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Context: Mindfulness interventions (yoga, meditation) in traumatic brain injury populations show promising improvements in injury outcomes. However, most studies include all injury severities and use in-person, general programming lacking accessibility and specificity to the nuance of concussion. Therefore, this study investigated the feasibility and preliminary effectiveness of an online, concussion-focused meditation intervention among young adults with a concussion history. Design: Unblinded, single-arm, pilot intervention. Methods: Fifteen young adults aged 18 to 30 with a concussion history within the past 5 years completed 10 to 20 minutes per day of online, guided meditations for 6 weeks. Feasibility was assessed using the Feasibility of Intervention Measure. Concussion symptoms were measured using the Rivermead Post-Concussion Symptom Questionnaire, perceived stress the Perceived Stress Scale-10, and mindfulness the Five Facet Mindfulness Questionnaire. Descriptive statistics described the study sample and determined intervention adherence and feasibility. Paired sample t tests were used to examine preintervention/postintervention changes in concussion symptoms, perceived stress, and mindfulness, with descriptive statistics further detailing significant t tests. Results: Fifteen participants were enrolled, and 12 completed the intervention. The majority completed 5+ days per week of the meditations, and Feasibility of Intervention Measure (17.4 [1.8]) scores indicated high feasibility. Concussion symptom severity significantly decreased after completing the meditation intervention (11.3 [10.3]) compared with before the intervention (24.5 [17.2]; t[11] = 3.0, P =.01). The number of concussion symptoms reported as worse than before their concussion significantly decreased after completing the meditation intervention (2.7 [3.9]) compared with before the intervention (8.0 [5.7]; t[11] = 3.7, P =.004). Postintervention, 83.33% (n = 10) reported lower concussion symptom severity, and 75.00% (n = 9) reported less concussion symptoms as a mild, moderate, or severe problem (ie, worse than before injury). Conclusions: Findings suggest positive adherence and feasibility of the meditation intervention, with the majority reporting concussion symptom improvement postintervention. Future research is necessary to expand these pilot findings into a large trial investigating concussion-specific meditation programming. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the clinical accuracy of a robotically assisted implant guidance system in partially edentulous patients without the use of postoperative CBCT. Materials and Methods: A total of 10 implants (7 patients) were placed in partially edentulous patients utilizing a robotically assisted implant guidance system. Following the implant placement, an intraoral scan was performed to register the implant position after attaching a scan body. The virtual plan and the postoperative intraoral scan with the scan bodies were exported as STL files and superimposed, and discrepancies were analyzed using Geomagic Control X software. Positional deviations were measured between the midpoint of the platform and apex of the planned and achieved implant positions. Results: Seven of the 10 implants in this study were defined as fully robotically guided, while 3 were partially robotically guided. For the fully robotic dynamically guided group, the mean deviation at the midpoint of the restorative platform of the implant, the apex of the implant, the top of the scan body, and the mean angular deviation were 1.31 ± 0.46 mm, 1.58 ± 0.61 mm, 1.11 ± 0.57 mm, and 2.34 ± 1.71 degrees, respectively. For the partially robotic dynamically guided cases, these values were 1.31 ± 0.49 mm, 1.45 ± 0.3 mm, 1.74 ± 0.47 mm, and 3.75 ± 2.53 degrees, respectively. Eight of the 10 implants (irrespective of full or partial guidance) showed a buccal displacement. Conclusions: Robotic surgery offers a level of accuracy similar to fully guided implant placement, without the need for a physical template, and allows for changes in the surgical plan at any time. The analytical method described in this study is an effective and radiation-free quality-control tool that can be used in implant dentistry as well as in other areas of dental research. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine factors associated with participation of community-dwelling older Australians (≥65 years) in the Exercise Right for Active Ageing program, consisting of 12 low- to moderate-intensity group exercise classes, delivered weekly, in person or online, by accredited exercise scientists and physiologists across Australia. Out of 6,949 participants recruited, 6,626 (95%) attended one or more classes and were included in the primary analysis, and 49% of participants attended all 12 classes. Factors associated with higher class attendance included participation in yoga/flexibility/mobility classes, attendance at a free trial class (adjusted incidence rate ratio [95% confidence interval]: 1.05 [1.03, 1.08]), and attending online classes (1.19 [1.11, 1.26]). Factors associated with lower class attendance included state of residence, living in inner regional areas (0.95 [0.93, 0.98]), and having two or more comorbidities (0.97 [0.95, 0.99]). High class attendance suggests that the Exercise Right for Active Ageing program was well received by older Australians, particularly in states less impacted by COVID-19 lockdowns. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of removable partial dentures (RPDs) on masticatory performance (MP) of partially edentulous subjects. Materials and Methods: Electronic database and hand searches were conducted to explore clinical trials reporting the evidence of the effect of metal- and acrylic-based RPDs on mastication. The validated objective and subjective measures of assessment of mastication were included. The article selection, data extraction, and assessment of risk of bias were conducted by two reviewers independently. Results: Out of 11,200 studies, 1 randomized controlled trial and 23 clinical trials met the inclusion criteria. Positive impact on different parameters of masticatory function after RPD treatment was reported in 14 studies. Subjective evaluation of chewing ability (CA) displayed an improvement in 83.3% of studies, while improvement was evidenced only in 69.5% of studies upon objective evaluation. Most studies reported data on free-end saddles. Of the 13 studies associated with bilateral free-end saddle dentures, 9 studies showed a positive effect on masticatory efficiency. Various factors were found to have an impact on the MP of RPDs. Conclusions: Subjective evaluation displays higher positive impact of RPDs in MP than objective evaluation. Assessment of patients' perspectives is important in clinical decision-making. Multiple factors affect the MP with RPD treatment. [ABSTRACT FROM AUTHOR]

