The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres.

Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in the shelterin component TIN2 by introducing a TIN2-R282H mutation into cultured telomerase-positive human cells via a knock-in approach. The resulting heterozygous TIN2-R282H mutation does not perturb occupancy of other shelterin components on telomeres, result in activation of telomeric DNA damage signaling or exhibit other characteristics indicative of a telomere deprotection defect. Using a novel assay that monitors the frequency and extension rate of telomerase activity at individual telomeres, we show instead that telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. These observations suggest a direct role for TIN2 in mediating telomere length through telomerase, separable from its role in telomere protection.

Cell-Based Therapies in Vascularized Composite Allotransplantation.

BACKGROUND: Dendritic cells (DCs) are bone marrow-derived, professional antigen-presenting cells with tolerogenic function. The ability of DCs to regulate alloantigen-specific T cell responses and to promote tolerance has aligned them ideally for a role in vascularized composite allotransplantation (VCA). In this study, we summarize the current evidence for DC therapies for tolerance induction to alleviate the requirement for chronic immunosuppression. METHOD: A comprehensive and structured review of manuscripts published on VCA was performed using the MEDLINE and PubMed databases. All eligible studies published from the year 2000 to 2017 were included in the final results. RESULT: Nineteen original preclinical and clinical studies that employed cell therapy for VCA were included in this review. In vivo DC therapy was found to direct the alloimmune response toward either transplant rejection or tolerance in VCA models. While injection of mature DCs rapidly increases T-cell activity in humans and promotes transplant rejection, the injection of immature DCs acts as an immunosuppressant and inhibits T-cell activity. In addition to immature DCs, mesenchymal stem cells were also found to have a positive effect on allotransplantation of solid organs and bone marrow via cytokine expression which decreases the alloreactive effector lymphocytes and increases CD4+/CD25+/FoxP3 Tregs. Despite the promising findings, the efficacy of cell-based therapies varies greatly across studies, partly due to different methods of cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. CONCLUSION: Additional research is needed to evaluate the efficacy and safety of DC and other cell-based therapeutic measures in human allotransplant recipients. Future direction will focus on the development of novel methods to reduce immunosuppression and develop more individualized management, as well as the clinical application of basic research in the mechanisms of immunologic tolerance.

A Systematic Review of the Use of Telemedicine in Plastic and Reconstructive Surgery and Dermatology.

BACKGROUND: Telemedicine, the use of information technology and telecommunication to provide healthcare at a distance, is a burgeoning field with applications throughout medicine. Given the visual nature of plastic surgery and dermatology, telemedicine has a myriad of potential applications within the field. METHODS: A comprehensive literature review of articles published on telemedicine since January 2010 was performed. Articles were selected for their relevance to plastic and reconstructive surgery and dermatology, and then reviewed for their discussion of the applications, benefits, and limitations of telemedicine in practice. RESULTS: A total of 3119 articles were identified in the initial query. Twenty-three articles met the inclusion criteria in plastic surgery (7 wound management, 5 burn management, 5 trauma, 4 free flap care, 2 in cleft lip/palate repair). Twenty-three (100%) reported a benefit of telemedicine often related to improved postoperative monitoring, increased access to expertise in rural settings, and cost savings, either predicted or actualized. Eight (35%) reported limitations and barriers to the application of telemedicine, including overdiagnosis and dependence on functional telecommunication systems. Sixty-six articles focused on telemedicine in dermatology and also demonstrated significant promise. CONCLUSIONS: Telemedicine holds special promise in increasing the efficiency of postoperative care for microsurgical procedures, improving care coordination and management of burn wounds, facilitating interprofessional collaboration across time and space, eliminating a significant number of unnecessary referrals, and connecting patients located far from major medical centers with professional expertise without impinging on-and in some cases improving-the quality or accuracy of care provided. Teledermatology consultation was found to be safe and has a comparable or superior efficacy to the traditional in-patient consultation. The system was consistently rated as convenient and easy to use by patients, referring physicians, and consulting dermatologists. Teledermatology has also been used as an educational tool for patients. A significant number of studies detailed strategies to improve the current state of teledermatology, either by implementing new programs or improving technologies. Telemedicine use is widespread among plastic surgeons and is enabling the spread of expertise beyond major medical centers. Further research is needed to conclusively demonstrate benefit in routine clinical care.

Bictegravir-Induced Drug Reaction With Eosinophilia and Systemic Symptoms in a Patient With Acute Human Immunodeficiency Virus.

Although drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with antiretrovirals, there are no published reports of bictegravir-induced DRESS. Bictegravir is recommended as first-line treatment for patients with human immunodeficiency virus (HIV). Recognition of DRESS, its skin manifestations, and potential complications is vital for appropriate care and management of acute HIV.

How and why studies disagree about the effects of education on health: A systematic review and meta-analysis of studies of compulsory schooling laws.

Rich literatures across multiple disciplines document the association between increased educational attainment and improved health. While quasi-experimental studies have exploited variation in educational policies to more rigorously estimate the health effects of education, there remains disagreement about whether education and health are causally linked. The aim of this study was to conduct a systematic review and meta-analysis to characterize this literature, with a focus on quasi-experimental studies of compulsory schooling laws (CSLs). Articles from 1990 to 2015 were obtained through electronic searches and manual searches of reference lists. We searched for English-language studies and included manuscripts if: (1) they involved original data analysis; (2) outcomes were health-related; and (3) the primary predictor utilized variation in CSLs. We identified 89 articles in 25 countries examining over 25 health outcomes, with over 600 individual point estimates. We systematically characterized heterogeneity on key study design features and conducted a meta-analysis of studies with comparable health outcome and exposure variables. Within countries, studies differed in terms of birth cohorts included, the measurement of health outcomes within a given category, and the type of CSL variation examined. Over 90% of manuscripts included multiple analytic techniques, such as econometric and standard regression methods, with as many as 31 "primary" models in a single study. A qualitative synthesis of study findings indicated that educational attainment has an effect on the majority of health outcomes-most beneficial, some negative-while the meta-analysis demonstrated small beneficial effects for mortality, smoking, and obesity. Future work could focus on inconsistent findings identified by this study, or review the health effects of other types of educational policies.