Exploring the biomechanics and fatigue patterns of eccentric quasi-isometric muscle actions in the knee extensors and flexors.

PURPOSE: Eccentric quasi-isometric (EQI) resistance training is emerging as a promising option in sports medicine and rehabilitation. Despite prior research on EQI contractions in quadriceps and biceps brachii, their use in hamstring injury contexts is underexplored. Therefore, our study examines and contrasts the biomechanics and fatigue effects of EQI training on knee extensors and flexors. METHODS: Following familiarization, 16 healthy, active participants (9 men, 7 women; 23.5 ± 2.6 years, 72.1 ± 12.8 kg, 173.4 ± 10.7 cm) performed, in random order, four EQI contractions for knee extensions and flexions, respectively. EQI contractions were isotonically loaded to 70% of concentric (60°·s-1) maximal voluntary contraction. Rest between repetitions was set at three minutes, while four minutes separated each muscle group. Peak torque, mean torque, and optimal angle were evaluated pre- and post-bouts. Inter-repetition contraction time and angular velocity were also assessed. RESULTS: Average torque was 160.9 ± 44.2 and 71.5 ± 23.2 Nm for the extensors and flexors. Peak and mean torque significantly decreased for both extensors (p < 0.001, d = 0.70-0.71) and flexors (p ≤ 0.022, d = 0.36) after EQI contractions, respectively. However, the optimal angle increased for extensors (p < 0.001, d = 1.00) but not flexors (p = 0.811, d = 0.06). During EQI contractions, knee flexors exhibited greater intra-repetition velocity than extensors (p = 0.002; η2 = 0.50). Decreases in inter-repetition time and range of motion were more consistent for the extensors. CONCLUSIONS: Distinct responses exist when comparing EQI contractions of the knee extensors and flexors, particularly their effect on peak torque angles. These findings suggest knee flexors may require lower relative intensities to align more closely with extensor EQI contractions.

Interleaved Multi-Contact Peripheral Nerve Stimulation to Enhance Reproduction of Tactile Sensation: A Computational Modeling Study.

Peripheral nerve stimulation (PNS) is an effective means to elicit sensation for rehabilitation of people with loss of a limb or limb function. While most current PNS paradigms deliver current through single electrode contacts to elicit each tactile percept, multi-contact extraneural electrodes offer the opportunity to deliver PNS with groups of contacts individually or simultaneously. Multi-contact PNS strategies could be advantageous in developing biomimetic PNS paradigms to recreate the natural neural activity during touch, because they may be able to selectively recruit multiple distinct neural populations. We used computational models and optimization approaches to develop a novel biomimetic PNS paradigm that uses interleaved multi-contact (IMC) PNS to approximate the critical neural coding properties underlying touch. The IMC paradigm combines field shaping, in which two contacts are active simultaneously, with pulse-by-pulse contact and parameter variations throughout the touch stimulus. We show in simulation that IMC PNS results in better neural code mimicry than single contact PNS created with the same optimization techniques, and that field steering via two-contact IMC PNS results in better neural code mimicry than one-contact IMC PNS. We also show that IMC PNS results in better neural code mimicry than existing PNS paradigms, including prior biomimetic PNS. Future clinical studies will determine if the IMC paradigm can improve the naturalness and usefulness of sensory feedback for those with neurological disorders.

Community Reintegration After Traumatic Brain Injury.

Achieving effective community reintegration is important to maximize recovery in patients with traumatic brain injury, simultaneously limiting caregiver burden and improving satisfaction with quality of life. Certain medical complications that are common after brain injury may impact community reintegration, and should be addressed by the physician in a systematic approach. Additionally certain social and environmental factors such as mobility or return to work or school may arise, and should be addressed proactively by the physician. Inpatient/residential or outpatient programs with case management and a multi-disciplinary team can facilitate community reentry for patients, and should be considered when available.

A distributed, high-channel-count, implanted bidirectional system for restoration of somatosensation and myoelectric control.

