Efficient induction of immune tolerance to coagulation factor IX following direct intramuscular gene transfer

BACKGROUND: The formation of inhibitory anti-factor IX (anti-FIX) antibodies is a major complication of FIX protein replacement-based treatment for hemophilia B. It is difficult to treat patients with anti-FIX antibodies. Gene therapy is emerging as a potentially effective treatment for hemophilia. Direct i.m. injection of adeno-associated virus (AAV) is a safe and efficient procedure for hemophilia B gene therapy. However, the development of anti-FIX antibodies following i.m. of AAV may impede its application to patients. OBJECTIVE: We aimed to investigate induction of immune tolerance to human FIX (hFIX) by i.m. of AAV1, further validating i.m. of AAV1 for hemophilia B gene therapy. METHODS AND RESULTS: Cohorts of hemostatically normal and hemophilia B mice with diverse genetic and MHC backgrounds received i.m. of AAV-hFIX. Human FIX antigen and anti-hFIX antibodies were examined. I.m. of 1 x 10(11) vector genomes (VG) of AAV2 elicits formation of anti-hFIX antibodies comparable to those by hFIX protein replacement. I.m. of 1 x 10(11) VG of AAV1 results in expression of therapeutic levels of hFIX (up to 950 ng mL(-1), mean = 772 ng mL(-1), SEM +/- 35.7) and hFIX-specific immune tolerance in C57BL/6 mice. CONCLUSIONS: A single i.m. of AAV1 can result in efficient expression of therapeutic levels of hFIX and induction of hFIX tolerance in hemostatically normal and hemophilic B mice. Our results substantiate the prospect of i.m. of AAV1 for hemophilia B gene therapy and FIX tolerance induction.     

艾滋病合并新型隐球菌脑膜炎临床分析

目的通过对25例艾滋病合并新型隐球菌脑膜炎的临床分析,提高对艾滋病合并新型隐球菌脑膜炎的认识。方法对本院2000年8月—2006年2月收治的25例艾滋病合并新型隐球菌脑膜炎病例进行回顾性分析。结果25例新型隐球菌脑膜炎患者均为艾滋病晚期患者,T细胞亚群检测11例:CD4<50/mm39例,CD450~100/mm32例;平均26.18/mm3。在确诊时已合并多种机会感染。结论艾滋病患者合并新型隐球菌脑膜炎病情重,预后差,实验室病原学检查结果是诊断新型隐球菌脑膜炎的主要依据。     

“I'm Leaving”: Factors That Impact Against Medical Advice Disposition Post-Trauma

BackgroundDischarge against medical advice (AMA) is an important, yet understudied, aspect of health care—particularly in trauma populations. AMA discharges result in increased mortality, increased readmission rates, and higher health care costs.ObjectiveThe goal of this analysis was to determine what factors impact a patient's odds of leaving the hospital prior to treatment.MethodsWe performed a retrospective analysis of the National Trauma Data Bank on adult trauma patients (older than 14 years) from 2013 to 2015. Of the 1,770,570 patients with known disposition, excluding mortality, 24,191 patients (1.4%) left AMA. We ascertained patient characteristics including age, sex, race, ethnicity, insurance status, ETOH, drug use, geographic location, Injury Severity Score (ISS), injury mechanism, and anatomic injury location. Multivariate logistic regression models were used to determine which patient factors were associated with AMA status.ResultsUninsured (odds ratio [OR] 2.72; 95% confidence interval [CI] 2.58–2.86) or Medicaid-insured (OR 2.50; 95% CI 2.37–2.63) trauma patients were significantly more likely to leave AMA than patients with private insurance. Compared to white patients, African-American patients (OR 1.06; 95% CI 1.02–1.11) were more likely, and Native-American (OR 0.62; 95% CI 0.52–0.75), Asian (OR 0.59; 95% CI 0.49–0.69), and Hispanic (OR 0.80; 95% CI 0.75–0.85) patients were less likely, to leave AMA when controlling for age, sex, ISS, and type of injury.ConclusionsInsurance status, race, and ethnicity are associated with a patient's decision to leave AMA. Uninsured and Medicaid patients have more than twice the odds of leaving AMA. These findings demonstrate that racial and socioeconomic disparities are important targets for future efforts to reduce AMA rates and improve outcomes from blunt and penetrating trauma.     

