Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model.

Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.

Computer Algorithm-Based Hydroxyurea Dosing Facilitates Titration to Maximum Tolerated Dose in Sickle Cell Anemia.

Adults with sickle cell disease (SCD) experience acute and chronic complications and die prematurely. When taken at maximum tolerated dose (MTD), hydroxyurea prolongs survival; however, it has not consistently reversed organ dysfunction. Patients also frequently do not take hydroxyurea, at least in part because of physician discomfort with prescribing hydroxyurea. We sought to develop a computer program that could easily titrate hydroxyurea to MTD. This was a single-arm, open-label pilot study. Fifteen patients with homozygous SCD were enrolled in the protocol, and 10 patients were followed at baseline and then for 1 year after hydroxyurea initiation or dose titration. Fetal hemoglobin significantly increased in all 10 patients from 8.3% to 25.1% (P < .001). Nine patients were titrated to MTD in an average of 7.9 months, and the tenth patient's hydroxyurea dose was increased to 33 mg/kg/day. Computer program dosing recommendations were the same as manual dosing decisions made using the same algorithm for all patients and at all times. We also evaluated markers of cardiopulmonary, liver and renal damage. Although cardiopulmonary function did not significantly improve, direct bilirubin and alanine aminotransferase levels significantly decreased (P < .001 and P < .01, respectively). Last, although kidney function did not improve, degree of proteinuria was significantly reduced (P < .05). We have developed a computer program that reliably titrates hydroxyurea to MTD. A larger study is indicated to test the program either as a computer program or a downloadable application.

Community-derived recommendations for healthcare systems and medical students to support people who are houseless in Portland, Oregon: a mixed-methods study.

BACKGROUND: People who are houseless (also referred to as homeless) perceive high stigma in healthcare settings, and face disproportionate disparities in morbidity and mortality versus people who are housed. Medical students and the training institutions they are a part of play important roles in advocating for the needs of this community. The objective of this study was to understand perceptions of how medical students and institutions can meet needs of the self-identified needs of the houseless community. METHODS: Between February and May 2018, medical students conducted mixed-methods surveys with semi-structured qualitative interview guides at two community-based organizations that serve people who are houseless in Portland, Oregon. Medical students approach guests at both locations to ascertain interest in participating in the study. Qualitative data were analyzed using thematic analysis rooted in an inductive process. RESULTS: We enrolled 38 participants in this study. Most participants were male (73.7%), white (78.9%), and had been houseless for over a year at the time of interview (65.8%). Qualitative themes describe care experiences among people with mental health and substance use disorders, and roles for medical students and health-care institutions. Specifically, people who are houseless want medical students to 1) listen to and believe them, 2) work to destigmatize houselessness, 3) engage in diverse clinical experiences, and 4) advocate for change at the institutional level. Participants asked healthcare institutions to use their power to change laws that criminalize substance use and houselessness, and build healthcare systems that take better care of people with addiction and mental health conditions. CONCLUSIONS: Medical students, and the institutions they are a part of, should seek to reduce stigma against people who are houseless in medical systems. Additionally, institutions should change their approaches to healthcare delivery and advocacy to better support the health of people who are houseless.

Facial protection for healthcare workers during pandemics: a scoping review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to personal protective equipment (PPE) shortages, requiring mask reuse or improvisation. We provide a review of medical-grade facial protection (surgical masks, N95 respirators and face shields) for healthcare workers, the safety and efficacy of decontamination methods, and the utility of alternative strategies in emergency shortages or resource-scarce settings. METHODS: We conducted a scoping review of PubMed and grey literature related to facial protection and potential adaptation strategies in the setting of PPE shortages (January 2000 to March 2020). Limitations included few COVID-19-specific studies and exclusion of non-English language articles. We conducted a narrative synthesis of the evidence based on relevant healthcare settings to increase practical utility in decision-making. RESULTS: We retrieved 5462 peer-reviewed articles and 41 grey literature records. In total, we included 67 records which met inclusion criteria. Compared with surgical masks, N95 respirators perform better in laboratory testing, may provide superior protection in inpatient settings and perform equivalently in outpatient settings. Surgical mask and N95 respirator conservation strategies include extended use, reuse or decontamination, but these strategies may result in inferior protection. Limited evidence suggests that reused and improvised masks should be used when medical-grade protection is unavailable. CONCLUSION: The COVID-19 pandemic has led to critical shortages of medical-grade PPE. Alternative forms of facial protection offer inferior protection. More robust evidence is required on different types of medical-grade facial protection. As research on COVID-19 advances, investigators should continue to examine the impact on alternatives of medical-grade facial protection.

Time-to-completed-imaging, survival and function in patients with spinal epidural abscess: Description of a series of 34 patients, 2015-2018.

INTRODUCTION: Spinal epidural abscess (SEA) is a rare and life-threatening infection with increasing incidence over the past two decades. Delays in diagnosis can cause significant morbidity and mortality among patients. OBJECTIVE: The objective of this study was to describe trends in time-to-imaging and intervention, risk factors, and outcomes among patients presenting to the emergency department with SEA at a single academic medical center in Portland, Oregon. METHODS: This retrospective cohort study analyzed data from patients with new SEA diagnosis at a single hospital from October 1, 2015 to April 1, 2018. We describe averages to time-to-imaging and interventions, and frequencies of risk factors and outcomes among patients presenting to the emergency department with SEA. RESULTS: Of the 34 patients included, 7 (20%) died or were discharged with plegia during the study period. Those who died or were discharged with plegia (n = 7) had shorter mean time-to-imaging order (20.8 h versus 29.2 h). Patients with a history of intravenous drug use had a longer mean time-to-imaging order (30.2 h versus 23.7 h) as compared to those without intravenous drug use. Patients who died or acquired plegia had longer times from imaging completed to final imaging read (20.9 h versus 7.1 h), but shorter times from final imaging read to surgical intervention among patients who received surgery (4.9 h versus 46.2 h). Further, only three (42.9%) of the seven patients who died or acquired plegia presented with the three-symptom classic triad of fever, neurologic symptoms, and neck or back pain. CONCLUSIONS: SEA is a potentially deadly infection that requires prompt identification and treatment. This research provides baseline data for potential quality improvement work at the study site. Future research should evaluate multi-center approaches for identifying and intervening to treat SEA, particularly among patients with intravenous drug use.