Objective. We intend to chronically restore somatosensation and provide high-fidelity myoelectric control for those with limb loss via a novel, distributed, high-channel-count, implanted system.Approach.We have developed the implanted Somatosensory Electrical Neurostimulation and Sensing (iSens®) system to support peripheral nerve stimulation through up to 64, 96, or 128 electrode contacts with myoelectric recording from 16, 8, or 0 bipolar sites, respectively. The rechargeable central device has Bluetooth® wireless telemetry to communicate to external devices and wired connections for up to four implanted satellite stimulation or recording devices. We characterized the stimulation, recording, battery runtime, and wireless performance and completed safety testing to support its use in human trials.Results.The stimulator operates as expected across a range of parameters and can schedule multiple asynchronous, interleaved pulse trains subject to total charge delivery limits. Recorded signals in saline show negligible stimulus artifact when 10 cm from a 1 mA stimulating source. The wireless telemetry range exceeds 1 m (direction and orientation dependent) in a saline torso phantom. The bandwidth supports 100 Hz bidirectional update rates of stimulation commands and data features or streaming select full bandwidth myoelectric signals. Preliminary first-in-human data validates the bench testing result.Significance.We developed, tested, and clinically implemented an advanced, modular, fully implanted peripheral stimulation and sensing system for somatosensory restoration and myoelectric control. The modularity in electrode type and number, including distributed sensing and stimulation, supports a wide variety of applications; iSens® is a flexible platform to bring peripheral neuromodulation applications to clinical reality. ClinicalTrials.gov ID NCT04430218.

Stepped Palliative Care for Patients With Advanced Lung Cancer: A Randomized Clinical Trial.

Importance: Despite the evidence for early palliative care improving outcomes, it has not been widely implemented in part due to palliative care workforce limitations. Objective: To evaluate a stepped-care model to deliver less resource-intensive and more patient-centered palliative care for patients with advanced cancer. Design, Setting, and Participants: Randomized, nonblinded, noninferiority trial of stepped vs early palliative care conducted between February 12, 2018, and December 15, 2022, at 3 academic medical centers in Boston, Massachusetts, Philadelphia, Pennsylvania, and Durham, North Carolina, among 507 patients who had been diagnosed with advanced lung cancer within the past 12 weeks. Intervention: Step 1 of the intervention was an initial palliative care visit within 4 weeks of enrollment and subsequent visits only at the time of a change in cancer treatment or after a hospitalization. During step 1, patients completed a measure of quality of life (QOL; Functional Assessment of Cancer Therapy-Lung [FACT-L]; range, 0-136, with higher scores indicating better QOL) every 6 weeks, and those with a 10-point or greater decrease from baseline were stepped up to meet with the palliative care clinician every 4 weeks (intervention step 2). Patients assigned to early palliative care had palliative care visits every 4 weeks after enrollment. Main Outcomes and Measures: Noninferiority (margin = -4.5) of the effect of stepped vs early palliative care on patient-reported QOL on the FACT-L at week 24. Results: The sample (n = 507) mostly included patients with advanced non-small cell lung cancer (78.3%; mean age, 66.5 years; 51.4% female; 84.6% White). The mean number of palliative care visits by week 24 was 2.4 for stepped palliative care and 4.7 for early palliative care (adjusted mean difference, -2.3; P < .001). FACT-L scores at week 24 for the stepped palliative care group were noninferior to scores among those receiving early palliative care (adjusted FACT-L mean score, 100.6 vs 97.8, respectively; difference, 2.9; lower 1-sided 95% confidence limit, -0.1; P < .001 for noninferiority). Although the rate of end-of-life care communication was also noninferior between groups, noninferiority was not demonstrated for days in hospice (adjusted mean, 19.5 with stepped palliative care vs 34.6 with early palliative care; P = .91). Conclusions and Relevance: A stepped-care model, with palliative care visits occurring only at key points in patients' cancer trajectories and using a decrement in QOL to trigger more intensive palliative care exposure, resulted in fewer palliative care visits without diminishing the benefits for patients' QOL. While stepped palliative care was associated with fewer days in hospice, it is a more scalable way to deliver early palliative care to enhance patient-reported outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT03337399.

