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Abstract Background A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms. Trial registration EudraCT, 2018–001795-38. Registered 2020-05-15, Clinicaltrials.gov , NCT04307576 . Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576

Background and Aims: Exercise is recommended for the management of metabolic dysfunction‐associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12–20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI‐measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Results: Eighty‐eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5‐fold (OR [95%CI]: 4.86 [1.72, 13.8], p =.002) greater odds of ≥30% relative reduction in MRI‐measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum‐ and imaging‐based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight‐neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD. [ABSTRACT FROM AUTHOR]

* OBJECTIVE: To ascertain whether manipulating contextual effects (eg, interaction with patients, or beliefs about treatments) boosted the outcomes of nonpharmacological and nonsurgical treatments for chronic primary musculoskeletal pain. * DESIGN: Systematic review of randomized controlled trials * DATA SOURCES: We searched for trials in 6 databases, citation tracking, and clinical trials registers. We included trials that compared treatments with enhanced contextual effects with the same treatments without enhancement in adults with chronic primary musculoskeletal pain. * DATA SYNTHESIS: The outcomes of interest were pain intensity, physical functioning, global ratings of improvement, quality of life, depression, anxiety, and sleep. We evaluated risk of bias and certainty of the evidence using Cochrane Risk of Bias tool 2.0 and the GRADE approach, respectively. * RESULTS: Of 17 637 records, we included 10 trials with 990 participants and identified 5 ongoing trials. The treatments were acupuncture, education, exercise training, and physical therapy. The contextual effects that were improved in the enhanced treatments were patient-practitioner relationship, patient beliefs and characteristics, therapeutic setting/environment, and treatment characteristics. Our analysis showed that improving contextual effects in nonpharmacological and nonsurgical treatments may not make much difference on pain intensity (mean difference [MD], -1.77; 95% confidence interval [CI]: -8.71, 5.16; k = 7 trials; N = 719 participants; Scale: 0-100; GRADE: Low) or physical functioning (MD, -0.27; 95% CI: -1.02, 0.49; 95% prediction interval [PI]: -2.04, 1.51; k = 6; N = 567; Scale: 0-10; GRADE: Low) in the short term and at later followups. Sensitivity analyses revealed similar findings. * CONCLUSION: While evidence gaps exist, per current evidence, it may not be possible to achieve meaningful benefit for patients with chronic musculoskeletal pain by manipulating the context of nonpharmacological and nonsurgical treatments. [ABSTRACT FROM AUTHOR]

Background:Musculoskeletal (MSK) pain is the leading cause of disability worldwide. Telemedicine is of growing importance, yet impacts on treatment efficacy remain unclear. Objective:This umbrella review (CRD42022298047) examined the effectiveness of telemedicine interventions on pain intensity, disability, psychological function, quality of life, self-efficacy, and adverse events in MSK pain. Methods:PubMed, SPORTDiscus, Cochrane Library, EMBASE, and CINAHL were searched from inception to August 9, 2022, for systematic reviews with meta-analysis, including telemedicine-delivered exercise, education, and psychological interventions, in randomized controlled trials (RCTs). AMSTAR-2 was implemented. Standardized mean differences (SMDs; negative favors telemedicine) were extracted as effect estimates. Results:Of 1,135 records, 20 reviews (RCTs: n = 97, participants: n = 15,872) were included. Pain intensity SMDs were −0.66 to 0.10 for mixed pain (estimates: n = 16), −0.64 to −0.01 for low-back pain (n = 9), −0.31 to −0.15 for osteoarthritis (n = 7), −0.29 for knee pain (n = 1), −0.66 to −0.58 for fibromyalgia (n = 2), −0.16 for back pain (n = 1), and −0.09 for rheumatic disorders (n = 1). Disability SMDs were −0.50 to 0.10 for mixed pain (n = 14), −0.39 to 0.00 for low-back pain (n = 8), −0.41 to −0.04 for osteoarthritis (n = 7), −0.22 for knee pain (n = 1), and −0.56 for fibromyalgia (n = 1). Methodological quality was "critically low" for 17 reviews. Effectiveness tended to favor telemedicine for all secondary outcomes. Conclusions:Primary RCTs are required that compare telemedicine interventions with in-person delivery of the intervention (noninferiority trials), consider safety, assess videoconferencing, and combine different treatment approaches. [ABSTRACT FROM AUTHOR]

Background and Objective: Contextual effects (e.g. patient expectations) may play a role in treatment effectiveness. This study aimed to estimate the magnitude of contextual effects for conservative, non‐pharmacological interventions for musculoskeletal pain conditions. A systematic review and meta‐analysis of randomized controlled trials (RCTs) that compared placebo conservative non‐pharmacological interventions to no treatment for musculoskeletal pain. The outcomes assessed included pain intensity, physical functioning, health‐related quality of life, global rating of change, depression, anxiety and sleep at immediate, short‐, medium‐ and/or long‐term follow‐up. Databases and Data Treatment: MEDLINE, EMBASE, CINAHL, Web of Science Core Collection, CENTRAL and SPORTDiscus were searched from inception to September 2021. Trial registry searches, backward and forward citation tracking and searches for prior systematic reviews were completed. The Cochrane risk of bias 2 tool was implemented. Results: The study included 64 RCTs (N = 4314) out of 8898 records. For pain intensity, a mean difference of (MD: −5.32, 95% confidence interval (CI): −7.20, −3.44, N = 57 studies with 74 outcomes, GRADE: very low) was estimated for placebo interventions. A small effect in favour of the placebo interventions for physical function was estimated (SMD: −0.22, 95% CI: −0.35, −0.09; N = 37 with 48 outcomes, GRADE: very low). Similar results were found for a broad range of patient‐reported outcomes. Meta‐regression analyses did not explain heterogeneity among analyses. Conclusion: The study found that the contextual effect of non‐pharmacological conservative interventions for musculoskeletal conditions is likely to be small. However, given the known effect sizes of recommended evidence‐based treatments for musculoskeletal conditions, it may still contribute an important component. Significance: Contextual effects of non‐pharmacological conservative interventions for musculoskeletal conditions are likely to be small for a broad range of patient‐reported outcomes (pain intensity, physical function, quality of life, global rating of change and depression). Contextual effects are unlikely, in isolation, to offer much clinical care. But these factors do have relevance in an overall treatment context as they provide almost 30% of the minimally clinically important difference. [ABSTRACT FROM AUTHOR]