SARS-CoV-2 variants divergently infect and damage cardiomyocytes in vitro and in vivo.

BACKGROUND: COVID-19 can cause cardiac complications and the latter are associated with poor prognosis and increased mortality. SARS-CoV-2 variants differ in their infectivity and pathogenicity, but how they affect cardiomyocytes (CMs) is unclear. METHODS: The effects of SARS-CoV-2 variants were investigated using human induced pluripotent stem cell-derived (hiPSC-) CMs in vitro and Golden Syrian hamsters in vivo. RESULTS: Different variants exhibited distinct tropism, mechanism of viral entry and pathology in the heart. Omicron BA.2 most efficiently infected and injured CMs in vitro and in vivo, and induced expression changes consistent with increased cardiac dysfunction, compared to other variants tested. Bioinformatics and upstream regulator analyses identified transcription factors and network predicted to control the unique transcriptome of Omicron BA.2 infected CMs. Increased infectivity of Omicron BA.2 is attributed to its ability to infect via endocytosis, independently of TMPRSS2, which is absent in CMs. CONCLUSIONS: In this study, we reveal previously unknown differences in how different SARS-CoV-2 variants affect CMs. Omicron BA.2, which is generally thought to cause mild disease, can damage CMs in vitro and in vivo. Our study highlights the need for further investigations to define the pathogenesis of cardiac complications arising from different SARS-CoV-2 variants.

Falls and patterns of physical activity participation over 18 years in the Australian Longitudinal Study on Women's Health.

OBJECTIVE: To explore the relationship between long-term physical activity (PA) participation and falls. METHODS: Participants in the Australian Longitudinal Study of Women's Health born 1946-1951 self-reported amounts of PA every 3 years since 1998 (mean age: 54 years, n=11 796). Latent class analysis described profiles of self-reported PA participation over 18 years. Associations between patterns of PA participation and self-reported falls measured in 2019 were examined using multinomial logistic regression adjusted for directed-acyclic graph-informed potential confounders, with the highly active group as the reference category. RESULTS: Women were grouped into five PA participation profiles. Compared with consistently highly active patterns (maintaining ≥300 min/week, 22%), consistently lower levels of PA<100 min/week (18%), consistently some PA<150 min/week (18%) and decreasing PA but maintaining≥150 min/week (n=3540, 30%) had higher odds of non-injurious falls (odds Ratiolower level (OR): 1.59, 95% CI 1.29 to 1.97; ORsome PA: 1.27, 95% CI 1.04 to 1.55; ORdecreasing activity:1.29, 95% CI 1.02 to 1.63) and injurious falls (ORlow level: 1.32, 95% CI 1.06 to 1.64; ORsome PA: 1.27, 95% CI 1.04 to 1.54; ORdecreasing activity: 1.47, 95% CI 1.18 to 1.83). No association was found between increasing PA (≥150 min/week, 11%) for non-injurious (OR 1.07, 95% CI 0.89 to 1.29) and injurious falls (OR 1.07, 95% CI 0.90 to 1.29). After adjusting for potential confounders, consistently lower levels of PA remained associated with increased non-injurious falls odds (OR1998 survey: 1.40, 95% CI 1.11 to 1.77; OR2016 survey: 1.35, 95% CI 1.07 to 1.71). CONCLUSION: The increased odds of falls among women with consistently lower levels of PA over 18 years supports ongoing participation of 150+ min/week of PA.

Commonly used software tools produce conflicting and overly-optimistic AUPRC values.

The precision-recall curve (PRC) and the area under the precision-recall curve (AUPRC) are useful for quantifying classification performance. They are commonly used in situations with imbalanced classes, such as cancer diagnosis and cell type annotation. We evaluate 10 popular tools for plotting PRC and computing AUPRC, which were collectively used in more than 3000 published studies. We find the AUPRC values computed by the tools rank classifiers differently and some tools produce overly-optimistic results.

Identification of novel single nucleotide variants in the drug resistance mechanism of Mycobacterium tuberculosis isolates by whole-genome analysis.