Using Data Science Tools to Reveal and Understand Subtle Relationships of Inhibitor Structure in Frontal Ring-Opening Metathesis Polymerization.

The rate of frontal ring-opening metathesis polymerization (FROMP) using the Grubbs generation II catalyst is impacted by both the concentration and choice of monomers and inhibitors, usually organophosphorus derivatives. Herein we report a data-science-driven workflow to evaluate how these factors impact both the rate of FROMP and how long the formulation of the mixture is stable (pot life). Using this workflow, we built a classification model using a single-node decision tree to determine how a simple phosphine structural descriptor (Vbur-near) can bin long versus short pot life. Additionally, we applied a nonlinear kernel ridge regression model to predict how the inhibitor and selection/concentration of comonomers impact the FROMP rate. The analysis provides selection criteria for material network structures that span from highly cross-linked thermosets to non-cross-linked thermoplastics as well as degradable and nondegradable materials.

Exploring the associations between skeletal muscle echogenicity and physical function in aging adults: A systematic review with meta-analyses.

BACKGROUND: Assessment and quantification of skeletal muscle within the aging population is vital for diagnosis, treatment, and injury/disease prevention. The clinical availability of assessing muscle quality through diagnostic ultrasound presents an opportunity to be utilized as a screening tool for function-limiting diseases. However, relationships between muscle echogenicity and clinical functional assessments require authoritative analysis. Thus, we aimed to (a) synthesize the literature to assess the relationships between skeletal muscle echogenicity and physical function in older adults (≥60 years), (b) perform pooled analyses of relationships between skeletal muscle echogenicity and physical function, and (c) perform sub-analyses to determine between-muscle relationships. METHODS: CINAHL, Embase, MEDLINE, PubMed, and Web of Science databases were systematically searched to identify articles relating skeletal muscle echogenicity to physical function in older adults. Risk-of-bias assessments were conducted along with funnel plot examination. Meta-analyses with and without sub-analyses for individual muscles were performed utilizing Fisher's Z transformation for the most common measures of physical function. Fisher's Z was back-transformed to Pearson's r for interpretation. RESULTS: Fifty-one articles (n = 5095, female = ∼2759, male = ∼2301, 72.5 ± 5.8 years, mean ± SD (1 study did not provide sex descriptors)) were extracted for review, with previously unpublished data obtained from the authors of 13 studies. The rectus femoris (n = 34) and isometric knee extension strength (n = 22) were the most accessed muscle and physical qualities, respectively. The relationship between quadriceps echogenicity and knee extensor strength was moderate (n = 2924, r = -0.36 (95% confidence interval: -0.38 to -0.32), p < 0.001), with all other meta-analyses (grip strength, walking speed, sit-to-stand, timed up-and-go) resulting in slightly weaker correlations (r:  -0.34 to -0.23, all p < 0.001). Sub-analyses determined minimal differences in predictive ability between muscle groups, although combining muscles (e.g., rectus femoris + vastus lateralis) often resulted in stronger correlations with maximal strength. CONCLUSION: While correlations were modest, the affordable, portable, and noninvasive ultrasonic assessment of muscle quality was a consistent predictor of physical function in older adults. Minimal between-muscle differences suggest that echogenicity estimates of muscle quality are systemic. Therefore, practitioners may be able to scan a single muscle to estimate full-body skeletal muscle quality/composition, while researchers should consider combining multiple muscles to strengthen the model.

Development of a Conceptual Model of Physical Functioning Limitations Experienced by Patients with Late-Stage Chronic Kidney Disease: A Qualitative Interview Study.

