Size-Based Microfluidic-Enriched Mesenchymal Stem Cell Subpopulations Enhance Articular Cartilage Repair.

BACKGROUND: The functional heterogeneity of culture-expanded mesenchymal stem cells (MSCs) has hindered the clinical application of MSCs. Previous studies have shown that MSC subpopulations with superior chondrogenic capacity can be isolated using a spiral microfluidic device based on the principle of inertial cell focusing. HYPOTHESIS: The delivery of microfluidic-enriched chondrogenic MSCs that are consistent in size and function will overcome the challenge of the functional heterogeneity of expanded MSCs and will significantly improve MSC-based cartilage repair. STUDY DESIGN: Controlled laboratory study. METHODS: A next-generation, fully automated multidimensional double spiral microfluidic device was designed to provide more refined and efficient isolation of MSC subpopulations based on size. Analysis of in vitro chondrogenic potential and RNA sequencing was performed on size-sorted MSC subpopulations. In vivo cartilage repair efficacy was demonstrated in an osteochondral injury model in 12-week-old rats. Defects were implanted with MSC subpopulations (n = 6 per group) and compared with those implanted with unsegregated MSCs (n = 6). Osteochondral repair was assessed at 6 and 12 weeks after surgery by histological, micro-computed tomography, and mechanical analysis. RESULTS: A chondrogenic MSC subpopulation was efficiently isolated using the multidimensional double spiral device. RNA sequencing revealed distinct transcriptomic profiles and identified differential gene expression between subpopulations. The delivery of a chondrogenic MSC subpopulation resulted in improved cartilage repair, as indicated by histological scoring, the compression modulus, and micro-computed tomography of the subchondral bone. CONCLUSION: We have established a rapid, label-free, and reliable microfluidic protocol for more efficient size-based enrichment of a chondrogenic MSC subpopulation. Our proof-of-concept in vivo study demonstrates the enhanced cartilage repair efficacy of these enriched chondrogenic MSCs. CLINICAL RELEVANCE: The delivery of microfluidic-enriched chondrogenic MSCs that are consistent in size and function can overcome the challenge of the functional heterogeneity of expanded MSCs, resulting in significant improvement in MSC-based cartilage repair. The availability of such rapid, label-free enriched chondrogenic MSCs can enable better cell therapy products for cartilage repair with improved treatment outcomes.

A Systematic Review and Meta-Analysis of the Clinical Use of Megestrol Acetate for Cancer-Related Anorexia/Cachexia.

Cancer-related anorexia/cachexia is known to be associated with worsened quality of life and survival; however, limited treatment options exist. Although megestrol acetate (MA) is often used off-label to stimulate appetite and improve anorexia/cachexia in patients with advanced cancers, the benefits are controversial. The present meta-analysis aimed to better elucidate the clinical benefits of MA in patients with cancer-related anorexia/cachexia. A systematic search of PubMed, EMBASE, OVID Medline, Clinicaltrials.gov, and Google Scholar databases found 23 clinical trials examining the use of MA in cancer-related anorexia. The available randomized, controlled trials were appraised using Version 2 of the Cochrane risk-of-bias tool (RoB 2) and they had moderate-to-high risk of bias. A total of eight studies provided sufficient data on weight change for meta-analysis. The studies were divided into high-dose treatment (>320 mg/day) and low-dose treatment (≤320 mg/day). The overall pooled mean change in weight among cancer patients treated with MA, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ2 = 9.35, I2 = 96%). Patients who received high-dose MA tended to have weight loss rather than weight gain. There were insufficient studies to perform a meta-analysis for the change in tricep skinfold, midarm circumference, or quality of life measures. MA was generally well-tolerated, except for a clear thromboembolic risk, especially with higher doses. On balance, MA did not appear to be effective in providing the symptomatic improvement of anorexia/cachexia in patients with advanced cancer.

A scoping review of qualitative studies on pre-hospital analgesia administration and practice.

BACKGROUND: Pain is an exceedingly common complaint in the pre-hospital setting. Despite advancements in organizational protocols and guidelines, many emergency medical services (EMS) systems still fail to provide optimal pain management. This scoping review thus aimed to map the body of qualitative literature pertaining to factors influencing pre-hospital analgesia administration and practice in order to clarify concepts and understanding as well as to identify any knowledge gaps. METHODS: The review protocol was guided by the framework outlined by Arksey and O'Malley and ensuing recommendations made by Levac and colleagues. Five databases were searched from inception till October 26, 2021, namely MEDLINE, EMBASE, CINAHL, The Cochrane Library, and Scopus. The search strategy was developed in consultation with a medical information specialist. A total of 5848 records were screened by abstract and title by four independent researchers. 199 records were included for full text review. From these, 15 articles were eligible for thematic analysis based on pre-defined inclusion criteria. RESULTS: Included studies found that practitioner, patient, and environmental factors influenced the administration and practice of pre-hospital analgesia. Key barriers included the difficulty in assessing pain, poor inter-professional relationship, knowledge deficits, stress and anxiety, and miscellaneous factors, such as concerns over drug-seeking behaviours. Some possible solutions were proposed, and pre-hospital EMS systems and healthcare institutions could consider bridging some of these gaps. There was a notable paucity of Asian studies, and a variety of EMS settings with different protocols and workflows were examined, hence systemic factors including guidelines and legislations cannot and should not be generalized across every healthcare system. CONCLUSION: The factors influencing pre-hospital analgesia administration and practice remain incompletely understood. Existing tools and practice guidelines were also inadequate. This scoping review provided an overarching perspective of the extant literature, highlighting some of the significant barriers, enablers, and areas for further research.