BACKGROUND: Tuberculosis (TB) represents a major global health challenge. Drug resistance in Mycobacterium tuberculosis (MTB) poses a substantial obstacle to effective TB treatment. Identifying genomic mutations in MTB isolates holds promise for unraveling the underlying mechanisms of drug resistance in this bacterium. METHODS: In this study, we investigated the roles of single nucleotide variants (SNVs) in MTB isolates resistant to four antibiotics (moxifloxacin, ofloxacin, amikacin, and capreomycin) through whole-genome analysis. We identified the drug-resistance-associated SNVs by comparing the genomes of MTB isolates with reference genomes using the MuMmer4 tool. RESULTS: We observed a strikingly high proportion (94.2%) of MTB isolates resistant to ofloxacin, underscoring the current prevalence of drug resistance in MTB. An average of 3529 SNVs were detected in a single ofloxacin-resistant isolate, indicating a mutation rate of approximately 0.08% under the selective pressure of ofloxacin exposure. We identified a set of 60 SNVs associated with extensively drug-resistant tuberculosis (XDR-TB), among which 42 SNVs were non-synonymous mutations located in the coding regions of nine key genes (ctpI, desA3, mce1R, moeB1, ndhA, PE_PGRS4, PPE18, rpsA, secF). Protein structure modeling revealed that SNVs of three genes (PE_PGRS4, desA3, secF) are close to the critical catalytic active sites in the three-dimensional structure of the coding proteins. CONCLUSION: This comprehensive study elucidates novel resistance mechanisms in MTB against antibiotics, paving the way for future design and development of anti-tuberculosis drugs.

Comparative analysis of asian carps parvalbumin reveals the divergence pattern of major fish allergen.

BACKGROUND: Asian carps, a popular freshwater fish globally, are valued for their flavor and serve as a crucial protein source, especially for infants. However, grass carp parvalbumin is highly allergenic, surpassing the allergenicity of fish like salmon and cod. The allergenic potential of parvalbumin in other Asian carps remains unknown, underscoring the need for allergen identification to improve the precision of fish allergy diagnosis and treatment. OBJECTIVE: To identify all parvalbumin homologs in Asian carps and investigate the role of gene divergence in allergenic homolog formation. METHODS: Three annotated genomes of Asian carp, including grass carp, black carp and bighead carp, were constructed using a hybrid assembly approach. Through sequence homology at the genomic level, all the homologs of major fish allergens were identified. Bioinformatics tools were then employed to reveal the gene structures, expression levels, and protein conformations of parvalbumin. RESULTS: Grass carp genome analysis showed nine parvalbumin homologs, with Cid_PV2 most similar to Cten i 1. Bighead and black carp genomes had ten homologs, including potentially allergenic Mpi_PV7 and Hno_PV7. Tissue-specific expression patterns revealed alternative usage of parvalbumin homologs. Gene duplication events expanded parvalbumin copies in bony fish, with two gene clusters identified in Asian carp genomes. CONCLUSION: All the homologs of Asian carps' parvalbumin were accurately identified and gene divergence contributed to the formation of allergenic homologs. Together with a comprehensive gene sequence profile of carps' parvalbumin, those could be applied to achieve a more precise clinical diagnostic test.

Effective fall prevention exercise in residential aged care: an intervention component analysis from an updated systematic review.