INTRODUCTION: Limitations in physical functioning are common in patients with late-stage chronic kidney disease (CKD) and can greatly affect their lives. Using patient interviews, this study reports experiences associated with physical functioning limitations for patients with late-stage CKD. METHODS: A preliminary conceptual model on concepts relevant to physical functioning limitations in patients with CKD was developed using data from a targeted literature review (patients with CKD stages IV-V) and previous interviews (patients with CKD stages IIIa-IIIb). The preliminary conceptual model informed a semi-structured interview guide designed to capture experiences of physical functioning limitations in patients with CKD. Patients with CKD stages IV-V who were not receiving dialysis were interviewed; their responses were used to develop a comprehensive conceptual model summarizing their experiences associated with physical functioning limitations. RESULTS: A total of 25 patients with CKD stage IV (n = 19) or V (n = 6) were interviewed. Based on patient responses, the reported concepts were grouped into one of six categories: physical functioning limitations/difficulties, behavioural impacts, activity participation restrictions, symptoms attributed to physical functioning limitations, impacts on sleep and emotional functioning impacts related to physical functioning limitations. Twenty-three patients reported concepts associated with physical functioning limitations, most frequently 'walking up and down stairs' (83%) and 'walking distances' (74%). All 23 patients also reported behavioural impacts, including 'need to rest/subsequent periods of rest' (100%) and 'participation in fewer activities' (91%). As well as summarizing the reported concepts, the comprehensive conceptual model shows how concepts may relate to one another; for example, challenging symptoms or difficulty completing tasks can lead to changes in patient behaviour such as purposely reducing or avoiding activities. CONCLUSIONS: This study found that patients with late-stage CKD not receiving dialysis who experience physical functioning limitations report a range of impacts on their daily lives. The comprehensive conceptual model summarizes the concepts reported and the relationships between them, providing a holistic understanding of how patients with late-stage CKD are affected by physical functioning limitations. Infographic available for this article. INFOGRAPHIC.

The Sacroiliac Joint Fusion Patient Population and Its Prevalence of Total Hip Arthroplasty.

INTRODUCTION: The prevalence of sacroiliac joint (SIJ) pathology generating lower back pain is increasing, often requiring SI joint fusion in refractory cases. Similarly, total hip arthroplasty (THA) is an increasing procedure in the older growing population. Prior SIJ fusion in patients undergoing THA has increased hip dislocation. This study aims to determine the prevalence of preexisting THA in SIJ fusion patients at our institution. METHODS: After institutional review board approval, we completed a retrospective review of consecutive SIJ fusion cases performed by fellowship-trained orthopaedic spine surgeons between October 2019 and June 2022. The senior surgeon reviewed pelvis radiographs to determine whether a THA was present. Patient demographics, surgical history, SIJ fusion date, and laterality information from study participants' medical records were collected and analyzed. RESULTS: We screened 157 consecutive cases and excluded 45 not meeting the inclusion criteria. One hundred twelve radiographs were reviewed, with seven additional patients excluded. The final analysis consisted of 105 patients (33M:72F). The mean age was 50.4 ± 13.8 years, and the mean body mass index was 29.1 ± 6.1 kg/m2. SIJ fusion laterality included 51 right (48.6%), 44 left (41.9%), and 10 bilateral (9.5%). One patient (0.95%) had a preexisting right THA, and two patients (1.9%) underwent ipsilateral THA after SIJ fusion. CONCLUSIONS: This study demonstrated a low prevalence (0.95%) of preexisting THA in SIJ fusion patients at our institution, similar to the THA prevalence of the total US population. Additional research is needed to determine the outcomes of patients with preexisting THA undergoing SIJ fusion.

Rubber Band Training Improves Athletic Performance in Young Female Handball Players.

