Cardiac Development Long Non-Coding RNA (CARDEL) Is Activated during Human Heart Development and Contributes to Cardiac Specification and Homeostasis.

Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

In vivo PSC differentiation as a platform to identify factors for improving the engraftability of cultured muscle stem cells.

Producing an adequate number of muscle stem cells (MuSCs) with robust regenerative potential is essential for the successful cell therapy of muscle-wasting disorders. We have recently developed a method to produce skeletal myogenic cells with exceptional engraftability and expandability through an in vivo pluripotent stem cell (PSC) differentiation approach. We have subsequently mapped engraftment and gene expression and found that leukemia inhibitory factor receptor (Lifr) expression is positively correlated with engraftability. We therefore investigated the effect of LIF, the endogenous ligand of LIFR, on cultured MuSCs and examined their engraftment potential. We found that LIF-treated MuSCs exhibited elevated expression of PAX7, formed larger colonies from single cells, and favored the retention of PAX7+ "reserve cells" upon myogenic differentiation. This suggested that LIF promoted the maintenance of cultured MuSCs at a stem cell stage. Moreover, LIF enhanced the engraftment capability of MuSCs that had been expanded in vitro for 12 days by 5-fold and increased the number of MuSCs that repopulated the stem cell pool post-transplantation. These results thereby demonstrated the effectiveness of our in vivo PSC differentiation platform to identify positive regulators of the engraftability of cultured MuSCs.

Inducing positive inotropy in human iPSC-derived cardiac muscle by gene editing-based activation of the cardiac α-myosin heavy chain.

Human induced pluripotent stem cells and their differentiation into cardiac myocytes (hiPSC-CMs) provides a unique and valuable platform for studies of cardiac muscle structure-function. This includes studies centered on disease etiology, drug development, and for potential clinical applications in heart regeneration/repair. Ultimately, for these applications to achieve success, a thorough assessment and physiological advancement of the structure and function of hiPSC-CMs is required. HiPSC-CMs are well noted for their immature and sub-physiological cardiac muscle state, and this represents a major hurdle for the field. To address this roadblock, we have developed a hiPSC-CMs (ß-MHC dominant) experimental platform focused on directed physiological enhancement of the sarcomere, the functional unit of cardiac muscle. We focus here on the myosin heavy chain (MyHC) protein isoform profile, the molecular motor of the heart, which is essential to cardiac physiological performance. We hypothesized that inducing increased expression of α-MyHC in ß-MyHC dominant hiPSC-CMs would enhance contractile performance of hiPSC-CMs. To test this hypothesis, we used gene editing with an inducible α-MyHC expression cassette into isogeneic hiPSC-CMs, and separately by gene transfer, and then investigated the direct effects of increased α-MyHC expression on hiPSC-CMs contractility and relaxation function. Data show improved cardiac functional parameters in hiPSC-CMs induced with α-MyHC. Positive inotropy and relaxation was evident in comparison to ß-MyHC dominant isogenic controls both at baseline and during pacing induced stress. This approach should facilitate studies of hiPSC-CMs disease modeling and drug screening, as well as advancing fundamental aspects of cardiac function parameters for the optimization of future cardiac regeneration, repair and re-muscularization applications.

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: A population-based cohort study.