OBJECTIVE: The effect of fall prevention exercise programmes in residential aged care (RAC) is uncertain. This paper reports on an intervention component analysis (ICA) of randomised controlled trials (RCTs), from an update of a Cochrane review, to develop a theory of features of successful fall prevention exercise in RAC. METHODS: Trial characteristics were extracted from RCTs testing exercise interventions in RAC identified from an update of a Cochrane review to December 2022 (n=32). Eligible trials included RCTs or cluster RCTs in RAC, focusing on participants aged 65 or older, assessing fall outcomes with stand-alone exercise interventions. ICA was conducted on trials with >30 participants per treatment arm compared with control (n=17). Two authors coded trialists' perceptions on intervention features that may have contributed to the observed effect on falls. Inductive thematic analysis was used to identify the key differences between the trials which might account for positive and negative outcomes. RESULTS: 32 RCTs involving 3960 residents including people with cognitive (57%) and mobility (41%) impairments were included. ICA on the 17 eligible RCTs informed the development of a theory that (1) effective fall prevention exercise delivers the right exercise by specifically targeting balance and strength, tailored to the individual and delivered simply at a moderate intensity and (2) successful implementation needs to be sufficiently resourced to deliver structured and supervised exercise at an adequate dose. CONCLUSIONS: This analysis suggests that delivering the right exercise, sufficiently resourced, is important for preventing falls in RAC. This clinical guidance requires confirmation in larger trials.

The effect of adding real-time postural feedback in balance and mobility training in older adults: A systematic review and meta-analysis.

OBJECTIVES: This study aimed to systematically review the additional value of providing real-time postural feedback during balance and mobility training in older people. METHODS: PubMed, Embase, CINAHL, and Web-of-Science were searched from inception to August 2023. Studies comparing the effectiveness of feedback-based versus non-feedback-based postural balance or mobility training on balance or mobility outcomes were selected. Similar outcomes were pooled in meta-analyses using a random-effect model. The quality of evidence for available outcomes was rated by Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Eight studies were identified with 203 subjects. Two studies showed that providing postural feedback immediately improved stability in static balance and gait. For the post-training effect, however, no significant change was found in trunk movement during single-leg standing (i.e., pitch angle, MD=0.65, 95 %CI=-0.77 to 2.07, low-quality; roll angle, MD=0.96, 95 %CI=-0.87 to 2.80, moderate-quality), in the Mini-BESTest (MD=1.88, 95 %CI=-0.05 to 3.80, moderate-quality), and in balance confidence (MD=0.29, 95 %CI=-3.43 to 4.2, moderate-quality). A worsened functional reach distance was associated with providing feedback during balance training (MD=-3.26, 95 %CI=-6.31 to -0.21, high-quality). Meta-analyses on mobility outcomes were mostly insignificant, except for the trunk-roll angle of walking (MD=0.87, 95 %CI=0.05 to 1.70, low-quality) and trunk-pitch angle of walking with head-turning (MD=1.87, 95 %CI=0.95 to 2.79, moderate-quality). CONCLUSION: Adding real-time postural feedback to balance and mobility training might immediately improve stability in balance and mobility in older people. However, mixed results were reported for its post-training effect.

Quantity and quality are increasing but there's room for improvement: A scoping review of physical activity intervention trials.

BACKGROUND: Observing trends in research publications helps to identify the quantity and quality of research produced, as well as reveal evidence gaps. No comprehensive review of the quality and quantity of physical activity intervention trials has been conducted. OBJECTIVE: We aimed to investigate i) the volume and quality (and changes in these over time) of randomized controlled trials evaluating physical activity interventions, and ii) the association between journal ranking and trial quality. METHODS: We searched the Physiotherapy Evidence Database (PEDro) for trials investigating physical activity interventions (no restrictions for population, comparison, or language). Descriptive statistics were used to describe the volume and quality of trials. The association between journal ranking (Journal Impact Factor) and trial quality (PEDro Scale) was examined using Spearman's rho correlation. RESULTS: We identified 1779 trials, of which 40% (n = 710) were published between 2016 and 2020. The mean (SD) total PEDro score was 5.3 (1.5) points out of 10, increasing over time from 2.5 (0.7) points in 1975-1980 to 5.6 (1.4) points in 2016-2020. Quality criteria that were least reported included blinding of intervention deliverers (therapists) (n = 3, 0.2%), participants (n = 21, 1.2%), or assessors (n = 541, 31%); concealed allocation to groups (n = 526, 30%); and intention to treat analysis (n = 764, 43%). There was a small correlation between trial quality and Journal Impact Factor (0.21, p < 0.001). CONCLUSION: A large volume of trials has investigated physical activity interventions. The quality of these trial reports is suboptimal but improving over time. Journal ranking should not be used for selecting high quality trials.