Purpose: To compare the outcomes of immediate and delayed implant placement with bone-level tapered implants. Materials and Methods: In this post-market, multicenter prospective randomized controlled study with a primary endpoint of 1 year, 53 patients were randomized to receive either immediate implant placement (test group) or delayed implant placement (control group). The mean crestal bone level changes from implant loading to 12 months postloading were measured using standardized digital periapical radiographs. Changes in facial plate thickness (as measured on CBCT images), implant success and survival, implant stability, soft tissue changes, patient-centered outcomes, and adverse events were measured to assess outcomes between the test and control treatments at 12 months postloading. Results: Of the original 53 patients, 46 patients completed the study (23 in each group). Mean bone changes from loading to the 12-month follow-up were recorded with no statistically significant difference (P = .950) between the groups. The hypothesis was confirmed that immediate implant placement (test) in extraction sockets produces in similar outcomes as delayed placement (control). The test group was found to be similar to the control group (P = .022) in terms of mean changes in facial plate thickness. Implant survival and success were 95.8% in the test group and 92% in the control group. Stability in the control group was superior at the time of surgery, but there was no difference between the groups at implant loading, producing a nonsignificant P value of .563). Conclusions: This randomized controlled multicenter study showed comparable outcomes 1 year after prosthetic loading in the immediate and delayed implant placement groups. [ABSTRACT FROM AUTHOR]

Purpose: An inspiratory muscle warm-up (IMW) improves inspiratory muscle function, but the effects of high-intensity exercise are inconsistent. We aimed to determine the effects of high-intensity IMW on high-intensity exercise performance and muscle oxygenation. Methods: Ten healthy men (maximal oxygen uptake [ V ˙ O 2 max ] 52.2 [5.0] mL·kg–1·min–1) performed constant-load exercise to exhaustion on a cycle ergometer at V ˙ O 2 max under 2 IMW conditions: a placebo condition (PLA) and a high-intensity IMW condition (HIGH). The inspiratory loads were set at 15% and 80% of maximal inspiratory pressure, respectively. Maximal inspiratory pressure was measured before and after IMW. Oxyhemoglobin was measured in the vastus lateralis by near-infrared spectroscopy during exercise. Rating of perceived exertion (RPE) for a leg was measured after 1 and 2 minutes of exercise. Results: Exercise tolerance was significantly higher under HIGH than PLA (228 [49] s vs 218 [49] s, P =.003). Maximal inspiratory pressure was significantly increased by IMW under HIGH (from 125 [20] to 136 [25] cm H2O, P =.031). Oxyhemoglobin was significantly higher under HIGH than PLA at 80% of the total duration of exercise (P =.048). RPE for the leg was significantly lower under HIGH than PLA after 2 minutes of exercise (P =.019). Conclusions: Given that oxyhemoglobin is an index of local oxygen supply, the results of this study suggest that high-intensity IMW increases the oxygen supply to active limbs. It may also reflect a reduction in RPE in the leg. In addition, high-intensity IMW may improve exercise performance. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinsons disease; however, individuals with Parkinsons disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinsons disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinsons disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinsons disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more high risk factors for a genetic aetiology: early onset (

IntroductionRecruitment challenges in people with and without Down syndrome (DS) can delay research progress and risk sample bias. This study identified and quantified differences in research attitudes across populations of research enrollment decision-makers for individuals with and without DS.MethodsWe performed analyses using data from two registries: the University of California, Irvine Consent-to-Contact (C2C) Registry and DS-Connect. The former represented a sample of non-DS decision-makers (N = 4818), while for the latter, we excluded individuals with DS, leaving a population of DS family decision-makers (N = 976). We assessed scores on the Research Attitudes Questionnaire (RAQ) between DS and non-DS decision-makers. We compared total RAQ scores using linear regression and assessed item-level RAQ differences using proportional odds regression.ResultsMean total RAQ scores were not statistically different between decision-makers in the two registries, after adjusting for age, sex, race and ethnicity, education, and the coronavirus disease 2019 (COVID-19) time frame (Est. Diff = 0.11, 95% confidence interval [CI]: -0.22, 0.43; p = 0.531). However, in a pre-specified analysis, we did find evidence of differential attitudes on item-level RAQ scores. Specifically, decision-makers for participants with DS had increased odds of a more favorable response to the question of responsibility to help others (DS vs. non-DS: odds ratio [OR] = 1.26, 95% CI: 1.08, 1.48) and decreased odds of a more favorable response to the question regarding the belief that medical research would find cures for major diseases during their lifetime (DS vs. non-DS: OR = 0.77, 95% CI: 0.66, 0.90).DiscussionOur findings provide insights for researchers to develop strategies for recruiting individuals with and without DS into clinical research. The observed item-level differences warrant further investigation to instruct precise recruitment strategies.HighlightsResearch attitudes between decision-makers for individuals with Down syndrome (DS) and decision-makers without DS were observed to be similar on average.Item-level differences in research attitudes were observed to differ for DS and non-DS decision-makers.These results can help facilitate precise recruitment strategies for populations with DS.