A Pre-Clinical Animal Study for Zonal Articular Cartilage Regeneration Using Stratified Implantation of Microcarrier Expanded Zonal Chondrocytes.

OBJECTIVE: The zonal properties of articular cartilage critically contribute to the mechanical support and lubrication of the tissue. Current treatments for articular cartilage have yet to regenerate this zonal architecture, thus compromising the functional efficacy of the repaired tissue and leading to tissue degeneration in the long term. In this study, the efficacy of zonal cartilage regeneration through bilayered implantation of expanded autologous zonal chondrocytes was investigated in a porcine chondral defect model. DESIGN: Autologous chondrocytes extracted from articular cartilage in the non-weight bearing trochlea region of the knee were subjected to an expansion-sorting strategy, integrating dynamic microcarrier (dMC) culture, and spiral microchannel size-based zonal chondrocyte separation. Zonal chondrocytes were then implanted as bilayered fibrin hydrogel construct in a porcine knee chondral defect model. Repair efficacy was compared with implantation with cell-free fibrin hydrogel and full thickness (FT) cartilage-derived heterogenous chondrocytes. Cartilage repair was evaluated 6 months after implantation. RESULTS: Sufficient numbers of zonal chondrocytes for implantation were generated from the non-weight bearing cartilage. Six-month repair outcomes showed that bilayered implantation of dMC-expanded zonal chondrocytes resulted in substantial recapitulation of zonal architecture, including chondrocyte arrangement, specific Proteoglycan 4 distribution, and collagen alignment, that was accompanied by healthier underlying subchondral bone. CONCLUSION: These results demonstrate that with appropriate expansion and isolation of zonal chondrocytes, the strategy of stratified zonal chondrocyte implantation represents a significant advancement to Autologous Chondrocyte Implantation-based cartilage regeneration, with the potential to improve the long-term integrity of the regenerated tissues.

Centile Charts for Monitoring of Weight Loss Trajectories After Bariatric Surgery in Asian Patients.

BACKGROUND: Following bariatric surgery, accurate charting of weight loss and regain is crucial. Various preoperative factors affect postoperative weight loss, including age, sex, ethnicity, and surgical type. These are not considered by current weight loss metrics, limiting comparison of weight loss outcomes between patients or centers and across time. METHODS: Patients (n=1022) who underwent sleeve gastrectomy (n=809) and gastric bypass (n=213) from 2008 to 2020 in a single center were reviewed. Weight loss outcomes (% total weight loss) were measured for 60 months postoperatively. Longitudinal centile lines were plotted using the post-estimation predictions of quantile regression models, adjusted for type of procedure, sex, ethnicity, and baseline BMI. RESULTS: Median regression showed that %TWL was 1.0% greater among males than females (ß = +1.1, 95% CI: +0.6 to +1.7, P = <0.0001). Participants who underwent SG had less %TWL compared to GB (ß = -1.3, 95% CI: -1.9 to -0.8, P < 0.0001). There was a trend towards less %TWL among the Indian and Malay participants compared to Chinese. Age and diabetes were not significant predictors. Reference centile charts were produced for the overall cohort, as well as specific charts adjusted for type of bariatric procedure, sex, ethnicity, and baseline BMI. CONCLUSION: Centile charts provide a clinically relevant method for monitoring of weight trajectories postoperatively and aid in realistic and personalised goal setting, and the early identification of "poor responders". This is the first study to present post-bariatric surgery centile charts for an Asian cohort.

Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants.