Commonly used software tools produce conflicting and overly-optimistic AUPRC values.

The precision-recall curve (PRC) and the area under it (AUPRC) are useful for quantifying classification performance. They are commonly used in situations with imbalanced classes, such as cancer diagnosis and cell type annotation. We evaluated 10 popular tools for plotting PRC and computing AUPRC, which were collectively used in >3,000 published studies. We found the AUPRC values computed by the tools rank classifiers differently and some tools produce overly-optimistic results.

Use of behavior change techniques in physical activity programs and services for older adults: findings from a rapid review.

BACKGROUND: Understanding behavior change techniques (BCTs) used in randomized controlled trials (RCTs) of physical activity programs/services for older adults can help us to guide their implementation in real-world settings. PURPOSE: This study aims to: (a) identify the number and type of BCTs used in physical activity programs/services for older adults evaluated in large, good quality RCTs and (b) explore the impact of different BCTs on different outcome domains. METHODS: This is a secondary data analysis of a WHO-commissioned rapid review of physical activity programs/services for older adults. Fifty-six trials testing 70 interventions were coded for the type and number of BCTs present using a published BCT taxonomy. The proportion of positive effects found from physical activity interventions using the most common BCTs was calculated for the outcomes of physical activity, intrinsic capacity, functional ability, social domain, cognitive and emotional functioning, and well-being and quality of life. RESULTS: Thirty-nine of the 93 possible BCTs were identified in the included trials and 529 BCTs in total (mean 7.6, range 2-17). The most common BCTs were "action planning" (68/70 interventions), "instructions on how to perform a behavior" (60/70), "graded tasks" (53/70), "demonstration of behavior" (44/70), and "behavioral practice/rehearsal" (43/70). Interventions that used any of the most common BCTs showed overwhelmingly positive impacts on physical activity and social domain outcomes. CONCLUSION: Consideration of which BCTs are included in interventions and their impact on outcomes can improve the effectiveness and implementation of future interventions. To enable this, providers can design, implement, and evaluate interventions using a BCT taxonomy.

Interventions aimed at modifying health-related behaviors, such as physical activity, are often complex, with numerous components. To better understand interventions' "active ingredients," we conducted a secondary analysis of a World Health Organization (WHO)-commissioned rapid review, using a behavior change technique (BCT) taxonomy. We aimed to classify the number and types of BCTs in physical activity programs for older adults, as identified in randomized controlled trials (RCTs), and examine their impact on outcomes, including physical activity, intrinsic capacity, functional ability, social domain, cognitive and emotional functioning, and well-being. Examining 56 trials testing 70 interventions, we identified 39 out of 93 possible BCTs, totaling 529 instances across interventions. Common BCTs included "action planning," "instructions on how to perform a behavior," "graded tasks," "demonstration of behavior," and "behavioral practice/rehearsal." Interventions using the 10 most common BCTs demonstrated overwhelmingly positive impacts on physical activity and social domain outcomes. However, these BCTs were not consistently present in interventions yielding positive outcomes in other domains, with greater variation in effects. Our study highlights the significance of identifying both BCTs and desired outcomes when designing physical activity interventions. We advocate for the use of a taxonomy in designing and implementing future programs to maximize effectiveness.

Harnessing the cytotoxic granule exocytosis to augment the efficacy of T-cell-engaging bispecific antibody therapy.

T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be established, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This approach reveals interleukin (IL)-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characterization strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cytotoxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.

Leisure-Time Physical Activity and Falls With and Without Injuries Among Older Adult Women.