ObjectiveAfter the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.DesignThese RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.SettingTransdisciplinary, international collaboration in university, specialty, and emergency practice.ResultsA total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.ConclusionsWhile the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.

ObjectiveTo describe the methodology used by the Reassessment Campaign on Veterinary Resuscitation (RECOVER) to re-evaluate the scientific evidence relevant to CPR in small and large animals, to newborn resuscitation, and to first aid and to formulate the respective consensus-based clinical guidelines.DesignThis report describes the evidence-to-guidelines process employed by RECOVER that is based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and includes Information Specialist-driven systematic literature search, evidence evaluation conducted by more than 200 veterinary professionals, and provision of clinical guidelines in the domains of Preparedness and Prevention, Basic Life Support, Advanced Life Support, Post-cardiac Arrest Care, Newborn Resuscitation, First Aid, and Large Animal CPR.SettingTransdisciplinary, international collaboration in academia, referral practice, and general practice.ResultsFor this update to the RECOVER 2012 CPR guidelines, we answered 135 Population, Intervention, Comparator, and Outcome (PICO) questions with the help of a team of Domain Chairs, Information Specialists, and more than 200 Evidence Evaluators. Most primary contributors were veterinary specialists or veterinary technician specialists. The RECOVER 2024 Guidelines represent the first veterinary application of the GRADE approach to clinical guideline development. We employed an iterative process that follows a predefined sequence of steps designed to reduce bias of Evidence Evaluators and to increase the repeatability of the quality of evidence assessments and ultimately the treatment recommendations. The process also allowed numerous important knowledge gaps to emerge that form the foundation for prioritizing research efforts in veterinary resuscitation science.ConclusionsLarge collaborative, volunteer-based development of evidence- and consensus-based clinical guidelines is challenging and complex but feasible. The experience gained will help refine the process for future veterinary guidelines initiatives.

ObjectiveTo systematically review evidence and devise treatment recommendations for basic life support (BLS) in dogs and cats and to identify critical knowledge gaps.DesignStandardized, systematic evaluation of literature pertinent to BLS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by 2 Evidence Evaluators, and findings were reconciled by BLS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk to benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.SettingTransdisciplinary, international collaboration in university, specialty, and emergency practice.ResultsTwenty questions regarding animal position, chest compression point and technique, ventilation strategies, as well as the duration of CPR cycles and chest compression pauses were examined, and 32 treatment recommendations were formulated. Out of these, 25 addressed chest compressions and 7 informed ventilation during CPR. The recommendations were founded predominantly on very low quality of evidence and expert opinion. These new treatment recommendations continue to emphasize the critical importance of high-quality, uninterrupted chest compressions, with a modification suggested for the chest compression technique in wide-chested dogs. When intubation is not possible, bag-mask ventilation using a tight-fitting facemask with oxygen supplementation is recommended rather than mouth-to-nose ventilation.ConclusionsThese updated RECOVER BLS treatment recommendations emphasize continuous chest compressions, conformation-specific chest compression techniques, and ventilation for all animals. Very low quality of evidence due to absence of clinical data in dogs and cats consistently compromised the certainty of recommendations, emphasizing the need for more veterinary research in this area.

ObjectiveTo systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.DesignStandardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.SettingTransdisciplinary, international collaboration in university, specialty, and emergency practice.ResultsSeventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.ConclusionsThese updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.

Purpose: To assess the effectiveness of converting a conventional mandibular denture (CMD) into a single-implant mandibular overdenture (SIMO). Materials and Methods: Edentulous patients received a new CMD and were randomly assigned to the CMD or SIMO group. For SIMO patients, a midline early-loaded implant was inserted and incorporated into the CMD after 3 weeks. Patient satisfaction and oral health--related quality of life were assessed at baseline and up to 1 year. Regression models were constructed using Generalized Estimating Equation (GEE). Results: After 12 months, 32 patients were assessed (CMD: n = 17; SIMO: n = 15). Significant improvement was observed for the SIMO group compared to baseline measures. Conclusions: SIMO may be considered an effective alternative for patients unsatisfied with their CMDs. [ABSTRACT FROM AUTHOR]

Purpose: To realize a systematic review with prospective meta-analysis aiming to compare the accuracy of static fully guided implant placement depending on the drill key modality (conventional drill key surgery systems vs newer keyless systems) and evaluate the impact of deviation factors. Materials and Methods: An electronic systematic search was conducted to identify prospective clinical trials matching inclusion criteria. The variables of interest were coronal global, apical, vertical, and angular deviations. The types of edentulism and surgical guide support were investigated as deviation factors. Meta-regression (mixed-effect model) was performed. Heterogeneity was assessed using Cochrane's I² test and interpretation thresholds. Results: A total of 1,233 implants in 475 patients were analyzed (18 studies included). Coronal global deviation was significantly lower in the keyless group than in the key group (-0.36 mm; 95% CI -0.62, -0.09; P = .008). Angulation control of the keyless system was superior to that of the key system (-0.36 degrees; 95% CI -0.75, 0.02; P = .063). Nonsignificant differences were found between both groups in apical (P = .684) and vertical deviations (P = .958). Significant influence of the type of edentulism (single, partial, total) and surgical guide support (tooth, mucosa, bone) on the overall amount of coronal global, apical, and angular deviations was found (P < .001). The lowest deviations were found in partial edentulism and tooth-supported surgical guide groups. (P < .001). Conclusions: Keyless static fully guided surgical systems allowed significantly better control of coronal and angular deviations than conventional systems. The types of edentulism and surgical guide support seemed to influence the positioning accuracy. [ABSTRACT FROM AUTHOR]

