half reported at least one complaint, very few regretted participating. Those who reported that ADRC participation fulfilled their goals or had fewer complaints were more likely to have perfect attendance. Study partners requested more feedback about test results and better management of study visits. CONCLUSION: Study partners are motivated by both personal and altruistic goals. The salience of each goal depends on their trust in researchers and the participant's cognitive status and age. Retention may improve with perceived goal fulfillment and fewer complaints. Potential areas for improving retention are providing more information about the participant's test results and better management of study visits.

Single-nucleus chromatin accessibility identifies a critical role for TWIST1 in idiopathic pulmonary fibrosis myofibroblast activity.

BACKGROUND: In idiopathic pulmonary fibrosis (IPF), myofibroblasts are key effectors of fibrosis and architectural distortion by excessive deposition of extracellular matrix and their acquired contractile capacity. Single-cell RNA-sequencing (scRNA-seq) has precisely defined the IPF myofibroblast transcriptome, but identifying critical transcription factor activity by this approach is imprecise. METHODS: We performed single-nucleus assay for transposase-accessible chromatin sequencing on explanted lungs from patients with IPF (n=3) and donor controls (n=2) and integrated this with a larger scRNA-seq dataset (10 IPF, eight controls) to identify differentially accessible chromatin regions and enriched transcription factor motifs within lung cell populations. We performed RNA-sequencing on pulmonary fibroblasts of bleomycin-injured Twist1-overexpressing COL1A2 Cre-ER mice to examine alterations in fibrosis-relevant pathways following Twist1 overexpression in collagen-producing cells. RESULTS: TWIST1, and other E-box transcription factor motifs, were significantly enriched in open chromatin of IPF myofibroblasts compared to both IPF nonmyogenic (log2 fold change (FC) 8.909, adjusted p-value 1.82×10-35) and control fibroblasts (log2FC 8.975, adjusted p-value 3.72×10-28). TWIST1 expression was selectively upregulated in IPF myofibroblasts (log2FC 3.136, adjusted p-value 1.41×10- 24), with two regions of TWIST1 having significantly increased accessibility in IPF myofibroblasts. Overexpression of Twist1 in COL1A2-expressing fibroblasts of bleomycin-injured mice resulted in increased collagen synthesis and upregulation of genes with enriched chromatin accessibility in IPF myofibroblasts. CONCLUSIONS: Our studies utilising human multiomic single-cell analyses combined with in vivo murine disease models confirm a critical regulatory function for TWIST1 in IPF myofibroblast activity in the fibrotic lung. Understanding the global process of opening TWIST1 and other E-box transcription factor motifs that govern myofibroblast differentiation may identify new therapeutic interventions for fibrotic pulmonary diseases.