Importance: Falls and fall-related injuries are common among older adults. Older adults are recommended to undertake 150 to 300 minutes of physical activity per week for health benefits; however, the association between meeting the recommended level of physical activity and falls is unclear. Objectives: To examine whether associations exist between leisure-time physical activity and noninjurious and injurious falls in older women. Design, Setting, and Participants: This population-based cohort study used a retrospective analysis of the Australian Longitudinal Study on Women's Health (ALSWH). ALSWH participants born from 1946 to 1951 who completed follow-up questionnaires in 2016 (aged 65-70 years) and 2019 (aged 68-73 years) were included. Statistical analysis was performed from September 2022 to February 2023. Exposure: Self-reported weekly amounts (0, 1 to <150, 150 to <300, ≥300 minutes) and types of leisure-time physical activity, including brisk walking and moderate- and vigorous-intensity physical activity, in the 2016 survey. Main outcome and measures: Noninjurious and injurious falls in the previous 12 months reported in the 2019 survey. Associations between leisure-time physical activity and falls were quantified using directed acyclic graph-informed multinomial logistic regression and presented in odds ratios (ORs) and 95% CIs. Results: This study included 7139 women (mean [SD] age, 67.7 [1.5] years). Participation in leisure-time physical activity at or above the level recommended by the World Health Organization (150 to <300 min/wk) was associated with reduced odds of noninjurious falls (150 to <300 min/wk: OR, 0.74 [95% CI, 0.59-0.92]; ≥300 min/wk: OR, 0.66 [95% CI, 0.54-0.80]) and injurious falls (150 to <300 min/wk: OR, 0.70 [95% CI, 0.56-0.88]; ≥300 min/wk: OR, 0.77 [95% CI, 0.63-0.93]). Compared with women who reported no leisure-time physical activity, those who reported brisk walking (OR, 0.83 [95% CI, 0.70-0.97]), moderate leisure-time physical activity (OR, 0.81 [95% CI, 0.70-0.93]), or moderate-vigorous leisure-time physical activity (OR, 0.84 [95% CI, 0.70-0.99]) had reduced odds of noninjurious falls. No statistically significant associations were found between the types of leisure-time physical activity and injurious falls. Conclusions and Relevance: Participation in leisure-time physical activity at the recommended level or above was associated with lower odds of both noninjurious and injurious falls. Brisk walking and both moderate and moderate-vigorous leisure-time physical activity were associated with lower odds of noninjurious falls.

A Novel Multi-Strain E3 Probiotic Formula Improved the Gastrointestinal Symptoms and Quality of Life in Chinese Psoriasis Patients.

Psoriasis is a chronic immune-mediated inflammatory disease affecting the skin and other systems. Gastrointestinal disease was found to be correlated with psoriasis in previous studies and it can significantly affect the quality of life of psoriasis patients. Despite the importance of the gut microbiome in gut and skin health having already been demonstrated in many research studies, the potential effect of probiotics on GI comorbidities in psoriasis patients is unclear. To investigate the effects of probiotics on functional GI comorbidities including irritable bowel syndrome, functional constipation, and functional diarrhea in psoriasis patients, we conducted a targeted 16S rRNA sequencing and comprehensive bioinformatic analysis among southern Chinese patients to compare the gut microbiome profiles of 45 psoriasis patients over an 8-week course of novel oral probiotics. All the participants were stratified into responders and non-responders according to their improvement in GI comorbidities, which were based on their Bristol Stool Form Scale (BSFS) scores after intervention. The Dermatological Life Quality Index (DLQI) score revealed a significant improvement in quality of life within the responder group (DLQI: mean 10.4 at week 0 vs. mean 15.9 at week 8, p = 0.0366). The proportion of psoriasis patients without GI comorbidity manifestation at week 8 was significantly higher than that at week 0 (week 0: Normal 53.33%, Constipation/Diarrhea 46.67%; week 8: Normal 75.56%, Constipation/Diarrhea 24.44%, p = 0.0467). In addition, a significant difference in the gut microbiome composition between the responders and non-responders was observed according to alpha and beta diversities. Differential abundance analysis revealed that the psoriasis patients exhibited (1) an elevated relative abundance of Lactobacillus acidophilus, Parabacteroides distasonis, and Ruminococcus bromii and (2) a reduced relative abundance of Oscillibacter, Bacteroides vulgatus, Escherichia sp., and Biophila wadsworthia after the 8-week intervention. The responders also exhibited a higher relative abundance of Fusicatenibacter saccharivorans when compared to the non-responders. In summary, our study discovers the potential clinical improvement effects of the novel probiotic formula in improving GI comorbidities and quality of life in psoriasis patients. We also revealed the different gut microbiome composition as well as the gut microbial signatures in the patients who responded to probiotics. These findings could provide insight into the use of probiotics in the management of psoriasis symptoms.