IMPORTANCE: The use of warfarin to prevent thromboembolism in patients with infective endocarditis (IE) remains controversial due to potentially increased bleeding risks. DESIGN: Population-based retrospective cohort study. PARTICIPANTS: Patients aged 18 or older and diagnosed with IE in Hong Kong between January 1st, 1997 and August 31st, 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched for baseline characteristics using 1:1 propensity score matching. EXPOSURE: Warfarin use within 14 days of IE diagnosis. MAIN OUTCOMES AND MEASURES: Patients were followed up to 90 days for the outcomes of ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox regression was used to determine hazard ratios (HRs) [95 % confidence intervals (CIs)] between treatment groups. Fine-Gray competing risk regression with all-cause mortality as the competing event was performed as a sensitivity analysis. In addition to 90-day analyses, landmark analyses were performed at 30 days of follow-up. RESULTS: The matched cohort consisted of 675 warfarin users (57.0 % male, age 59 ± 16 years) and 675 warfarin non-users (53.5 % male, age 61 ± 19 years). Warfarin users had a 50 % decreased 90-day risk in all-cause mortality (HR:0.50 [0.39-0.65]), without significantly different 90-day risks of ischemic stroke (HR:1.04 [0.70-1.53]), intracranial hemorrhage (HR:1.25 [0.77-2.04]), and gastrointestinal bleeding (HR:1.04 [0.60-1.78]). Thirty-day landmark analysis showed similar results. Competing risk regression showed significantly higher 30-day cumulative incidence of intracranial hemorrhage in warfarin users (sub-HR:3.34 [1.34-8.31]), but not at 90-day (sub-HR:1.63 [0.95-2.81]). Results from Fine-Gray regression were otherwise congruent with those from Cox regression. CONCLUSIONS AND RELEVANCE: Warfarin initiated within 14 days of IE diagnosis was associated with significantly decreased risks of mortality but higher risks of intracranial hemorrhage, with similar risks of ischemic stroke and gastrointestinal bleeding, compared with non-use of warfarin with 14 days of IE diagnosis. KEY POINTS: Question: Is warfarin, initiated within 14 days of a diagnosis of infective endocarditis (IE), efficacious and safe? FINDINGS: In this propensity score-matched, population-based, prospective cohort study from Hong Kong, warfarin use within 14 days of IE diagnosis was associated with a 50 % decrease in the risk of all-cause mortality, albeit with higher risk of intracranial hemorrhage, and without significant differences in the risk of ischaemic stroke and gastrointestinal bleeding. Meaning: In patients with IE, warfarin use within 14 days of diagnosis may have mortality benefits, despite increased risks of intracranial hemorrhage.

Clinical effectiveness of mindfulness-based music therapy on improving emotional regulation in blind older women: A randomized controlled trial.

Background: This study aimed to investigate clinical effectiveness of a structured eight-week mindfulness-based music therapy (MBMT) program on improving mood regulation in older women with blindness. This investigation compared a MBMT group with a mindfulness intervention (MI) group and a control group. Methods: Ninety-two older females with blindness from a residential setting in Hong Kong were recruited and randomly allocated to a MBMT (n = 31), MI (n = 30), or control (n = 31) group. Psychological measurements regarding mood regulation and general mood states (namely, Difficulties in Emotion Regulation Scale [DERS], Geriatric Depression Scale [GDS], and Depression Anxiety Stress Scales-21), were taken at pretest and posttest. Outcome assessors were blinded to group assignment. Results: Data was analyzed based on intention-to-treat basis. At posttest, DERS scores in the MBMT group (mean differences and 95% confidence interval: 12.1, 5.5 to 18.8) and the MI group (7.2, 0.5 to 13.8) were lower than that in the control group. GDS scores in the MBMT group (2.9, 1.7 to 4.0) and the MI group (1.7, 0.6 to 2.9) were lower than those in the control group. Compared with the MI group, the MBMT group improved emotional awareness sub-scores in DERS (2.1, 0.2 to 4.1) and appeared to lower depression in GDS scores (1.1, -0.0 to 2.3; p = 0.053). Conclusion: MBMT seems more beneficial than MI alone for improving emotional regulation in older women with blindness. The combination of mindfulness and music can generate a synergetic effect by enhancing both attention and appraisal components within the emotional-regulation process. Trial registration: ClinicalTrials.gov, NCT05583695.

The effects of psychosocial and behavioral interventions on depressive and anxiety symptoms during the COVID-19 pandemic: a systematic review and meta-analysis.

Psychosocial and behavioral interventions have been shown to significantly reduce depressive and anxiety symptoms in different populations. Recent evidence suggests that the mental health of the general population has deteriorated significantly since the start of Coronavirus Disease 2019 (COVID-19) pandemic. We conducted a systematic review and meta-analysis of studies on the therapeutic effects of psychosocial and behavioral interventions on depression and anxiety during the COVID-19 pandemic. We systematically searched six electronic databases between December 2019 and February 2022 including PubMed, PsycINFO, Scopus, Web of Science, CNKI, and Wanfang Data. We included randomized clinical trials of psychosocial and behavioral interventions in individuals with depressive or anxiety symptoms during the COVID-19 outbreak compared to various control conditions. A total of 35 eligible studies with 5457 participants were included. The meta-analysis results showed that psychosocial and behavioral interventions had statistically significant moderate effects on depression [SMD = - 0.73, 95% CI (- 1.01, - 0.45), I2 = 90%] and large effects on anxiety [SMD = - 0.90, 95% CI (- 1.19, - 0.60), I2 = 92%], especially in the general population and COVID-19 survivors. Exercise and cognitive behavioral therapy were found to be the most effective treatments with moderate-to-large effect size for depression and anxiety during the outbreak of COVID-19. We also found the internet-based approach could also achieve almost equally significant effects on depression and anxiety compared with face-to-face traditional approach. Our findings suggest that cognitive behavioral therapy and physical exercise intervention are significantly effective for depression and anxiety related to the COVID-19 pandemic regardless of the delivery modes, and gender differences should be taken into consideration for better implementation of interventions in clinical and community practice.

Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

Background: The strategy of dual blockade of TGF-ß and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFß1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

Evaluating the Patient Boarding during Omicron Surge in Hong Kong: Time Series Analysis.

The fifth wave of COVID-19 outbreaks in Hong Kong (HK) from January to March 2022 has the highest confirmed cases and deaths compared with previous waves. Severe hospital boarding (to inpatient wards) was noted in various Emergency Departments (EDs). Our objective is to identify factors associated with hospital boarding during Omicron surge in HK. We conducted a retrospective cohort study including all ED visits and inpatient (IP) ward admissions from January 1st to March 31st, 2022. Vector Autoregression model evaluated the effects of a single variable on the targeted hospital boarding variables. Admissions from elderly homes with 6 lag days held the highest positive value of statistical significance (t-stat = 2.827, P < .05) caused prolonged admission waiting time, while medical patients with 4 lag days had the highest statistical significance (t-stat = 2.530, P < .05) caused an increased number of boarding patients. Within one week after impulses, medical occupancy's influence on the waiting time varied from 0.289 on the 1st day to -0.315 on the 7th day. While occupancy of medical wards always positively affected blocked number of patients, and its response was maximized at 0.309 on the 2nd day. Number of confirmed COVID-19 cases was not the sole significant contributor, while occupancy of medical wards was still a critical factor associated with patient boarding. Increasing ward capacity and controlling occupancy were suggested during the outbreak. Moreover, streamlining elderly patients in ED could be an approach to relieve pressure on the healthcare system.

Association of Molnupiravir and Nirmatrelvir-Ritonavir with reduced mortality and sepsis in hospitalized omicron patients: a territory-wide study.

This study evaluates the association between antivirals (Molnupiravir and Nirmatrelvir-Ritonavir) and all-cause and respiratory mortality and organ dysfunction among high-risk COVID-19 patients during an Omicron outbreak. Two cohorts, Nirmatrelvir-Ritonavir versus control and Molnupiravir versus control, were constructed with inverse probability treatment weighting to balance baseline characteristics. Cox proportional hazards models evaluated the association of their use with all-cause mortality, respiratory mortality, and all-cause sepsis (a composite of circulatory shock, respiratory failure, acute liver injury, coagulopathy, and acute liver impairment). Patients recruited were hospitalized and diagnosed with the COVID-19 Omicron variant between February 22, 2022 and April 15, 2022, and followed up until May 15, 2022. The study included 17,704 patients. There were 4.67 and 22.7 total mortalities per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio, - 18.1 [95% CI - 23.0 to - 13.2]; hazard ratio, 0.18 [95% CI, 0.11-0.29]). There were 6.64 and 25.9 total mortalities per 1000 person-days in the Molnupiravir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, - 19.3 [95% CI - 22.6 to - 15.9]; hazard ratio, 0.23 [95% CI 0.18-0.30]). In all-cause sepsis, there were 13.7 and 35.4 organ dysfunction events per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, - 21.7 [95% CI - 26.3 to - 17.1]; hazard ratio, 0.44 [95% CI 0.38-0.52]). There were 23.7 and 40.8 organ dysfunction events in the Molnupiravir and control groups respectively before adjustment (weighted incidence ratio per 1000 person-days, - 17.1 [95% CI, - 20.6 to - 13.6]; hazard ratio, 0.63 [95% CI 0.58-0.69]). Among COVID-19 hospitalized patients, use of either Nirmatrelvir-Ritonavir or Molnupiravir compared with no antiviral use was associated with a significantly lower incidence of 28-days all-cause and respiratory mortality and sepsis.

Producing Engraftable Skeletal Myogenic Progenitors from Pluripotent Stem Cells via Teratoma Formation.

