Articular cartilage defect repair is a problem that has long plagued clinicians. Although mesenchymal stem cells (MSCs) have the potential to regenerate articular cartilage, they also have many limitations. Recent studies have found that MSC-derived exosomes (MSC-Exos) play an important role in tissue regeneration. The purpose of this study was to verify whether MSC-Exos can enhance the reparative effect of the acellular cartilage extracellular matrix (ACECM) scaffold and to explore the underlying mechanism. The results of in vitro experiments show that human umbilical cord Wharton's jelly MSC-Exos (hWJMSC-Exos) can promote the migration and proliferation of bone marrow-derived MSCs (BMSCs) and the proliferation of chondrocytes. We also found that hWJMSC-Exos can promote the polarization of macrophages toward the M2 phenotype. The results of a rabbit knee osteochondral defect repair model confirmed that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration. We demonstrated that hWJMSC-Exos can regulate the microenvironment of the articular cavity using a rat knee joint osteochondral defect model. This effect was mainly manifested in promoting the polarization of macrophages toward the M2 phenotype and inhibiting the inflammatory response, which may be a promoting factor for osteochondral regeneration. In addition, microRNA (miRNA) sequencing confirmed that hWJMSC-Exos contain many miRNAs that can promote the regeneration of hyaline cartilage. We further clarified the role of hWJMSC-Exos in osteochondral regeneration through target gene prediction and pathway enrichment analysis. In summary, this study confirms that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration.
We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard-risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III-IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5-year cumulative transplant-related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5-year relapse rate post-transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5-year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5-year disease-free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3-year GVHD-free, relapse-free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard-risk adults with ALL in CR1 who lack matched donors.
Background and Purpose Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke, but little is known about its epidemiology. We studied the prevalence of ICAS and its association with vascular risk factors using high resolution magnetic resonance angiography (MRA) in a U.S. cardiovascular cohort. Methods The Atherosclerosis Risk in Communities (ARIC) study recruited participants from four U.S. communities from 1987-1989. Using stratified sampling, we selected 1980 participants from visit-5 (2011-2013) for high resolution 3T-MRA. All images were analyzed in a centralized lab and ICAS was graded as — no stenosis, <50% stenosis, 50-69% stenosis, 70-99% stenosis and complete occlusion. We calculated per-vessel and per-person prevalence of ICAS (weighted for n=6,538 visit-5 participants), and also estimated the U.S. prevalence. We used multivariable logistic regression to identify variables independently associated with ICAS. Results Subjects who had an adequate MRA (n=1765) were aged 67-90 years, 41% were men, 70% were white and 29% were African-American. ICAS was prevalent in 31% of participants and 9% had ICAS ≥50%. Estimated U.S. prevalence of ICAS≥50% for 65-90 years old was 8% for Whites and 12% for African-Americans. Older age, African-American race, higher systolic blood pressure, and higher low density lipoprotein cholesterol levels were associated with increased odds of ICAS, while higher levels of high density lipoprotein cholesterol and use of cholesterol lowering medications were associated with decreased odds of ICAS. Body mass index and smoking were not associated with ICAS. Conclusion The prevalence of ICAS in older adults is high, and could be a target for primary prevention of stroke and dementia in this population.
SummaryStudies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings.IntroductionOsteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited.MethodsWe examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients’ fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates.ResultsFracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39–51%), zoledronic acid (50%; 95% CI 47–52%), oral bisphosphonates (24%; 95% CI 22–26%), and teriparatide (72%; 95% CI 69–75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42–59%), zoledronic acid (25%; 95% CI 17–32%), oral bisphosphonates (23%; 95% CI 20–26%), and teriparatide (64%; 95% CI 58–69%) during the subsequent 12 months.ConclusionIn summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.Electronic supplementary materialThe online version of this article (10.1007/s11657-018-0439-3) contains supplementary material, which is available to authorized users.
Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.
Aims: Chronic, infrequent voiding may be a risk factor for lower urinary tract symptoms (LUTS) in women. To inform this hypothesis, we conducted a rapid literature review and meta-analysis of LUTS by occupation as an indirect measure of infrequent voiding behaviors. Methods: Two independent medical librarians searched Pubmed.gov studies (1990–2017) on adult women for occupations, industries, and workplace environment and LUTS outcomes: overactive bladder (OAB), urinary incontinence (UI), urinary tract infections (UTIs), and individual voiding and storage LUTS. Two authors reviewed full text articles meeting content criteria. Among studies with similar UI definitions, we estimated the prevalence of monthly UI using a random effects meta-analysis model. Results: Of 1078 unique citations identified, 113 underwent full article review and 33 met inclusion criteria. Twenty-six of these studies examined specific occupation groups, including nurses/midwives (n = 6 studies), healthcare workers/support staff (n = 6), military personnel (n = 3), teachers (n = 3), and other groups (n = 7), whereas eight compared findings across broad occupation groups. UI was reported in 30 studies (23% using validated measures), OAB in 6 (50% validated), and UTIs in 2 (non-validated). In pooled models, the degree of heterogeneity was too high (I2 = 96.9–99.2%) among the studies to perform valid prevalence estimates for LUTS. Conclusions: Current literature limits the ability to evaluate LUTS by occupation types. Future studies should characterize voiding frequency and toilet access in a consistent manner by occupation and explore its relation to LUTS development.
Background Each rare disease only affects a small number of population. However, a total of 7000 rare diseases may affect 10% of the population. Due to the severity and lack of rare disease awareness, rare disease represents a huge challenge for the healthcare system. In Western countries, patient organizations have been playing an integral role in raising awareness, advocating legislation, and supporting drug development. This study aims to assess the unmet needs of rare disease patient organizations in China, and identify their unmet needs, providing essential information for the government and legislators. Results A total of 28 individuals representing 28 patient organizations in China were interviewed. Most organizations do not have official registration, employees, written standard operation protocol, or reliable financial resources. Misdiagnosis or delayed diagnosis is common, and treatment is often lacking. Due to the lack of financial resources, no organizations have been able to sponsor academic research, unlike their counterparts in Western countries. As to challenges, 71.4% of interviewees listed lack of rare disease awareness among the general public, while 67.9% selected lack of financial resources. Further, only 7.3% of these organizations received support from the government, and 28.6% received support from the general public. As to recommendations to the government, 82.1% of interviewees selected special insurance programs for rare diseases because rare diseases have been generally excluded from the national medical insurance programs. In addition, 78.6% of interviewees recommended to stimulate rare disease research, 75% recommended to import orphan drugs, and 71.4% recommended legislation of an orphan drug act, highlighting the urgent need of therapies. Conclusions Due to lack of support and rare disease awareness, patient organizations in China are still in the early phase. To empower these patient organizations, the interviewees’ recommendations, including legislating orphan drug act and releasing official definition of rare diseases, should be considered by the government and legislators.
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