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BACKGROUND: Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI). METHODS: The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEV1 (ppFEV1) of 70% or more, or those aged 18 years or older with ppFEV1 of 60% or more, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. Participants on both hypertonic saline and dornase alfa were randomly assigned to one of the two trials, and those on a single therapy were assigned to the applicable trial. All participants were then randomly assigned 1:1 to continue or discontinue therapy for 6 weeks using permuted blocks of varying size, stratified by baseline ppFEV1 (week 0; ≥90% or

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV1) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = −1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire–Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis. [ABSTRACT FROM AUTHOR]

ObjectiveTo determine the effect of state-level dependent coverage expansion (DCE) with and without other state health reforms on exit from dependent coverage for adolescents and young adults (AYA).Data sourcesAdministrative longitudinal data for 131,542 privately insured AYA in Massachusetts (DCE with other reforms) versus Maine and New Hampshire (DCE without other reforms) across three periods: prereform (1/00-12/06), poststate reform (1/07-9/10), and postfederal reform (10/10-12/12).Study designA difference-in-differences estimator was used to determine the rate of exit from dependent coverage, age at exit from dependent coverage, and re-uptake of dependent coverage among AYA in states with comprehensive reforms versus DCE only.Principal findingsImplementation of DCE with other reforms was significantly associated with a 23 percent reduction in exit from dependent coverage among AYA compared to the reduction observed for DCE alone. Additionally, comprehensive reforms were associated with over two additional years of dependent coverage for the average AYA and a 33 percent increase in the odds of regaining dependent coverage after a prior loss.ConclusionsFindings suggest that an individual mandate and other reforms may enhance the effect of DCE in preventing loss of coverage among AYA.

Wearable ExoNETs offer a novel, wearable solution to support and facilitate upper extremity gravity compensation in healthy, unimpaired individuals. In this study, we investigated the safety and feasibility of gravity compensating ExoNETs on 10 healthy, unimpaired individuals across a series of tasks, including activities of daily living and resistance exercises. The direct muscle activity and kinematic effects of gravity compensation were compared to a sham control and no device control. Mixed effects analysis revealed significant reductions in muscle activity at the biceps, triceps and medial deltoids with effect sizes of -3.6%, -4.5%, and -7.2% rmsMVC, respectively, during gravity support. There were no significant changes in movement kinematics as evidenced by minimal change in coverage metrics at the wrist. These findings reveal the potential for the ExoNET to serve as an alternative to existing bulky and encumbering devices in post-stroke rehabilitation settings and pave the way for future clinical trials. [ABSTRACT FROM AUTHOR]

Efficient muscle-tendon performance during cyclical tasks is dependent on both active and passive mechanical tissue properties. Here we examine whether age-related changes in the properties of muscle-tendon units (MTUs) compromise their ability to do work and utilize elastic energy storage. We empirically quantified passive and active properties of the medial gastrocnemius muscle and material properties of the Achilles tendon in young (∼6 mo) and old (∼32 mo) rats. We then used these properties in computer simulations of a Hill-type muscle model operating in series with a Hookean spring. The modeled MTU was driven through sinusoidal length changes and activated at a phase that optimized muscle-tendon tuning to assess the relative contributions of active and passive elements to the force and work in each cycle. In physiologically realistic simulations where young and old MTUs started at similar passive forces and developed similar active forces, the capacity of old MTUs to store elastic energy and produce positive work was compromised. These results suggest that the observed increase in the metabolic cost of locomotion with aging may be in part due to the recruitment of additional muscles to compensate for the reduced work at the primary MTU. Furthermore, the age-related increases in passive stiffness coupled with a reduced active force capacity in the muscle can lead to shifts in the force-length and force-velocity operating range that may significantly impact mechanical and metabolic performance. Our study emphasizes the importance of the interplay between muscle and tendon mechanical properties in shaping MTU performance during cyclical contractions.