Generating engraftable skeletal muscle progenitor cells is a promising cell therapy approach to treating degenerating muscle diseases. Pluripotent stem cell (PSC) is an ideal cell source for cell therapy because of its unlimited proliferative capability and potential to differentiate into multiple lineages. Approaches such as ectopic overexpression of myogenic transcription factors and growth factors-directed monolayer differentiation, while able to differentiate PSCs into the skeletal myogenic lineage in vitro, are limited in producing muscle cells that reliably engraft upon transplantation. Here we present a novel method to differentiate mouse PSCs into skeletal myogenic progenitors without genetic modification or monolayer culture. We make use of forming a teratoma, in which skeletal myogenic progenitors can be routinely obtained. We first inject mouse PSCs into the limb muscle of an immuno-compromised mouse. Within 3-4 weeks, α7-integrin+ VCAM-1+ skeletal myogenic progenitors are purified by fluorescent-activated cell sorting. We further transplant these teratoma-derived skeletal myogenic progenitors into dystrophin-deficient mice to assess engraftment efficiency. This teratoma formation strategy is capable of generating skeletal myogenic progenitors with high regenerative potency from PSCs without genetic modifications or growth factors supplementation.

Efficient Muscle Regeneration by Human PSC-Derived CD82+ ERBB3+ NGFR+ Skeletal Myogenic Progenitors.

Differentiation of pluripotent stem cells (PSCs) is a promising approach to obtaining large quantities of skeletal myogenic progenitors for disease modeling and cell-based therapy. However, generating skeletal myogenic cells with high regenerative potential is still challenging. We recently reported that skeletal myogenic progenitors generated from mouse PSC-derived teratomas possess robust regenerative potency. We have also found that teratomas derived from human PSCs contain a skeletal myogenic population. Here, we showed that these human PSC-derived skeletal myogenic progenitors had exceptional engraftability. A combination of cell surface markers, CD82, ERBB3, and NGFR enabled efficient purification of skeletal myogenic progenitors. These cells expressed PAX7 and were able to differentiate into MHC+ multinucleated myotubes. We further discovered that these cells are expandable in vitro. Upon transplantation, the expanded cells formed new dystrophin+ fibers that reconstituted almost ¾ of the total muscle volume, and repopulated the muscle stem cell pool. Our study, therefore, demonstrates the possibility of producing large quantities of engraftable skeletal myogenic cells from human PSCs.

The Effects of a Mindfulness-Based Family Psychoeducation Intervention for the Caregivers of Young Adults with First-Episode Psychosis: A Randomized Controlled Trial.

OBJECTIVE: In this study, we investigated the effects of a mindfulness-based family psychoeducation (MBFPE) program on the mental-health outcomes of both caregivers and young adults with first-episode psychosis with an onset in the past three years through a multi-site randomized controlled trial. We also studied the outcomes of three potential mediating effects of interpersonal mindfulness, expressed emotions, and non-attachment on the program. METHOD: We randomly assigned 65 caregivers of young adults with psychosis to MBFPE (n = 33) or an ordinary family psychoeducation (FPE) program (n = 32); among them, 18 young adults in recovery also participated in the evaluation of outcomes. RESULTS: Intent-to-treat analyses were conducted. No significant time × group interaction effects of MBFPE and FPE programs were found in any of the caregivers' outcomes. However, the young adults with psychosis reported higher levels of recovery after the MBFPE program than after the ordinary FPE program (F = 8.268, p = 0.012, d = 1.484). They also reported a larger reduction in over-involvement of their caregivers (F = 4.846, p = 0.044, d = 1.136), showing that MBFPE had a superior effect to FPE in promoting recovery and reducing over-involvement. CONCLUSIONS: A brief psychoeducation program may not reduce the burden on or improve the mental-health outcome of caregivers of individuals with recent-onset psychosis. However, integrating mindfulness into a conventional family psychoeducation program may reduce the expressed emotions of caregivers, especially over-involvement. Further studies should explore how psychoeducation programs can reduce the impact of psychosis on family through sustainable effects in terms of reducing their burden and expressed emotions, using a rigorous study and adequate sample size.

Association of Molnupiravir and Nirmatrelvir-Ritonavir with preventable mortality, hospital admissions and related avoidable healthcare system cost among high-risk patients with mild to moderate COVID-19.