Purpose: Fran is one of the most popular CrossFit benchmark workouts used to control CrossFitters' improvements. Detailed physiological characterization of Fran is needed for a more specific evaluation of CrossFitters' training performance improvements. The aim of the study was to analyze the oxygen uptake ( V ˙ O 2 ) kinetics and characterize the energy system contributions and the degree of postexercise fatigue of the unbroken Fran. Methods: Twenty trained CrossFitters performed Fran at maximal exertion. V ˙ O 2 and heart-rate kinetics were assessed at baseline and during and post-Fran. Blood lactate and glucose concentrations and muscular fatigue were measured at baseline and in the recovery period. Results: A marked increase in V ˙ O 2 kinetics was observed at the beginning of Fran, remaining elevated until the end (V ˙ O 2 peak : 49.2 [3.7] mL·kg−1·min−1, V ˙ O 2 amplitude: 35.8 [5.2] mL·kg−1·min−1, time delay: 4.7 [2.5] s and time constant: 23.7 [11.1] s; mean [SD]). Aerobic, anaerobic lactic, and alactic pathways accounted for 62% (4%), 26% (4%), and 12% (2%) of energy contribution. Reduction in muscle function in jumping ability (jump height: 8% [6%], peak force: 6% [4%], and maximum velocity: 4% [2%]) and plank prone test (46% [20%]) was observed in the recovery period. Conclusions: The Fran unbroken workout is a high-intensity effort associated with an elevated metabolic response. This pattern of energy response highlights the primary contribution of aerobic energy metabolism, even during short and very intense CrossFit workouts, and that recovery can take >24 hours due to cumulative fatigue. [ABSTRACT FROM AUTHOR]

Background: Weakness of the shoulder girdle muscles has been reported in patients with chronic lateral elbow tendinopathy. The aim of this study was to assess the short- and long-term effects of a conventional treatment plus scapular exercises program in patients with chronic lateral elbow tendinopathy. Methods: A single-group prestudy and poststudy were conducted. The primary outcome was the Patient-Rated Tennis Elbow Evaluation questionnaire score. Secondary outcomes were grip strength; Disabilities of the Arm, Shoulder, and Hand questionnaire score; Visual Analogue Scale score at rest and at grip, and presence of scapular dyskinesis. Results: A total of 65 patients (72.3% females), with a mean age of 41.8 years, were analyzed. At the end of 6 weeks, the results showed clinically and statistically significant differences (P< .05). At 1-year follow-up, the differences were: Patient-Rated Tennis Elbow Evaluation -31 points (P<.001); grip strength +33.6% (P<.001); Disabilities of the Arm, Shoulder, and Hand -34.2 points (P < .001); Visual Analogue Scale at rest -2.5 cm (P < .001); and Visual Analogue Scale at grip -2.3 cm (P < .001). Conclusion: At the end of 6 weeks and at 1-year follow-up, conventional treatment plus scapular exercises program showed statistically and clinically significant differences in all functional outcomes assessed in patients with lateral elbow tendinopathy. [ABSTRACT FROM AUTHOR]

The current study examined the acquisition, retention, and transfer effects of a motor program. Children with autism spectrum disorder participated in a 9-week program that targeted 13 fundamental motor skills based upon the Test of Gross Motor Development-3. Assessments were conducted before and after the program, as well as at 2-month follow-up. Significant improvements were found on not only the trained fundamental motor skills (acquisition) but also the untrained tasks on balance (transfer). The follow-up tests revealed continuous improvement on the trained locomotor skills (retention), as well as the untrained skills on balance (retention + transfer). These findings highlight the importance of continuous support and long-term participation on motor practices. [ABSTRACT FROM AUTHOR]

Despite a strong body of evidence supporting benefits of exercise to reduce severity of motor symptoms of Parkinson's Disease (PD) over time, research on the immediate impact of exercise as an adjunctive therapy for nonpharmacologic management of motor symptoms and mobility performance in people with PD is limited. The purpose of this study was to examine immediate effects of a single bout of high-cadence cycling on motor symptoms of PD and performance-based outcomes. Twenty individuals with idiopathic PD participated in a pretest/posttest study investigating immediate impacts of a single high-cadence cycling session on performance-based outcomes across multiple domains of motor function, mobility, and balance. Outcomes were analyzed based on time since last dose of levodopa/carbidopa medication. Immediate improvements were observed in motor symptoms of PD with significant improvements in performance across multiple balance systems, dynamic gait, and upper-extremity coordination following a cycling intervention. [ABSTRACT FROM AUTHOR]

Exercise is the single most effective strategy to reduce the risk of falls. Online classes have grown in popularity, but the benefits of online classes remain unknown. Zoomers on the Go is a peer-led 12-week exercise program offered twice weekly to adults 50+ years old. The main outcome was lower body strength measured by the 30-s chair stand test. Other outcomes included dropout, attendance, balance, cardiorespiratory fitness, and perceived health. A total of 74 participants (age 66.3 ± 7.1 years) in the online group and 84 participants in the in-person group (age 67.3 ± 7.2 years) completed the program, with attendance for the online group. Both groups significantly improved their 30-s chair stand, cardiorespiratory fitness, and balance (p <.001) with no difference in functional benefits between groups. The in-person group improved their perceived health and significantly reduced levels of stress and depression, while no such changes were observed in the online group. [ABSTRACT FROM AUTHOR]