Differences in Falls and Physical Activity in Older Women From Two Generations.

BACKGROUND: Falls and physical inactivity increase with age. However, physical activity, falls and their associations in older people born at different times are unclear. METHODS: Women born 1921-26 and 1946-51 who completed follow-up questionnaires in 1999 (n = 8 403, mean (SD) age: 75 (1) years) and 2019 (n = 7 555; 71 (1) years) in the Australian Longitudinal Study on Women's Health. Self-reported noninjurious and injurious falls in the previous 12 months and weekly amounts and types of physical activity (brisk walking, moderate- and vigorous-intensity) were compared between the cohorts using Chi-square tests. Associations between physical activity, and noninjurious and injurious falls were estimated using multinomial logistic regressions informed by a directed acyclic graph. RESULTS: A greater proportion of the later (1946-51) cohort (59%) reached 150-300 minutes of weekly physical activity, as recommended by the World Health Organization, compared to the earlier (1921-26) cohort (43%, p < .001). A greater proportion of the later cohort reported noninjurious falls (14% vs 8%). Both cohorts reported similar proportions of injurious falls (1946-51:15%, 1921-26:14%). In both cohorts, participation in 150-300 minutes of physical activity was associated with lower odds of noninjurious falls (adjusted Odds Ratio, 95% CI: 1921-26: 0.66, 0.52-0.84; 1946-51: 0.78, 0.63-0.97) and injurious falls (1921-26: 0.72, 0.60-0.87; 1946-51: 0.78, 0.64-0.96). CONCLUSIONS: Participation in recommended levels of physical activity was associated with reduced falls in both cohorts. However, generational differences were found with more falls and more physical activities in the women born later. Future studies could examine the reasons contributing to the generational differences.

Thermally activated delayed fluorescence tetradentate ligand-containing gold(III) complexes with preferential molecular orientation and their application in organic light-emitting devices.

A new class of thermally activated delayed fluorescence (TADF) pyridine-/pyrazine-containing tetradentate C^C^N^N gold(III) complexes have been designed and synthesized. Displaying photoluminescence quantum yields (PLQYs) of up to 0.77 in solid-state thin films, these complexes showed at-least a six-fold increase in the radiative decay rate constant (kr) in toluene upon increasing temperature from 210 to 360 K. Using variable-temperature (VT) ultrafast transient absorption (TA) spectroscopy, the reverse intersystem crossing (RISC) processes were directly observed and the activation parameters were determined, in line with the results of the Boltzmann two-level model fittings, in which the energy separation values between the lowest-lying singlet excited state (S1) and the lowest-lying triplet excited state (T1), ΔE(S1-T1), of these complexes were estimated to be in the range of 0.16-0.18 eV. Through strategic modification of the position of the electron-donating -tBu substituent in the cyclometalating ligand, the permanent dipole moments (PDMs) of these tetradentate gold(III) emitters could be manipulated to enhance their horizontal alignment in the emitting layer of organic light-emitting devices (OLEDs). Consequently, the resulting vacuum-deposited OLEDs demonstrated a 30% increase in the theoretical out-coupling efficiency (ηout), as well as promising electroluminescence (EL) performance with maximum external quantum efficiencies (EQEs) of up to 15.7%.

Exercise Interventions Delivered Through Telehealth to Improve Physical Functioning for Older Adults with Frailty, Cognitive, or Mobility Disability: A Systematic Review and Meta-Analysis.