Background: Real-world data is currently limited on the association between oral antiviral therapy and healthcare system burden in patients with mild-to-moderate COVID-19. This study aims to evaluate the clinical and cost effectiveness of Molnupiravir and Nirmatrelvir-ritonavir use in reducing mortality in this population. Methods: This is a retrospective cohort study involving 54,355 COVID-19 patients during February 22-March 31,2022 in Hong Kong. Inverse probability of treatment weighting (IPTW) was used to adjust patient characteristics. Our exposure of interest was Molnupiravir/Nirmatrelvir-Ritonavir prescription, with all-cause mortality as the primary outcome. IPTW-adjusted multivariate regressions were used to estimate treatment impact on clinic re-attendance and unplanned admissions. Finally, attributed cost and incremental cost-effectiveness ratios (ICER) were estimated. Findings: In the outpatient cohort (N = 33,217, 61.1%), 16.1% used Molnupiravir and 13.4% used Nirmatrelvir-Ritonavir, while in the inpatient cohort (N = 21,138, 38.9%), 3.8% used Molnupiravir and 1.3% used Nirmatrelvir-Ritonavir. IPTW-adjusted Cox model estimated that Molnupiravir (hazard ratio (HR)(95%CI)=0.31 (0.24-0.40), P< 0.0001) and Nirmatrelvir-Ritonavir (HR=0.10 (95%CI 0.05-0.21), P< 0.0001) were significantly associated with a reduced mortality hazard. In the outpatient cohort, both antiviral prescriptions were associated with reduced odds for unplanned hospital admissions (Molnupiravir: odds ratio (OR) =0.72 (0.52-0.98), P=0.039; Nirmatrelvir-Ritonavir: OR=0.37 (0.23-0.60), P<0.0001). Among hospitalised patients, both antiviral prescriptions were associated with significant reductions in the odds ratios for 28-days readmission (Molnupiravir: OR=0.71 (0.52-0.97), P=0.031; Nirmatrelvir-Ritonavir: OR=0.47 (0.24-0.93), P=0.030). ICERs for death averted for Molnupiravir stood at USD493,345.09 in outpatient settings and USD2,629.08 in inpatient settings. In outpatient settings, Nirmatrelvir-ritonavir cost USD331,105.27 to avert one death, but saved USD5,502.53 to avert one death in comparison with standard care. Interpretation: In high-risk patients in Hong Kong with mild-to-moderate COVID-19, Molnupiravir and Nirmatrelvir-Ritonavir prescriptions were associated with reduced all-cause mortality and significant cost savings. Funding: Centre for Health Systems & Policy Research is funded by The Tung's Foundation; and The Laboratory of Data Discovery for Health Limited(D24H) is funded the AIR@InnoHK platform administered by the Innovation and Technology Commission of Hong Kong. Funders did not have any role in study design, data collection, data analysis, interpretation and writing of this manuscript.

Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages.

Many developmental signaling pathways have been implicated in lineage-specific differentiation; however, mechanisms that explicitly control differentiation timing remain poorly defined in mammals. We report that murine Hedgehog signaling is a heterochronic pathway that determines the timing of progenitor differentiation. Hedgehog activity was necessary to prevent premature differentiation of second heart field (SHF) cardiac progenitors in mouse embryos, and the Hedgehog transcription factor GLI1 was sufficient to delay differentiation of cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro, akin to that of SHF progenitors in vivo, which prevented the onset of the cardiac differentiation program. A Hedgehog signaling-dependent active-to-repressive GLI transition functioned as a differentiation timer, restricting the progenitor network to the SHF. GLI1 expression was associated with progenitor status across germ layers, and it delayed the differentiation of neural progenitors in vitro, suggesting a broad role for Hedgehog signaling as a heterochronic pathway.

The effects of an integrated mindfulness-based tai chi chuan programme on sleep disturbance among community-dwelling elderly people: protocol for a randomized controlled trial.