This study's objective was to investigate the impact of a 10-week in season contrast rubber band training program on athletic performance in young female handball players. Youth athletes (15.8 ± 0.2 years) were randomly assigned to an intervention (n = 16) or a control group (n = 14). The intervention group performed contrast rubber band training (20 sessions over two weeks), while the control group maintained regular in-season training. The modified T-test, squat jump, countermovement jump, standing long jump, repeated sprint ability, 1-RM bench press and half squat, along with upper and lower limb force-velocity tests were performed. The intervention group experienced significantly larger performance enhancements than the control group in the modified T-test [p < 0.001; d = 1.45%Δ (intervention = -7.1, control = -0.8)], vertical jump [p ≤ 0.009; d ≥ 0.72; %Δ (8.4 < intervention < 19.8, 4.1 < control < 12.2)], 1-RM strength [p ≤ 0.04, d ≥ 0.80; %Δ (37.1 < intervention < 39.7, 7.2 < control < 11.2)], all force-velocity scores for the upper limbs [p ≤ 0.009; d ≥ 0.72; %Δ (21 < intervention < 82, 0.1 < control < 11.6)], three of four force-velocity scores for the lower limb performance [p ≤ 0.02; d ≥ 0.64; %Δ (6.4 < intervention < 31.3, 0.8 < control < 11.1)] and all repeated sprint times [p < 0.001; d ≥ 1.15; %Δ (-3.4 < intervention < -3.1, -1.9 < control < -0.5)]. It was concluded that ten weeks of contrast rubber band training positively affected most motor abilities in youth female handball athletes. Therefore, coaches and practitioners should consider utilizing contrast rubber band strength training as a time and resource-efficient means of improving physical fitness of youth handball players.

Metabolic loads and the costs of metazoan reproduction.

Reproduction includes two energy investments-the energy in the offspring and the energy expended to make them. The former is well understood, whereas the latter is unquantified but often assumed to be small. Without understanding both investments, the true energy costs of reproduction are unknown. We present a framework for estimating the total energy costs of reproduction by combining data on the energy content of offspring (direct costs) and the metabolic load of bearing them (indirect costs). We find that direct costs typically represent the smaller fraction of the energy expended on reproduction. Mammals pay the highest reproductive costs (excluding lactation), ~90% of which are indirect. Ectotherms expend less on reproduction overall, and live-bearing ectotherms pay higher indirect costs compared with egg-layers. We show that the energy demands of reproduction exceed standard assumptions.

Prevalence of total joint arthroplasty in the adult spine deformity population.

PURPOSE: The spine, hip, and knee are anatomically and biomechanically connected. Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are commonly employed to treat degenerative changes in the hip and knee, while fusion is used for spine degeneration. Spine deformity correction results in changes in sagittal alignment and pelvic parameters, and patients with stiff spines have higher rates of THA dislocation and revision due to instability. The goal of this study was to determine the prevalence of total joint arthroplasty (TJA) in adult spinal deformity (ASD) patients at our institution. METHODS: Following Institutional Review Board approval, we retrospectively reviewed a list of cases performed by the senior author from 4/2017 to 5/2021. Patients > 18 years old undergoing preoperative evaluation for symptomatic lumbar degeneration or ASD were included. Patients < 18 years old, those diagnosed with adolescent idiopathic scoliosis, and non-fusion cases were excluded. Perioperative full-length standing EOS images were examined for the presence or absence of THA, TKA, or both. Demographic data was collected from patient electronic medical records, and statistical analyses were completed. RESULTS: 572 consecutive cases were reviewed, and 322 were excluded. 250 cases (97M:153F) were included in the final analysis, with a mean age of 61.8 ± 11.2 years. A total of 74 patients had a TJA (29.4%). THA was present in 41 patients (16.4%), and TKA was present in 49 patients (19.6%). Males had a higher prevalence of TJA, THA, and TKA (29.9%, 16.5%, and 21.6%) than females (29.4%, 16.3%, and 18.3%). CONCLUSIONS: This study revealed a high prevalence TJA rate of 29.4% in ASD at our institution. This rate surpasses the prevalence rate reported among the general population in previous studies. High prevalence of patients with ASD and TJA may merit special surgical consideration.

