Low-frequency inherited complement receptor variants are associated with purpura fulminans.

ABSTRACT: Extreme disease phenotypes can provide key insights into the pathophysiology of common conditions, but studying such cases is challenging due to their rarity and the limited statistical power of existing methods. Herein, we used a novel approach to pathway-based mutational burden testing, the rare variant trend test (RVTT), to investigate genetic risk factors for an extreme form of sepsis-induced coagulopathy, infectious purpura fulminans (PF). In addition to prospective patient sample collection, we electronically screened over 10.4 million medical records from 4 large hospital systems and identified historical cases of PF for which archived specimens were available to perform germline whole-exome sequencing. We found a significantly increased burden of low-frequency, putatively function-altering variants in the complement system in patients with PF compared with unselected patients with sepsis (P = .01). A multivariable logistic regression analysis found that the number of complement system variants per patient was independently associated with PF after controlling for age, sex, and disease acuity (P = .01). Functional characterization of PF-associated variants in the immunomodulatory complement receptors CR3 and CR4 revealed that they result in partial or complete loss of anti-inflammatory CR3 function and/or gain of proinflammatory CR4 function. Taken together, these findings suggest that inherited defects in CR3 and CR4 predispose to the maladaptive hyperinflammation that characterizes severe sepsis with coagulopathy.

Bringing Generalists to Global Health: a Missed Opportunity and Call to Action.

The credo of the generalist physician has always been the promotion of health for all, in every aspect: not just multiple vulnerable organ systems, but multiple social, cultural, and political factors that contribute to poor health and exacerbate health inequity. In recent years, the field of global health has also adopted this same mission: working across both national and clinical specialty borders to improve health for all and end health disparities worldwide. Yet within the Society for General Internal Medicine, and among American generalists, engagement in global health, both within and outside the USA, remains uncommon. We see this gap as an opportunity, because in fact generalists in America already have the skills and experience that global health badly needs. SGIM could promote generalists to global health's vanguard, with three core steps. First, we generalists must continue to integrate health for the vulnerable into our domestic work, generating care models applicable in low-resource settings around the globe. Conversely, we must also engage with and implement international ideas and solutions for universal access to primary care for vulnerable patients in the USA. And lastly, we must build platforms to connect ourselves with colleagues worldwide to exchange these learnings.

COVID-19 Pandemic Impact on Academic Global Health Programs: Results of a Large International Survey.

Background: The COVID-19 pandemic caused significant disruptions in international communications and travel for academic global health programs (AGHPs) in both high-income countries (HICs) and low- and middle-income countries (LMICs). Given the importance of international travel and communication to AGHPs, the pandemic has likely had considerable impact on the education, research, and administrative components of these programs. To date, no substantive study has determined the impacts of the COVID-19 pandemic on AGHPs in HICs and LMICs. This study assessed the impacts and resultant adaptations of AGHPs to pandemic realities with the goal of sharing strategies and approaches. Methods: This study applied a mixed methods sequential explanatory design to survey AGHPs in HICs and LMICs about the impacts of the COVID-19 pandemic on three program domains: education, research, and administration. First, we surveyed a range of AGHP stakeholders to capture quantitative data on the pandemic's impact. Subsequently we conducted semi-structured interviews with select survey participants to gather qualitative data expanding on specific survey responses. Data from both phases were then compared and interpreted together to develop conclusions and suggest adaptive/innovative approaches for AGHPs. Results: AGHPs in both HICs and LMICs were significantly impacted by the pandemic in all three domains, though in different ways. While education initiatives managed to adapt by pivoting towards virtual learning, research programs were impacted more negatively by the disruptions in communication and international travel. The impact of the pandemic on scholarly output as well as on funding for education and research was quite variable, although LMIC programs were more negatively impacted. Administratively, AGHPs implemented a range of safety and risk mitigation strategies and showed a low risk tolerance for international travel. The pandemic posed many challenges but also revealed opportunities for AGHPs. Conclusions: The COVID-19 pandemic disrupted AGHPs in HICs and LMICs in expected and unexpected ways. Programs noted some unanticipated reductions in education program funding, negative impacts on research programs, and reduced scholarly output. Many programs reported well-coordinated adaptive responses to the pandemic including, for instance, virtual (in place of in-person) collaboration in research. The pandemic will likely have lasting impacts with regard to education, research collaborations, and administration of programs.

The Impact of Global Health Experiences on the Emergency Medicine Residency Milestones.

OBJECTIVES: Identify the impact of experiences in global health (GH) on the Accreditation Council for Graduate Medical Education (ACGME) competencies in emergency medicine (EM) residents and describe the individual characteristics of EM residents with global health experience compared to those without. METHODS: From 2015 to 2018, 117 residents from 13 nationally accredited United States EM residency training programs were surveyed. Specifically, the survey gathered demographic data and information regarding timing, type, location and duration of short term experiences in global health (STEGH). The survey collected both qualitative and quantitative data regarding resident experiences, including number of procedures performed and self-assessment of the impact on their residency milestones. ACGME milestone data from survey respondents was collected from each resident's training program coordinators. Chi-squared analysis and t-tests were conducted to assess differences between residents with STEGH and those without. A generalized linear model (GLM) was utilized to assess the effects of time and experience with interaction on achieving milestones in each of the competency domains, to compare milestone achievement over time between residents with STEGH and those without. RESULTS: Out of 117 EM residents, 60 were female (44%), the mean age was 30 years (standard deviation = 3.1), and 84 (71.8%) reported STEGH in general, including prior to residency (64.5%). 33 (28.2%) reported having completed STEGH during residency. The results of the GLM analysis showed that residents with STEGH during residency had significantly higher scores compared to those without the experience or STEGH pre-residency across all six competencies. CONCLUSIONS: STEGH in EM residents was associated with higher milestone achievement in certain ACGME competency domains including medical knowledge, practice-based learning and improvement, and professionalism. Participation in STEGH during residency appeared to show the strongest effect, with higher scores across all six competencies.