BACKGROUND: Many elderly individuals who experience sleep disturbances would consider complementary and alternative medicine as an alternative therapeutic option in light of the limitations of traditional treatments. Mindfulness-based interventions (MBIs) and Tai Chi Chuan (TCC) are two alternative forms of complementary and alternative medicine. They both share the common feature of a focus on breathing but represent distinct approaches with different mechanisms and philosophical orientations. The trial described in this protocol aims to evaluate the effects of an integrated form of mindfulness-based Tai Chi Chuan (MBTCC) programme and the underlying mechanisms of the beneficial effects over a 12-month follow-up. METHODS: The planned study is a four-armed randomized controlled trial with repeated measures. A total of 256 community-dwelling older adults with sleep problems will be recruited and randomized into four groups: (1) an MBTCC group, (2) an MBI group, (3) a TCC group, and (4) a sleep hygiene education (SHE) control group. The outcome measures in terms of insomnia severity, interoception, sleep-wake pattern, health status, rumination, and hyperarousal level will be collected at four time points: at baseline (T1), after the 8-week intervention (T2), 6 months after the intervention (T3), and 1 year after the intervention (T4). In addition, qualitative evaluation through focus group interviews will be conducted at the end of the 12-month assessment period (T4). DISCUSSION: This trial will illuminate the synergetic effect of combining both MBIs and TCC on optimizing improvements in sleep disturbance. The findings from this study can provide empirical support for this integrated treatment, which provides an alternative for healthcare professionals in elderly service to select appropriate practices to treat elderly people with sleep disturbance. It can further help to lessen the growing public health burden of sleep disturbances among the elderly living in the community. TRIAL REGISTRATION: ClinicalTrials.gov . NCT05396092 . Published on 24 May 2022.

Effects of mindfulness-based intervention programs on sleep among people with common mental disorders: A systematic review and meta-analysis.

BACKGROUND: Sleep problems are particularly prevalent in people with depression or anxiety disorder. Although mindfulness has been suggested as an important component in alleviating insomnia, no comprehensive review and meta-analysis has been conducted to evaluate the effects of different mindfulness-based intervention (MBI) programs on sleep among people with depression or anxiety disorder. AIM: To compare the effects of different MBI programs on sleep among people with depression or anxiety disorder. METHODS: Related publications in Embase, Medline, PubMed and PsycINFO databases were systematically searched from January 2010 to June 2020 for randomised controlled trials. Data were synthesized using a random-effects or a fixed-effects model to analyse the effects of various MBI programs on sleep problems among people with depression or anxiety disorder. The fixed-effects model was used when heterogeneity was negligible, and the random-effects model was used when heterogeneity was significant to calculate the standardised mean differences (SMDs) and 95% confidence intervals (CIs). RESULTS: We identified 397 articles, of which 10 randomised controlled trials, involving a total of 541 participants, were included in the meta-analysis. Studies of internet mindfulness meditation intervention (IMMI), mindfulness meditation (MM), mindfulness-based cognitive therapy (MBCT), mindfulness-based stress reduction (MBSR) and mindfulness-based touch therapy (MBTT) met the inclusion criteria. The greatest effect sizes are reported in favour of MBTT, with SMDs of -1.138 (95%CI: -1.937 to -0.340; P = 0.005), followed by -1.003 (95%CI: -1.645 to -0.360; P = 0.002) for MBCT. SMDs of -0.618 (95%CI: -0.980 to -0.257; P = 0.001) and -0.551 (95%CI: -0.842 to -0.260; P < 0.0001) were reported for IMMI and MBSR in the pooling trials, respectively. Significant effects on sleep problem improvement are shown in all reviewed MBI programs, except MM, for which the effect size was shown to be non-significant. CONCLUSION: All MBI programs (MBTT, MBCT, IMMI and MBSR), except MM, are effective options to improve sleep problems among people with depression or anxiety disorder.

Defining the Skeletal Myogenic Lineage in Human Pluripotent Stem Cell-Derived Teratomas.

Skeletal muscle stem cells are essential to muscle homeostasis and regeneration after injury, and have emerged as a promising cell source for treating skeletal disorders. An attractive approach to obtain these cells utilizes differentiation of pluripotent stem cells (PSCs). We recently reported that teratomas derived from mouse PSCs are a rich source of skeletal muscle stem cells. Here, we showed that teratoma formation is also capable of producing skeletal myogenic progenitors from human PSCs. Using single-cell transcriptomics, we discovered several distinct skeletal myogenic subpopulations that represent progressive developmental stages of the skeletal myogenic lineage and recapitulate human embryonic skeletal myogenesis. We further discovered that ERBB3 and CD82 are effective surface markers for prospective isolation of the skeletal myogenic lineage in human PSC-derived teratomas. Therefore, teratoma formation provides an accessible model for obtaining human skeletal myogenic progenitors from PSCs.

The Association between Trajectories of Loneliness and Physical Frailty in Chinese Older Adults: Does Age Matter?