A growing body of research on the mechanics and energetics of terrestrial locomotion has demonstrated that elastic elements acting in series with contracting muscle are critical components of sustained, stable and efficient gait. Far fewer studies have examined how the nervous system modulates muscle-tendon interaction dynamics to optimize 'tuning' or meet varying locomotor demands. To explore the fundamental neuromechanical rules that govern the interactions between series elastic elements (SEEs) and contractile elements (CEs) within a compliant muscle-tendon unit (MTU), we used a novel work loop approach that included implanted sonomicrometry crystals along muscle fascicles. This enabled us to decouple CE and SEE length trajectories when cyclic strain patterns were applied to an isolated plantaris MTU from the bullfrog (Lithobates catesbeianus). Using this approach, we demonstrate that the onset timing of muscle stimulation (i.e. stimulation phase) that involves a symmetrical MTU stretch-shorten cycle during active force production results in net zero mechanical power output, and maximal decoupling of CE and MTU length trajectories. We found it difficult to 'tune' the muscle-tendon system for strut-like isometric force production by adjusting stimulation phase only, as the zero power output condition involved significant positive and negative mechanical work by the CE. A simple neural mechanism - adjusting muscle stimulation phase - could shift an MTU from performing net zero to net positive (energy producing) or net negative (energy absorbing) mechanical work under conditions of changing locomotor demand. Finally, we show that modifications to the classical work loop paradigm better represent in vivo muscle-tendon function during locomotion.

ImportanceA timely, well-coordinated transfer from pediatric- to adult-focused primary care is an important component of high-quality health care, especially for youths with chronic health conditions. Current recommendations suggest that primary-care transfers for youths occur between 18 and 21 years of age. However, the current epidemiology of transfer timing is unknown.ObjectiveTo examine the timing of transfer to adult-focused primary care providers (PCPs), the time between last pediatric-focused and first adult-focused PCP visits, and the predictors of transfer timing.Design, setting, and participantsRetrospective cohort study of patients insured by Harvard Pilgrim Health Care (HPHC), a large not-for-profit health plan. Our sample included 60 233 adolescents who were continuously enrolled in HPHC from 16 to at least 18 years of age between January 2000 and December 2012. Pediatric-focused PCPs were identified by the following provider specialty types, but no others: pediatrics, adolescent medicine, or pediatric nurse practitioner. Adult-focused PCPs were identified by having any provider type that sees adult patients. Providers with any specialty provider designation (eg, gastroenterology or gynecology) were not considered PCPs.Main outcomes and measuresWe used multivariable Cox proportional hazards regression to model age at first adult-focused PCP visit and time from the last pediatric-focused to the first adult-focused PCP visit (gap) for any type of office visit and for those that were preventive visits.ResultsYounger age at transfer was observed for female youths (hazard ratio [HR], 1.32 [95% CI, 1.29-1.36]) who had complex (HR, 1.06 [95% CI, 1.01-1.11]) or noncomplex (HR, 1.08 [95% CI, 1.05-1.12]) chronic conditions compared with those who had no chronic conditions. Transfer occurred at older ages for youths who lived in lower-income neighborhoods compared with those who lived in higher-income neighborhoods (HR, 0.89 [95% CI, 0.83-0.95]). The gap between last pediatric-focused to first adult-focused PCP visit was shorter for female youths than male youths (HR, 1.57 [95% CI, 1.53-1.61]) and youths with complex (HR, 1.35 [95% CI, 1.28-1.41]) or noncomplex (HR, 1.24 [95% CI, 1.20-1.28]) chronic conditions. The gap was longer for youths living in lower-income neighborhoods than for those living in higher-income neighborhoods (HR, 0.80 [95% CI, 0.75-0.85]). Multivariable models showed an adjusted median age at transfer of 21.8 years for office visits and 23.1 years for preventive visits and an adjusted median gap length of 20.5 months for office visits and 41.6 months for preventive visits.Conclusions and relevanceMost youths are transferring care later than recommended and with gaps of more than a year. While youths with chronic conditions have shorter gaps, they may need even shorter transfer intervals to ensure continuous access to care. More work is needed to determine whether youths are experiencing clinically important lapses in care or other negative health effects due to the delayed timing of transfer.