Principles of experimental design for ecology and evolution.

Good experimental design is critical for sound empirical ecology and evolution. However, many contemporary studies fail to replicate at the appropriate biological or organizational level, so causal inference might have less vigorous support than often assumed. Here, I provide a guide for how to identify the appropriate scale of replication for a range of common experimental designs in ecological and evolutionary studies. I discuss the merits of replicating multiple scales of biological organization. I suggest that experimental design be discussed in terms of the scale of replication relative to the scale at which inferences are sought when designing, discussing and reviewing experiments in ecology and evolution. I also suggest that more conversations about experimental design are needed, and I hope this piece stimulates such conversation.

Multiplexed, multimodal profiling of the intracellular activity, interactions, and druggability of protein variants using LABEL-seq.

Multiplexed assays of variant effect are powerful tools for assessing the impact of protein sequence variation, but are limited to measuring a single protein property and often rely on indirect readouts of intracellular protein function. Here, we developed LAbeling with Barcodes and Enrichment for biochemicaL analysis by sequencing (LABEL-seq), a platform for the multimodal profiling of thousands of protein variants in cultured human cells. Multimodal measurement of ~20,000 variant effects for ~1,600 BRaf variants using LABEL-seq revealed that variation at positions that are frequently mutated in cancer had minimal effects on folding and intracellular abundance but could dramatically alter activity, protein-protein interactions, and druggability. Integrative analysis of our multimodal measurements identified networks of positions with similar roles in regulating BRaf's signaling properties and enabled predictive modeling of variant effects on complex processes such as cell proliferation and small molecule-promoted degradation. LABEL-seq provides a scalable approach for the direct measurement of multiple biochemical effects of protein variants in their native cellular context, yielding insight into protein function, disease mechanisms, and druggability.

A 3-step method for preparing cryopreserved samples of apheresis products for post-thaw analysis yields a higher percentage of viable cells.

BACKGROUND: Standard flow cytometry protocols for CD34+ cell enumeration designed for fresh samples are not appropriate for cryopreserved products. Special protocols have been developed to remove the cryoprotectant by quickly washing a freshly thawed sample. Exposing cells to a large volume of hypotonic solution and subsequent washing process was hypothesized to cause lab-induced cell death. Moreover, standard gating strategies must be altered to avoid reporting falsely high viabilities. STUDY DESIGN AND METHODS: We developed a novel method whereby thawed samples were diluted step-wise to 1:2 by 3 additions of 1/3 sample volume using 1% Human Albumin in Dextran 40 (10% Low Molecular Weight Dextran in 0.9% NaCl) separated by 5 min between each addition. An additional 1:10 dilution was required to obtain a desired cell concentration for flow cytometry testing resulting in a 1:20 dilution. RESULTS: Twenty samples were tested simultaneously in a method comparison; the new method demonstrated significant increases in mean cell viabilities for white blood cells, hematopoietic progenitor cells, and T cells as well as reduced standard deviations for each parameter. DISCUSSION: Slow, step-wise dilutions of freshly thawed samples of cryopreserved apheresis products to 1:20 yielded higher and more precise viability measurements compared to quickly washing samples to remove DMSO.

A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Social jet lag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.