Specialty drugs treat complex, severe diseases and offer significant therapeutic advances. Despite their potential to transform patient care, little is known about the drivers of their diffusion. In this study, the authors develop a framework for the diffusion of specialty drugs that is motivated by the drugs' novelty, complexity, and importance, with a focus on the role of scientific evidence production. They propose that the effects of scientific evidence on specialty drug diffusion are multifaceted and generated through the three stages of the scientific evidence production process: unpublished clinical studies, publications in medical journals not cited in clinical guidelines, and clinical guidelines. The findings from the empirical analysis of two specialty drugs validate the framework, supporting the idea of multistage scientific evidence effects. In contrast, marketing activities do not have a significant effect. Although this could be attributed to specialty drug prescribers discounting information from commercial sources, it may also be due to limited marketing support. An additional analysis on a nonspecialty drug further validates the proposed framework. Calculations of scientific evidence contributions to trial prescriptions indicate that scientific evidence production can generate returns beyond the publication stage, which should provide specialty drug manufacturers with strong incentives to commit to quality and innovation. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effectiveness of an interproximal brush, a water flosser, and dental floss in removing plaque and reducing inflammation around implant-supported crowns. Materials and Methods: A randomised controlled trial was conducted involving 45 participants with implant-supported single crowns. The participants were randomly assigned to three groups: interproximal brush, water flosser, and dental floss. Plaque index scores, gingival index scores, and interleukin-6 (IL-6) levels were assessed at baseline and after a two-week period. Statistical analysis was performed to compare the outcomes among the groups. Results: Following the second visit, improvements in plaque control were observed across all three interdental cleaning methods. The water flosser demonstrated a slight reduction in IL-6 levels (60.17 ± 3.07 vs 58.79 ± 4.04) compared to the initial visit, although this decrease was not statistically significant. Conversely, both the interdental brush and dental floss exhibited a slight increase in IL-6 levels at the second visit (60.73 ± 2.93 and 55.7 ± 10.64, respectively) compared to the mean at the first visit (58.38 ± 3.24 and 54.6 ± 2.22, respectively). Among the groups, only the interproximal brush demonstrated a statistically significant difference in IL-6 levels (p=0.008), while no statistically significant differences were observed in the dental floss and water flosser groups. Conclusion: Within the study’s limitations, our findings suggest that all three methods of interdental cleaning effectively improve plaque control and reduce gingival inflammation. However, using a water flosser appears to reduce inflammation more effectively, highlighting its potential advantage over the other two methods. Further research is needed to evaluate the long-term efficacy and impact of these methods on implant survival. [ABSTRACT FROM AUTHOR]

Purpose: To examine the influence of abutment emergence angle and abutment height on marginal periimplant bone stability in patients not considered susceptible to peri-implantitis. Furthermore, it was analyzed whether titanium-base (Ti-base) abutments lead to wider abutment emergence angles compared to one-piece abutments. Materials and Methods: A total of 48 abutments (ie, 24 Ti-base and 24 one-piece abutments in 24 patients) were evaluated at abutment installation, after 1 year, and thereafter on a yearly basis for up to 5 years. Clinical and radiographic outcome variables were assessed. Results: With regard to peri-implant marginal bone stability, only moderately negative, albeit significant, correlations were found on the mesial sides of the one-piece abutments after 4 and 5 years for an abutment emergence angle > 30 degrees. No statistically significant negative correlations were found for distances of ≤ 1.5 mm between the restoration margin and the crestal peri-implant bone level for either Ti-base or for one-piece abutments. Furthermore, abutments bonded to Ti-bases were not associated with larger emergence angles than one-piece abutments. Conclusions: For patients at low risk of developing peri-implantitis, it can be concluded that neither a larger abutment emergence angle (> 30 degrees) nor a distance of ≤ 1.5 mm between the restoration margin and the crestal peri-implant bone level are associated with marginal peri-implant bone loss. Furthermore, abutments bonded to Ti-bases are not associated with wider emergence angles than one-piece abutments. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the accuracy of intraoral scanners by comparing the marginal fit of 70 all-ceramic crowns fabricated from both conventional impressions and intraoral scans. Materials and Methods: A total of 70 posterior teeth requiring single-crown restorations randomly underwent either intraoral scanning or conventional impression-taking, followed by laboratory scanning of the casts in a parallel-group randomized controlled trial (RCT). Subsequently, 70 monolithic all-ceramic crowns were CAD/CAM fabricated; only the impression technique differed. The marginal fit, internal fit, adjustment time required for insertion and occlusal contacts, and visual analog scale (VAS) scores assessing dentists' satisfaction with the crowns were clinically evaluated by a calibrated examiner who was blinded to the groups. Data were analyzed using independent samples t test and likelihood-ratio test or Fisher exact test. All tests were performed with α = .05. Results: The mean marginal fit with intraoral scanning (57.94 ± 22.51 µm) was better than with diagnostic cast scanning (82.98 ± 21.72 µm). The difference was statistically significant (P = .000). The differences in internal fit, adjustment time for crown insertion and occlusal contacts, and VAS scores were also significant, and the secondary outcomes were in favor of intraoral scanning. Conclusions: Within the limitations of this clinical trial, CAD/CAM--fabricated single-tooth restorations in the posterior region produced with an intraoral scanning technique using TRIOS were found to be a more accurate, efficient alternative to restorations based on conventional impressions in combination with the laboratory scanning technique. [ABSTRACT FROM AUTHOR]