BACKGROUND: Metabolic-bariatric surgery delivers substantial weight loss and can induce remission or improvement of obesity-related risks and complications. However, more robust estimates of its effect on long-term mortality and life expectancy-especially stratified by pre-existing diabetes status-are needed to guide policy and facilitate patient counselling. We compared long-term survival outcomes of severely obese patients who received metabolic-bariatric surgery versus usual care. METHODS: We did a prespecified one-stage meta-analysis using patient-level survival data reconstructed from prospective controlled trials and high-quality matched cohort studies. We searched PubMed, Scopus, and MEDLINE (via Ovid) for randomised trials, prospective controlled studies, and matched cohort studies comparing all-cause mortality after metabolic-bariatric surgery versus non-surgical management of obesity published between inception and Feb 3, 2021. We also searched grey literature by reviewing bibliographies of included studies as well as review articles. Shared-frailty (ie, random-effects) and stratified Cox models were fitted to compare all-cause mortality of adults with obesity who underwent metabolic-bariatric surgery compared with matched controls who received usual care, taking into account clustering of participants at the study level. We also computed numbers needed to treat, and extrapolated life expectancy using Gompertz proportional-hazards modelling. The study protocol is prospectively registered on PROSPERO, number CRD42020218472. FINDINGS: Among 1470 articles identified, 16 matched cohort studies and one prospective controlled trial were included in the analysis. 7712 deaths occurred during 1·2 million patient-years. In the overall population consisting 174 772 participants, metabolic-bariatric surgery was associated with a reduction in hazard rate of death of 49·2% (95% CI 46·3-51·9, p<0·0001) and median life expectancy was 6·1 years (95% CI 5·2-6·9) longer than usual care. In subgroup analyses, both individuals with (hazard ratio 0·409, 95% CI 0·370-0·453, p<0·0001) or without (0·704, 0·588-0·843, p<0·0001) baseline diabetes who underwent metabolic-bariatric surgery had lower rates of all-cause mortality, but the treatment effect was considerably greater for those with diabetes (between-subgroup I2 95·7%, p<0·0001). Median life expectancy was 9·3 years (95% CI 7·1-11·8) longer for patients with diabetes in the surgery group than the non-surgical group, whereas the life expectancy gain was 5·1 years (2·0-9·3) for patients without diabetes. The numbers needed to treat to prevent one additional death over a 10-year time frame were 8·4 (95% CI 7·8-9·1) for adults with diabetes and 29·8 (21·2-56·8) for those without diabetes. Treatment effects did not appear to differ between gastric bypass, banding, and sleeve gastrectomy (I2 3·4%, p=0·36). By leveraging the results of this meta-analysis and other published data, we estimated that every 1·0% increase in metabolic-bariatric surgery utilisation rates among the global pool of metabolic-bariatric candidates with and without diabetes could yield 5·1 million and 6·6 million potential life-years, respectively. INTERPRETATION: Among adults with obesity, metabolic-bariatric surgery is associated with substantially lower all-cause mortality rates and longer life expectancy than usual obesity management. Survival benefits are much more pronounced for people with pre-existing diabetes than those without. FUNDING: None.

Effects of Electromagnetic Field on Proliferation, Differentiation, and Mineralization of MC3T3 Cells.

IMPACT STATEMENT: We present the study about how the parameters of pulsed electromagnetic field (PEMF) stimulus affected calvarial osteoblast precursor cell in terms of growth, viability, and differentiation. This research provides insight and foundation to clinical application of noninvasive therapy using PEMF to improve bone regeneration.

Risk of weight gain associated with antipsychotic treatment: results from the Canadian National Outcomes Measurement Study in Schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain occurs in a substantial percentage of treated persons. There remains a paucity of naturalistic data that describe relative weight-gain liability with the available novel atypical antipsychotics (NAPs). This investigation describes comparative NAP-induced weight gain in a prospective naturalistic cohort of persons with schizophrenia and related psychotic disorders. METHODS: The Canadian National Outcomes Measurement Study in Schizophrenia (CNOMSS) is an ongoing prospective, longitudinal, naturalistic study involving 32 academic and community sites across Canada. Persons with DSM-IV-defined schizophrenia, schizophreniform or schizoaffective disorder, and psychosis not otherwise specified were consecutively enrolled. The overarching objectives of this initiative were to collect and compare global effectiveness, tolerability, safety, and humanistic outcomes in persons receiving commercially available NAPs in Canada. This analysis reports only weight change with the respective NAPs. Other outcomes were reported in separate companion papers. RESULTS: A spectrum of weight-gain liability was noted with quetiapine (QUE) (mean 7.55 kg, SD 9.20; P = 0.28), olanzapine (OLZ) (mean 3.72 kg, SD 0.56; P = 0.15), and risperidone (RIS) (mean 1.62 kg, SD 7.72; P = 0.43). Categorically defined weight gain (that is, over 7% of baseline weight) was observed in 55.6% of QUE patients, 24.1% of OLZ patients, and 23.7% of RIS patients. Adjusting for demographic and disease-specific confounding factors, QUE patients had greater odds of gaining over 7% of their baseline weight compared with RIS patients (odds ratio [OR] 3.62; 95% CI, 1.02 to 12.83; P = 0.05). No statistical difference was detected between OLZ patients and RIS patients for over 7% of baseline weight (OR 1.54; 95% CI, 0.63 to 3.75; P = 0.12) or over 10% weight gain (OR 1.44; 95% CI, 0.50 to 4.13; P = 0.58). CONCLUSION: Clinicians are reminded to monitor anthropometric and metabolic parameters in all NAP-treated persons. Clinically significant differences in weight gain liability exist among the available NAPs.