Social jet lag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. Ten-week-old C57BL/6J mice (n = 40) were allocated to four groups: control sedentary (CON-SED), control exercise (CON-EX), social jet lag sedentary (SJL-SED), and social jet lag exercise (SJL-EX). CON mice were housed under a 12:12-h light-dark cycle. SJL was simulated by implementing a 4-h phase delay for 3 days to simulate "weekends," followed by a 4-h phase advance back to "weekdays," for 6 wk. EX mice had free access to a running wheel. Graded exercise tests (GXTs) and glucose tolerance tests (GTTs) were performed at baseline and after intervention to monitor the effects of exercise and social jet lag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle and decreased average running distance (P < 0.05). SJL-SED mice gained significantly more weight compared with CON-SED and SJL-EX mice (P < 0.01). SJL impaired fasting blood glucose and glucose tolerance compared with CON mice (P < 0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise and that proper circadian hygiene is necessary for maintaining health and performance.NEW & NOTEWORTHY In mice, disrupting circadian rhythms with social jet lag for 6 wk caused significant weight gain, higher fasting blood glucose, and impaired glucose tolerance compared with control. Voluntary exercise in mice experiencing social jet lag prevented weight gain, though the mice still experienced increased fasting blood glucose and impaired exercise performance compared with trained mice not experiencing social jet lag. Social jet lag seems to be a potent circadian rhythm disruptor that impacts exercise-induced training adaptations.

Multiply robust generalized estimating equations for cluster randomized trials with missing outcomes.

Generalized estimating equations (GEEs) provide a useful framework for estimating marginal regression parameters based on data from cluster randomized trials (CRTs), but they can result in inaccurate parameter estimates when some outcomes are informatively missing. Existing techniques to handle missing outcomes in CRTs rely on correct specification of a propensity score model, a covariate-conditional mean outcome model, or require at least one of these two models to be correct, which can be challenging in practice. In this article, we develop new weighted GEEs to simultaneously estimate the marginal mean, scale, and correlation parameters in CRTs with missing outcomes, allowing for multiple propensity score models and multiple covariate-conditional mean models to be specified. The resulting estimators are consistent provided that any one of these models is correct. An iterative algorithm is provided for implementing this more robust estimator and practical considerations for specifying multiple models are discussed. We evaluate the performance of the proposed method through Monte Carlo simulations and apply the proposed multiply robust estimator to analyze the Botswana Combination Prevention Project, a large HIV prevention CRT designed to evaluate whether a combination of HIV-prevention measures can reduce HIV incidence.

Group Coping Intervention in Patients With Chronic Graft-Versus-Host Disease: A Pilot Randomized Clinical Trial.

BACKGROUND: More than half the long-term survivors of allogeneic hematopoietic cell transplantation develop chronic graft-versus-host disease (GVHD), a debilitating inflammatory syndrome. Supportive interventions to assist survivors in coping with chronic GVHD are critically needed. PATIENTS AND METHODS: We conducted a pilot randomized clinical trial of a multidisciplinary group intervention (Horizons Program; n=39) versus minimally enhanced usual care (n=41) for patients with moderate or severe chronic GVHD. Horizons participants received 8 weekly sessions about GVHD and coping co-led by a transplant clinician and a behavioral health expert via a secure videoconferencing platform. Participants completed the following surveys before randomization, at 10 weeks, and at 18 weeks: Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) for quality of life (QoL), Lee Symptom Scale for symptom burden, and Hospital Anxiety and Depression Scale-Depression Symptoms (HADS) for mood. The primary endpoint was feasibility (≥50% enrollment, ≥80% attendance in half the sessions for the Horizons arm only, and ≥80% retention). We also explored preliminary efficacy of the Horizons intervention on changes in patient-reported outcomes with linear mixed effects models and estimates of effect size at 10 weeks. RESULTS: We enrolled and registered 80 (67.2%) of 119 eligible patients (mean age, 62 years; 48.8% female). Of the participants in the Horizons Program, 84.6% attended at least half the sessions. Of registered participants, 91.3% completed assessment follow-ups (Horizons, 35/39 [89.7%]; minimally enhanced usual care, 38/41 [92.7%]). Horizons participants reported improvements in QoL (b = 2.24; d=0.53), anxiety symptoms (b = -0.10; d=0.34), and depression symptoms (b = -0.71; d=0.44) compared with participants who received minimally enhanced usual care. CONCLUSIONS: Participation in a multidisciplinary group intervention study was feasible for patients with chronic GVHD, with promising signals for improving QoL and mood. A full-scale efficacy trial is needed to confirm effects on patient-reported outcomes.