Differentiation of regulatory myeloid and T-cells from adult human hematopoietic stem cells after allogeneic stimulation.

Introduction: Donor hematopoietic stem cell (DHSC) infusions are increasingly being studied in transplant patients for tolerance induction. Methods: To analyze the fate of infused DHSCs in patients, we developed an in vitro culture system utilizing CD34+DHSCs stimulated with irradiated allogeneic cells in cytokine supplemented medium long-term. Results: Flow cytometric analyses revealed loss of the CD34 marker and an increase in CD33+ myeloid and CD3+ T-cell proportion by 10.4% and 72.7%, respectively, after 21 days in culture. T-cells primarily expressed TcR-αß and were of both CD4+ and CD8+ subsets. Approximately 80% of CD3+ T cells lacked expression of the co-stimulatory receptor CD28. The CD4+ compartment was predominated by CD4+CD25+CD127-FOXP3+ Tregs (>50% CD4+CD127- compartment) with <1% of all leukocytes exhibiting a CD4+CD127+ phenotype. Molecular analyses for T-cell receptor excision circles showed recent and increased numbers of TcR rearrangements in generated T cells over time suggesting de novo differentiation from DHSCs. CD33+ myeloid cells mostly expressed HLA-DR, but lacked expression of co-stimulatory receptors CD80 and CD83. When studied as modulators in primary mixed lymphocyte reactions where the cells used to stimulate the DHSC were used as responders, the DHSC-lines and their purified CD8+, CD4+, CD33+ and linage negative subsets inhibited the responses in a dose-dependent and non-specific fashion. The CD8+ cell-mediated inhibition was due to direct lysis of responder cells. Discussion: Extrapolation of these results into the clinical situation would suggest that DHSC infusions into transplant recipients may generate multiple subsets of donor "chimeric" cells and promote recipient Treg development that could regulate the anti-donor immune response in the periphery. These studies have also indicated that T cell maturation can occur in vitro in response to allogeneic stimulation without the pre-requisite of a thymic-like environment or NOTCH signaling stimulatory cell line.

Addressing Surgeon Burnout Through a Multi-level Approach: A National Call to Action.

Purpose of Review: Physician burnout is an epidemic and there are unique aspects of surgery that dictate rates of burnout among general surgeons and surgical trainees. This review characterizes the scope of burnout and its drivers within the field of surgery and advocates for strategies to address burnout at the individual, institutional, and national levels. Recent Findings: Rates of burnout in surgery are increasing with higher numbers of young and female surgeons affected. Contributing factors are generally related to work-life balance, longer hours, and mistreatment in the workplace. Attempts have been made at implementing structured initiatives in an effort to combat work dissatisfaction and emotional exhaustion. Still, rates of burnout continue to increase. Summary: General surgeons and trainees are at high risk for burnout with resulting attrition, depression, and suicidal ideation. The solution to burnout must be addressed at individual, institutional, and national levels. Further research into the factors leading to surgeon burnout and enactment of effective strategies to mitigate burnout must be pursued.

Foxp3+ regulatory T cell therapy for tolerance in autoimmunity and solid organ transplantation.

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.

Adjudicated Heart Failure in HIV-Infected and Uninfected Men and Women.

Background HIV is associated with elevated risk of heart failure ( HF ). Despite poor agreement between automated, administrative code-based HF definitions and physician-adjudicated HF , no studies have evaluated incident adjudicated HF for people living with HIV ( PLWH ). Methods and Results We analyzed PLWH and uninfected controls receiving care in an urban medical system from January 1, 2000, to July 12, 2016. Physicians reviewed data from medical records to adjudicate HF diagnoses. We used multivariable-adjusted Cox models to analyze incident HF for PLWH versus controls and HIV -related factors associated with incident HF . We also analyzed the performance of automated versus physician-adjudicated HF definitions. Incident adjudicated HF occurred in 97 of 4640 PLWH (2.1%; mean: 6.8 years to HF ) and 55 of 4250 controls (1.3%; mean: 6.7 years to HF ; multivariable-adjusted hazard ratio: 2.10; 95% confidence interval, 1.38-3.21). Among PLWH , higher HIV viral load ( hazard ratio per log10 higher time-updated viral load: 1.22; 95% confidence interval, 1.11-1.33) was associated with greater HF risk and higher CD 4+ T cell count was associated with lower HF risk ( hazard ratio per 100 cells/mm3 higher time-updated CD 4 count: 0.80; 95% confidence interval, 0.69-0.92). In exploratory analyses, the most accurate automated HF definitions had sensitivities of 67% to 75% and positive predictive values of 54% to 60%. Conclusions In a cohort with rigorous HF adjudication, PLWH had greater risks of HF than uninfected people after adjustment for demographics and cardiovascular risk factors. Higher HIV viral load and lower CD 4+ T cell count were associated with higher HF risk among PLWH . Automated methods of HF ascertainment exhibited poor accuracy for PLWH and uninfected people.