Introductions: This study assessed the effects of telehealth-delivered exercise interventions on physical functioning for older adults and explored implementation measures related to program delivery. Methods: We conducted a systematic review of studies investigating effects of exercise interventions delivered through telehealth in adults 60+ years of age with frailty, mobility, or cognitive disability on mobility, strength, balance, falls, and quality of life (QoL). Electronic databases (MEDLINE, CINAHL, SPORTSDiscus, and Physiotherapy Evidence Database) were searched from inception until May 2022. Evidence certainty was assessed with Grading of Recommendations, Assessment, Development, and Evaluation and meta-analysis summarized study effects. Results: A total of 11 studies were included, 5 randomized controlled trials, 2 pilot studies, and 4 feasibility studies. The overall certainty of evidence was rated as "low" or "very low." Pooled between-group differences were not statistically significant, but effect sizes suggested that telehealth produced a moderate improvement on mobility (n = 5 studies; standardized mean difference [SMD] = 0.63; 95% confidence interval [CI] = -0.25 to 1.51; p = 0.000, I2 = 86%) and strength (n = 4; SMD = 0.73; 95% CI = -0.10 to 1.56; p = 0.000, I2 = 84%), a small improvement on balance (n = 3; SMD = 0.40; 95% CI = -035 to 1.15; p = 0.012, I2 = 78%), and no effect on QoL. Analysis of implementation measures suggested telehealth to be feasible in this population, given high rates of acceptability and adherence with minimal safety concerns. Discussion: Telehealth may provide small to moderate benefits on a range of physical outcomes and appears to be well received in aged care populations.

Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy.

T-cell-engaging bispecific antibodies (T-BsAb) have produced impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that a complex interplay between immune cells and tumor cells is implicated in the mechanism of action and therefore, understanding immune regulatory mechanisms might provide a clue for how to improve the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In a preclinical model of myeloma, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-B-cell maturation antigen (BCMA) T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to the production of interleukin-10 and inhibition of T-BsAb-mediated CD8 T-cell responses. The activation of Treg cells was also seen in bone marrow samples from myeloma patients after ex vivo treatment with T-BsAb, further supporting that T-BsAb have an impact on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, this information suggests that therapy-induced activation of Treg cells critically regulates anti-tumor immunity elicited by T-BsAb therapy, with important implications for improving the efficacy of such treatment.

Effects of sport or physical recreation for adults with physical or intellectual disabilities: a systematic review with meta-analysis.

OBJECTIVES: To evaluate the effects of sport or physical recreation on participation, mobility and quality of life for adults living with disabilities. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Six databases searched from inception to May 2022. ELIGIBILITY CRITERIA: Randomised controlled trials including adults living with a physical or intellectual disability, comparing sport or physical recreation to non-active control. RESULTS: Seventy-four trials (n=2954; mean age 55 years) were included. Most (70) trials included people with physical disabilities, none evaluated sport and the most common physical recreation activities tested were traditional Chinese exercise (35%), yoga (27%) and dance (18%). Mean frequency and duration was 65 min/session, two times per week for 13 weeks. Most (86%) interventions were led by people with experience and/or training in the recreation activity, and only 37% reported leader experience and/or training working with people with disabilities. Participation was measured as attendance (mean 81%, 30 intervention groups). Physical recreation improved mobility (standardised mean difference (SMD) 0.38, 95% CI 0.07 to 0.69, n=469) and walking endurance (mean difference (MD) 40.3 m, 95% CI 19.5 to 61.1, n=801) with low certainty evidence and balance (Berg Balance Scale, range 0-56 points; MD 3.4 points, 95% CI 2.3 to 4.4, n=906) and quality of life (physical health; SMD 0.37, 95% CI 0.02 to 0.72, n=468) with very low certainty evidence, but not walking speed (MD 0.03 m/s, 95% CI -0.05 to 0.11, n=486). CONCLUSION: Physical recreation may confer multiple benefits for people living with disabilities regardless of the activity chosen, thus offering a potentially enjoyable and scalable strategy to increase physical activity. PROSPERO REGISTRATION NUMBER: CRD42018104379.