BACKGROUND: Older adults with multimorbidity are under-represented in clinical drug trials. Their inclusion will not increase unless they are willing and able to participate. Data on motivators and barriers to participation in trials of new medications of older adults with multimorbidity are needed. METHODS: Cross-sectional internet and telephone survey of a nationally representative sample of adults ≥65 years with ≥3 chronic conditions (NORC University of Chicago Amerispeak Panel) conducted from March-April, 2023 to determine motivators and barriers to drug trial participation, described graphically and using statistics. RESULTS: Surveyed 1318 (1142 Internet, 176 phone) with mean age 72.3 ± 6.3 (SD), 52% women; race: 83% White, 10% Black or African American, 5% Hispanic or Latino, 1.1% Asian; 4.4 ± 1.9 chronic conditions (of 16 queried), taking 7.5 ± 3.3 medications. Barriers included fear of side effects (48%), taking too many medications (44%), placebo (44%), mobility (33%), bathroom needs (25%), hearing (19%), eyesight (15%), video visits (33%; higher in women, Black or African-American respondents, and those ≥80 years). Sixty-five percent would join all in-person trials, 49% would join all-video trials. Travel >1 h was difficult for 66%, most difficult for women. Trust was a concern in 25% of Black respondents. Caregiving responsibilities or lack of time were not obstacles. Participants were most likely to consider a drug trial for a problem they have (63%) versus prevention (44%) and if invited by a physician (80%) or University healthcare system (58%). Getting better care was ranked very important (79%) followed by helping others (57%). CONCLUSIONS: Major concerns of older patients with multimorbidity about participation in drug trials are potential side effects, taking too many medicines, and video visits. Physicians have the greatest influence on decisions and in-person visits are preferred. Proposed changes in trial design to increase enrollment of under-represented older adults may not align with patient-reported preferences.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. METHODS: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. RESULTS: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). CONCLUSION: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Under-representation of subgroups of the population in clinical trials has been and continues to be a problem despite goals of academia, industry, and government. Older adults are among the groups that are under-represented in trials of medications that they are likely to receive once marketing approval has been received. Recent legislation that mandates that clinical trial participants be representative of patient population has been passed and creates hope that greater numbers of older adults will be enrolled in clinical trials and that they will be representative of "typical" geriatric patients. However, there is the need for collection of current data on disease prevalences with granularity as to age, gender, and race as well as geriatric co-morbidities to assess the representativeness of clinical trial participants relative to patient populations. Consensus on definitions and collection of data relevant to geriatric patient populations are needed to evaluate effects of comorbidities, frailty, cognitive and physical function. There will also be a need for expansion of the geriatric research workforce, facilities for research both in academic centers but also in the community and long-term care facilities, and for engagement with and involvement of communities that have been traditionally under-represented to conduct clinical trials that enroll truly representative patient populations.

BackgroundAn ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice.MethodsIn this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure).FindingsOut of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant.InterpretationThis work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted.FundingThis work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

IntroductionTrialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials.MethodsWe used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants' responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status.ResultsReactions to disclosure did not significantly differ among participant groups based on self-reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self-reporting Hispanic/Latino ethnicity were observed to have higher mean IES in the elevated amyloid group.DiscussionThese results support continued use of current disclosure methods in preclinical AD trials.

INTRODUCTION: Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. METHODS: Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-μg doses were randomized to receive BNT162b2 30 μg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 μg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 μg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. RESULTS: Percentages of 12- to 30-year-olds (n = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 (n = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. CONCLUSIONS: Among 5- to