Background: The present study aimed to examine age differences in the relationship between trajectories of loneliness and physical frailty among Chinese older adults. Methods: A total of 4618 participants aged ≥60 years old were taken from pooled data created from the 2011−2015 China Health and Retirement Longitudinal Study (CHARLS). Loneliness was assessed by a single question from the Centre for Epidemiological Studies scale, whereas physical frailty (PF) was examined by the physical frailty phenotype scale. We characterized trajectories of loneliness and PF using transition types and changes within the survey period. Results: Logistic regression models revealed that baseline loneliness was significantly related to remaining robust PF (OR = 0.55, 95% CI = 0.49−0.63, p < 0.001) and worsening in PF (OR = 1.17, 95% CI = 1.05−1.30, p < 0.01) at follow-up. Baseline PF status was also significantly related to the transitions in loneliness (worsen: OR = 1.41, 95% CI = 1.11−1.78, p < 0.01; improve: OR = 0.65, 95% CI = 0.47−0.91, p < 0.05). The cross-lagged panel model found that baseline PF or loneliness had a significant predictive effect on the changes in each other. The associations between trajectories of loneliness and PF were weakened with age and clustered in the under 75 age groups. Conclusions: Bidirectional associations may exist between trajectories of loneliness and PF among Chinese older adults. Interventions should mainly target the young-old to reduce the adverse reciprocal effects of loneliness and PF.

Non-invasive brain stimulation combined with psychosocial intervention for depression: a systematic review and meta-analysis.

OBJECTIVES: This review investigates the efficacy and safety of non-invasive brain stimulation (NIBS) combined with psychosocial intervention on depressive symptoms. MATERIALS AND METHODS: We systematically searched five electronic databases from their inception to June 2021: PubMed, Embase, PsycINFO, Web of Science, and Medline. Randomized or non-randomized clinical trials in which NIBS plus psychosocial intervention was compared to control conditions in people with depressive symptoms were included. RESULTS: A total of 17 eligible studies with 660 participants were included. The meta-analysis results showed that NIBS combined with psychosocial therapy had a positive effect on moderate to severe depression ([SMD = - 0.46, 95%CI (- 0.90, - 0.02), I2 = 73%, p < .01]), but did not significantly improve minimal to mild depression ([SMD = - 0.12, 95%CI (- 0.42, 0.18), I2 = 0%, p = .63]). Compared with NIBS alone, the combination treatment had a significantly greater effect in alleviating depressive symptoms ([SMD = - 0.84, 95%CI (- 1.25, - 0.42), I2 = 0%, p = .93]). However, our results suggested that the pooled effect size of ameliorating depression of NIBS plus psychosocial intervention had no significant difference compared with the combination of sham NIBS [SMD = - 0.12, 95%CI (- 0.31, 0.07), I2 = 0%, p = .60] and psychosocial intervention alone [SMD = - 0.97, 95%CI (- 2.32, 0.38), I2 = 72%, p = .01]. CONCLUSION: NIBS when combined with psychosocial intervention has a significant positive effect in alleviating moderately to severely depressive symptoms. Further well-designed studies of NIBS combined with psychosocial intervention on depression should be carried out to consolidate the conclusions and explore the in-depth underlying mechanism.

Sequential multiple mediation of cognitive fusion and experiential avoidance in the relationship between rumination and social anxiety among Chinese adolescents.

BACKGROUND AND OBJECTIVES: The potential mechanism by which rumination influences social anxiety through cognitive fusion and experiential avoidance proposed by the Acceptance and Commitment Therapy model has not been well-documented. This study, therefore, aimed to examine the sequential multiple mediation of the two processes. DESIGN: A cross-sectional survey was conducted. METHOD: A total of 233 Chinese adolescents (42.06% girls) completed a set of printed self-report questionnaires measuring rumination, cognitive fusion, experiential avoidance, and social anxiety. The SPSS macro PROCESS (model 6) was used to test a sequential mediating model. A 95% confidence interval (CI) was calculated with 5000 bootstrapping re-samples. RESULTS: Bootstrap analyses indicated that there were indirect effects of rumination on social anxiety mediated by cognitive fusion together with experiential avoidance (B = 0.098, BootSE = 0.032, CI = 0.045 to 0.170), or solely by experiential avoidance (B = 0.048, BootSE = 0.020, CI = 0.014 to 0.093). The mediation of cognitive fusion alone was not significant (B = 0.065, BootSE = 0.038, CI = -0.006 to 0.144). CONCLUSIONS: The results indicated the sequential mediating role of cognitive fusion and experiential avoidance, and the relative prominence of the latter in the association between rumination and social anxiety.