Atrial arrhythmia prevalence and characteristics for human immunodeficiency virus-infected persons and matched uninfected controls.

BACKGROUND: Human Immunodeficiency Virus-Infected (HIV+) persons have elevated risks for various manifestations of cardiovascular disease (CVD). No studies to our knowledge have compared atrial fibrillation (AF) and atrial flutter (AFL) prevalence and associated characteristics for HIV+ persons and matched uninfected controls. METHODS AND FINDINGS: Persons with diagnoses of HIV receiving care at a large urban academic medical center were frequency-matched 1:2 on age, sex, race, zip code, and clinic location with uninfected persons. Possible AF/AFL was screened for using administrative codes and diagnoses of AF/AFL were subsequently adjudicated using electrocardiography and physician notes; adjudication was performed given the inconsistent validity of administrative code-derived AF diagnoses found in previous studies. There were 101 confirmed AF/AFL cases (2.00%) among 5,052 HIV+ patients and 159 confirmed AF/AFL cases (1.57%) among 10,121 uninfected controls [Odds Ratio (OR) 1.27, 95% Confidence Interval (CI) 0.99-1.64; p = 0.056]. The association between HIV serostatus and AF/AFL was attenuated after adjustment for demographics and CVD risk factors. Among HIV+ persons, nadir CD4+ T cell count <200 cells/mm3 was associated with approximately twofold elevated odds of AF/AFL even after adjustment for demographics and CVD risk factors (Multivariable-adjusted OR 1.98, 95% CI 1.21-3.25). There was no significant association between log10 of peak HIV viral load and AF/AFL (Multivariable-adjusted OR 1.03, 95% CI 0.86-1.24). Older age, diabetes, hypertension, and chronic obstructive pulmonary disease were associated with similarly elevated odds of AF/AFL for HIV+ persons and uninfected controls. CONCLUSION: HIV-related immunosuppression (nadir CD4 T cell count <200 cells/mm3) and traditional CVD risk factors are associated with significantly elevated odds of AF/AFL among HIV+ persons. Although atrial fibrillation and flutter was more common among HIV+ versus uninfected persons in this cohort, this difference was attenuated by adjustment for demographics and CVD risk factors.

Clinical characteristics of HIV-infected patients with adjudicated heart failure.

Aims HIV-infected persons may have elevated risks for heart failure, but factors associated with heart failure in the modern era of HIV therapy are insufficiently understood. Despite substantial disagreement between physician-adjudicated heart failure and heart failure diagnosis codes, few studies of HIV cohorts have evaluated adjudicated heart failure. We evaluated associations of HIV viremia, immunosuppression, and cardiovascular risk factors with physician-adjudicated heart failure. Methods and results We analyzed clinical characteristics associated with heart failure in a cohort of 5041 HIV-infected patients receiving care at an urban hospital system between 2000 and 2016. We also evaluated characteristics of HIV-infected patients who screened negative for heart failure, screened positive for possible heart failure but did not have heart failure after adjudication, and had adjudicated heart failure. HIV-infected patients with heart failure ( N = 216) were older and more likely to be black, hypertensive, and have diabetes than HIV-infected patients without heart failure; heart failure with reduced ejection fraction was more common than heart failure with preserved ejection fraction. In our primary analyses restricted to HIV-infected patients whose heart failure diagnoses did not precede their HIV diagnoses ( N = 149), peak HIV viral load ≥100,000 copies/mL (odds ratio (OR) 2.12, 1.28-3.52) and nadir CD4 T-cell count <200 cells/mm3 (OR 2.35, 1.04-5.31) were associated with significantly elevated odds of heart failure. Overall, 30.6% of patients with any diagnosis code of heart failure had adjudicated heart failure. Conclusion Higher peak HIV viremia and lower CD4 cell nadir are associated with significantly elevated odds of heart failure for HIV-infected persons. Physician adjudication of heart failure may be helpful in HIV cohorts.