This study investigated the effects of an acute dose (900 mg) of New Zealand Blackcurrant (NZBC) extract on 5-km running performance, alongside associated physiological and metabolic responses. Sixteen trained male runners (age 26 ± 5 years, stature 173.4 ± 7.3 cm, body mass 73.7 ± 6.9 kg, maximal oxygen consumption [ V ˙ O 2 max ] 55.4 ± 6.1 ml·kg−1·min−1) ingested either capsules containing NZBC extract (3 × 300 mg CurraNZ, 315 mg anthocyanins) or a matched placebo (3 × 300 mg gluten-free flour) 2 hr before exercise in a double-blind, randomized, crossover design. Performance time, physiological, and metabolic responses were assessed in a 5-km time trial, preceded by 10-min exercise at the lactate threshold on a treadmill. NZBC extract did not alter the physiological or metabolic responses to exercise at the lactate threshold (oxygen uptake, respiratory exchange ratio, minute ventilation, carbohydrate oxidation, fat oxidation, heart rate, blood lactate, or rating of perceived exertion, p >.05). The 5-km time trial was completed in a faster time in the NZBC extract condition compared with placebo (NZBC: 1,308.96 ± 122.36 s, placebo: 1,346.33 ± 124.44, p =.001, d = −0.23, confidence interval range = [−0.46, 0.00 s]). No differences in physiological or metabolic responses were apparent between conditions for the 5-km time trial (p >.05). Ingesting 900 mg of NZBC extract as an acute dose improves performance in trained male runners without altering physiological or metabolic responses to exercise. Further research is needed to assess a wider range of possible mechanisms (e.g., cardiovascular function, metabolite profiles) to advance insight into improved performance following supplementation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of bulb thickness on the weight of obturator prostheses and masticatory performance in edentulous hemimaxillectomy patients.Materials and Methods: A randomized, single-blind, three-period crossover trial was conducted with 17 edentulous patients. All patients were provided with three definitive 3D-printed obturator prostheses each. Obturators were divided into three groups: (1) group 1 (G1; 1-mm bulb); (2) group 2 (G2; 2-mm bulb); and (3) group 3 (G3; 3-mm bulb). After fabrication, the weight of each obturator was measured using a digital analytical balance. The patients used each obturator for a period of 2 weeks without a passive period (ie, they did not stop using the obturator). After using each obturator, masticatory function was evaluated with an adapted Sato questionnaire and the sieve test. Data were analyzed using one-way ANOVA and Pearson correlation analysis (α = .05).Results: According to the results of the Sato questionnaire and sieve test, G1 demonstrated the highest masticatory function scores (70.88 ± 9.39; 1.06 ± 0.06), while G3 exhibited the lowest scores (48.23 ± 7.69; 0.92 ± 0.05) (P < .001). The weight of the obturators was significantly different between groups (G1 = 31.58 ± 1.09 g; G2 = 33.99 ± 1.21 g; G3 = 36.57 ± 1.13 g) (P < .001). The correlation between masticatory function and the weight of the obturator was significant (P < .05).Conclusion: This study revealed that using 1-mm obturator bulb thickness was an effective fabrication method for improving masticatory function and reducing the weight of obturator prostheses in edentulous hemimaxillectomy patients. [ABSTRACT FROM AUTHOR]

Older adults must have the ability to walk at variable speeds/distances to meet community demands. This single group pre–post test study's purposes were to examine if actual cadences after 7 weeks of rhythmic auditory stimulation gait training matched target cadences, improved walking distance, duration, velocity, maximum cadence, balance, enjoyment, and/or changed spatial/temporal gait parameters. Fourteen female adults (72.6 ± 4.4 years) participated in 14 sessions, while variable cadences were progressively introduced. Eleven older adult responders walked faster (3.8 steps/min) than one target cadence (−10% pace) while matching the target cadences for the other paces when walking with rhythmic auditory stimulation. Two nonresponders walked near their baseline cadence with little variability while one walked at faster cadences; all three did not appear to adjust to the beat of the music. After training, participants increased their walking distance, 90.8 ± 46.5 m; t(1, 13) = −7.3; p ≤.005, velocity, 0.36 ± 0.15 m/s; t(1, 40) = −15.4; p <.001, and maximum cadence, 20.6 ± 9.1 steps/min; t(1, 40) = −14.6; p <.001; changes exceeded minimal clinically important differences. Twelve of 14 expressed enjoyment. Walk with rhythmic auditory stimulation training is a promising activity for older adults, which may translate to an individual's ability to adapt walking speeds to various community demands. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effects of a sleep hygiene strategy on parameters of sleep quality and quantity in youth elite rugby union players. Method: Eleven male players (age: 19.0 [1.4] y) undertook a sleep hygiene strategy composed of 2 theoretical sessions and 3 practical sessions over a 4-week period. Sleeping time, time in bed, total sleep time, sleep latency (SL), sleep efficiency (SE), wake after sleep onset, and wake bouts were recorded with an actigraphic device during the 4-week sleep hygiene strategy (baseline) and during 4 weeks after the last intervention (postintervention). Results: At baseline, the overall group reported poor sleep quantity (total sleep time = 6:27 [0:30] min), but sleep quality was considered acceptable (SL = 0:18 [0:08] min and SE = 77.8% [5.8%]). Postintervention, the overall group showed a small improvement in SL (d = −0.23 [−0.42 to −0.04], P =.003) and SE (d = 0.30 [0.03 to 0.57], P =.0004). For individual responses, sleeping time, time in bed, and total sleep time were positively influenced in only 4, 3, and 5 players, respectively. For parameters of sleep quality, SL and SE were positively influenced in a majority of players (n = 7 and 8, respectively). The magnitude of difference between baseline and postintervention was strongly associated with baseline values in SE (r = −.86; P =.0005) and wake after sleep onset (r = −.87; P =.0007). Conclusion: A sleep hygiene strategy is efficient to improve sleep quality but not sleep quantity in young rugby union players. The strategy was more efficient in players with lower initial sleep quality and should be implemented prior to a high cumulative fatigue period. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

BACKGROUND: Randomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials. The estimand framework outlined in the recent ICH E9(R1) addendum offers a timely opportunity for randomized trials of TB treatment to adopt broadly standardized outcome definitions and analytic approaches. We previously proposed and defined four estimands for use in this context. Our objective was to evaluate how the use of these estimands and choice of estimation method impacts results and interpretation of a large phase III TB trial. METHODS: We reanalyzed participant-level data from the REMoxTB trial. We applied four estimands and various methods of estimation to assess non-inferiority of both novel 4-month treatment regimens against standard of care. RESULTS: With each of the four estimands, we reached the same conclusion as the original trial analysis that the novel regimens were not non-inferior to standard of care. Each estimand and method of estimation gave similar estimates of the treatment effect with fluctuations in variance and differences driven by the methods applied for handling intercurrent events. CONCLUSIONS: Our application of estimands defined by the ICH E9 (R1) addendum offers a formalized framework for addressing the primary TB treatment trial objective and can promote uniformity in future trials by limiting heterogeneity in trial outcome definitions. We demonstrated the utility of our proposal using data from the REMoxTB randomized trial. We outlined methods for estimating each estimand and found consistent conclusions across estimands. We recommend future late-phase TB treatment trials to implement some or all of our estimands to promote rigorous outcome definitions and reduce variability between trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00864383. Registered on March 2009.