Emergency Medicine/Critical Care Medicine (EM/CCM) Trainees’ Performance on Standardized Critical Care Medicine Examinations: A Ten-Year Review

BackgroundEmergency Medicine/Critical Care Medicine (EM/CCM) trainees may obtain board certification through Internal Medicine (American Board of Internal Medicine [ABIM]), Surgery (American Board of Surgery [ABS]), and Anesthesiology (American Board of Anesthesiology [ABA]). However, EM/CCM trainees experience challenges, including: 1) additional training requirements and 2) an unwillingness to accept EM graduates by many programs.ObjectivesWe sought to: 1) compare EM/CCM knowledge acquisition to medicine (Internal Medicine [IM]/CCM), surgery (surgical critical care [SCC]), and anesthesiology (anesthesiology critical care medicine [ACCM]) Fellows at the local and national level using the Multidisciplinary Critical Care Knowledge Assessment Program (MCCKAP) in-service examination as an objective measure; and 2) compare American Board of Medical Specialties (ABMS) pass rates for EM/CCM.MethodsSingle-center retrospective analysis comparing scores obtained by EM/CCM on the MCCKAP examination with SCC and ACCM over a 10-year period. Scores are presented as means with standard deviations. We performed similar analysis on ABMS examination pass rates.ResultsThere were 117 MCCKAP scores (37 EM/CCM; 80 SCC and ACCM) evaluated. EM/CCM mean score 562.4 (SD 67.4); SCC and ACCM mean score 505.3, (SD 87.5) at the institutional level (p < 0.001). Similarly, EM/CCM scored higher than the national mean (562.4, SD 67.4 vs. 500 SD 100, p < 0.001). Nationally, ABIM-CCM board certification rate was 91.2% for 137 EM/CCM, compared with 93.2% for IM/CCM (p = 0.22); 28 EM/CCM have obtained ABA-CCM board certification with rates similar to ACCM (90.4 vs. 89.3%; p = 0.85).ConclusionsEM/CCM Fellows demonstrate successful knowledge acquisition both locally and at a national level. EM/CCM achieve ABMS pass rates similar to other CCM trainees. The current arbitrary additional training requirements placed on EM/CCM should be removed.     

“I Just Had No Idea What It Was Like to Be in Prison and What Might Be Helpful”: Educator and Learner Views on Clinical Placements in Correctional Health

Abstract

Phenomenon: Correctional health services can provide quality learning experiences for medical students and graduate medical trainees, including through motivating learners to work with people involved with the justice system, and promoting understanding of the social determinants of health. Approach: We conducted 38 semi-structured interviews to examine the views of learners and educators on how to promote high quality clinical learning in correctional settings, with a focus on the Australian context. Participants included medical students; general practitioners who had undertaken graduate trainee placements; clinical staff involved in teaching and clinical supervision; and graduate program medical educators and university teachers from Australia, New Zealand, and Canada. Data were analyzed thematically. Findings: Clinical placements in correctional settings provided learning about the health of people involved in the justice system, but also beneficial clinical learning for working with a wide range of patients with complex health needs. Valued learnings included managing complex consultations, mental health and substance use disorders, and overcoming anxiety related to interacting with people in prison. Learner concerns included limited patient contact time, apprehension prior to placements, and stress related to experiences during the placements. This apprehension and stress could be mitigated by orientation and debriefing, and by appreciating healthcare professionals in correctional settings as advocates for their patients. Clinical supervision was perceived to be demanding in this context. Independent patient interaction was not usually possible for students and there could be short windows of time in which to provide direct patient care, making pauses for teaching difficult. Insights: Clinical placements in correctional health services provide experiential learning of direct relevance to medical student, and potentially to general practice trainee, curricula which is valuable even when learners do not have particular interest in correctional health. Furthermore, these placements may increase the capacity of the medical workforce to provide skilled care to other underserved populations. High quality learner and clinical supervisor experiences, and program scale and sustainability, require enhanced learning support systems through partnerships between correctional health services and education institutions. Required supports for learners include orientation to security arrangements, debriefing sessions which assist learners to distill their learning and to reflect on challenging experiences, and alternative learning opportunities for when direct patient consultations are not accessible. Supervisor teaching supports include shared teaching approaches in the correctional health clinics and added student support from university-based staff.     

Medical training in Greece: A crisis in progress

Objectives. We sought to evaluate the opinions of medical students and graduates regarding the quality of medical education in Greece. Methods. Two online questionnaires concerning the undergraduate medical education and specialty training respectively were distributed. Results. Regarding the quality of undergraduate medical education, 52.1% of participants replied favorably while clinical training was found satisfactory by 45.1. Dissatisfaction rates with research opportunities and support from tutors reached 88.4 and 83.3%, respectively. The majority (75.3%) supported the introduction of examinations for commencing specialty training. 52.3% of physicians were satisfied with the quality of specialty training. The most common complaint was the absence of a formal educational program. 67.2% of participants were dissatisfied with working conditions during their specialty training, with 70.1% working >60 h per week. Physicians practicing medical specialties were more satisfied with the quality of specialty training than those practicing surgical specialties (odds ratio: 1.43; 95% confidence limits: 1.09–1.87) and were less likely to work for >60 h per week (odds ratio: 0.66; 95% confidence limits: 0.48–0.9). Conclusion. Opinions expressed in this survey highlight the need for reforming medical education in Greece.