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

The Microbicide Trials Network 042 study (MTN-042/DELIVER) is a two-arm, randomized, open-label Phase 3b trial that is evaluating the safety, adherence, and acceptability of the monthly ring and daily oral PrEP among HIV-uninfected pregnant people in four African countries. This analysis focuses on acceptability data captured qualitatively from a subset (n = 48) of the 150 people in the first cohort of the trial who were enrolled in late-stage pregnancy at 36 to 38 weeks gestational age and followed until after delivery. Single IDIs were conducted by trained interviewers at each clinic site using a semi-structured guide. Data excerpts of key codes pertaining to acceptability, pregnancy, and maternal health were summarized, reviewed and interpreted by multinational analyst teams. Although the product use period was relatively short, the data suggested several acceptability findings that may directly translate to longer durations of product use in pregnancy. The first was the overarching maternal sentiment that being able to protect both oneself and their baby was highly valued. The second was the importance of counseling support from providers not only because participants used methods that might generate side effects, but because pregnancy itself is a period with its own set of side effects. The third was that, similar to non-pregnant participants in other trials, here study products were generally liked and described as easy to use. Concerns about ring and oral PrEP use could be addressed with provider counseling and support and should form an essential component rollout among pregnant people.

INTRODUCTION: Depression occurs in over 50% of individuals living with multiple sclerosis (MS) and can be treated using many modalities. Yet, it remains: under-reported by patients, under-ascertained by clinicians and under-treated. To enhance these three behaviours likely to promote evidence-based depression care, we engaged multiple stakeholders to iteratively design a first-in-kind digital health tool. The tool, MS CATCH (Care technology to Ascertain, Treat, and engage the Community to Heal depression in patients with MS), closes the communication loop between patients and clinicians. Between clinical visits, the tool queries patients monthly about mood symptoms, supports patient self-management and alerts clinicians to worsening mood via their electronic health record in-basket. Clinicians can also access an MS CATCH dashboard displaying patients mood scores over the course of their disease, and providing comprehensive management tools (contributing factors, antidepressant pathway, resources in patients neighbourhood). The goal of the current trial is to evaluate the clinical effect and usability of MS CATCH in a real-world clinical setting. METHODS AND ANALYSIS: MS CATCH is a single-site, phase II randomised, delayed start, trial enrolling 125 adults with MS and mild to moderately severe depression. Arm 1 will receive MS CATCH for 12 months, and arm 2 will receive usual care for 6 months, then MS CATCH for 6 months. Clinicians will be randomised to avoid practice effects. The effectiveness analysis is superiority intent-to-treat comparing MS CATCH to usual care over 6 months (primary outcome: evidence of screening and treatment; secondary outcome: Hospital Anxiety Depression Scale-Depression scores). The usability of the intervention will also be evaluated (primary outcome: adoption; secondary outcomes: adherence, engagement, satisfaction). ETHICS AND DISSEMINATION: University of California, San Francisco Institutional Review Board (22-36620). The findings of the study are planned to be shared through conferences and publishments in a peer-reviewed journal. The deidentified dataset will be shared with qualified collaborators on request, provision of CITI and other certifications, and data sharing agreement. We will share the results, once the data are complete and analysed, with the scientific community and patient/clinician participants through abstracts, presentations and manuscripts. TRIAL REGISTRATION NUMBER: NCT05865405.

BACKGROUND: Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control. METHODS: The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania. Phase 1 of the study consists of a two-arm, cluster randomized trial across 32 health facilities to assess the effectiveness of a home visit plus one-time economic incentive on the proportion of out-of-care PLHIV with viral load suppression (

BACKGROUND: Despite the pivotal role of clinical trials in advancing orthopaedic oncology knowledge and treatment strategies, the persistent issues of trial discontinuation and nonpublication are significant problems. This study conducted an analysis examining clinical trial discontinuation rates, associations between intervention types and discontinuation/nonpublication, and the role of funding, enrollment size, and their implications for trial success and completion. METHODS: This study, conducted on May 1, 2023, utilized a cross-sectional design to comprehensively analyze phase 3 and 4 randomized controlled trials within the realm of orthopaedic oncology. We specifically incorporated Phase 3 and 4 trials as they are designed to evaluate prolonged outcomes in human subjects and are more likely to reach publication. Study characteristics of interest included the intervention utilized in the clinical trial, presence of funding, whether the trial was published, completed, and trial enrollment size. The investigation involved an examination of ClinicalTrials.gov, a prominent online repository of clinical trial data managed by the National Library of Medicine of the USA. Descriptive statistics and multivariate logistic regressions were used to determine statistical significance. RESULTS: Among the cohort of 130 trials, 19.2% were prematurely discontinued. Completion rates varied based on intervention type; 111 pharmaceutical trials demonstrated a completion rate of 83.8%, whereas 19 non-pharmaceutical trials exhibited a completion rate of 8.0% (P

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

In 2011, the UK medical research charity Cure Parkinsons set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinsons disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.