Piloting a Faculty Development Program in a Rural Haitian Teaching Hospital.

Background: Faculty development for nurse and physician educators has a limited evidence base in high income countries, and very little research from low- and middle-income countries. Health professions educators in many global settings do not receive training on how to educate effectively. Objective: To pilot and assess a faculty development program aimed at nurse and physician educators at a teaching hospital in rural Haiti. Methods: We developed a program covering a total of 22 topics in health professions education, including applied learning theory as well as nurse and physician targeted topics. We assessed impact through participant assessment of personal growth, participant evaluation of the program, knowledge testing pre and post program, and structured observations of program participants providing teaching during the program. Findings: Nineteen out of 37 participants completed the program. While participant reviews were uniformly positive, a pre- and post-test on general educational topics showed no significant change, and the effort to institute observation and feedback of teaching did not succeed. Conclusions: Our project showcases some benefits of faculty development, while also demonstrating the challenges of instituting faculty development in situations where participants have limited time and resources. We suspect more benefits may emerge as the program evolves to fit the learners and setting.

Simulated Cost-effectiveness and Long-term Clinical Outcomes of Addiction Care and Antibiotic Therapy Strategies for Patients With Injection Drug Use-Associated Infective Endocarditis.

IMPORTANCE: Emerging evidence supports the use of outpatient parenteral antimicrobial therapy (OPAT) and, in many cases, partial oral antibiotic therapy for the treatment of injection drug use-associated infective endocarditis (IDU-IE); however, long-term outcomes and cost-effectiveness remain unknown. OBJECTIVE: To compare the added value of inpatient addiction care services and the cost-effectiveness and clinical outcomes of alternative antibiotic treatment strategies for patients with IDU-IE. DESIGN, SETTING, AND PARTICIPANTS: This decision analytical modeling study used a validated microsimulation model to compare antibiotic treatment strategies for patients with IDU-IE. Model inputs were derived from clinical trials and observational cohort studies. The model included all patients with injection opioid drug use (N = 5 million) in the US who were eligible to receive OPAT either in the home or at a postacute care facility. Costs were annually discounted at 3%. Cost-effectiveness was evaluated from a health care sector perspective over a lifetime starting in 2020. Probabilistic sensitivity, scenario, and threshold analyses were performed to address uncertainty. INTERVENTIONS: The model simulated 4 treatment strategies: (1) 4 to 6 weeks of inpatient intravenous (IV) antibiotic therapy along with opioid detoxification (usual care strategy), (2) 4 to 6 weeks of inpatient IV antibiotic therapy along with inpatient addiction care services that offered medication for opioid use disorder (usual care/addiction care strategy), (3) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by OPAT (OPAT strategy), and (4) 3 weeks of inpatient IV antibiotic therapy along with addiction care services followed by partial oral antibiotic therapy (partial oral antibiotic strategy). MAIN OUTCOMES AND MEASURES: Mean percentage of patients completing treatment for IDU-IE, deaths associated with IDU-IE, life expectancy (measured in life-years [LYs]), mean cost per person, and incremental cost-effectiveness ratios (ICERs). RESULTS: All modeled scenarios were initialized with 5 million individuals (mean age, 42 years; range, 18-64 years; 70% male) who had a history of injection opioid drug use. The usual care strategy resulted in 18.63 LYs at a cost of $416 570 per person, with 77.6% of hospitalized patients completing treatment. Life expectancy was extended by each alternative strategy. The partial oral antibiotic strategy yielded the highest treatment completion rate (80.3%) compared with the OPAT strategy (78.8%) and the usual care/addiction care strategy (77.6%). The OPAT strategy was the least expensive at $412 150 per person. Compared with the OPAT strategy, the partial oral antibiotic strategy had an ICER of $163 370 per LY. Increasing IDU-IE treatment uptake and decreasing treatment discontinuation made the partial oral antibiotic strategy more cost-effective compared with the OPAT strategy. When assuming that all patients with IDU-IE were eligible to receive partial oral antibiotic therapy, the strategy was cost-saving and resulted in 0.0247 additional discounted LYs. When treatment discontinuation was decreased from 3.30% to 2.65% per week, the partial oral antibiotic strategy was cost-effective compared with OPAT at the $100 000 per LY threshold. CONCLUSIONS AND RELEVANCE: In this decision analytical modeling study, incorporation of OPAT or partial oral antibiotic approaches along with addiction care services for the treatment of patients with IDU-IE was associated with increases in the number of people completing treatment, decreases in mortality, and savings in cost compared with the usual care strategy of providing inpatient IV antibiotic therapy alone.

Global Health Crisis, Global Health Response: How Global Health Experiences Prepared North American Physicians for the COVID-19 Pandemic.

The COVID-19 pandemic plunged hospital systems into resource-deprived conditions unprecedented since the 1918 flu pandemic. It brought forward concerns around ethical management of scarcity, racism and distributive justice, cross-disciplinary collaboration, provider wellness, and other difficult themes. We, a group of medical educators and global health educators and clinicians, use the education literature to argue that experience gained through global health activities has greatly contributed to the effectiveness of the COVID-19 pandemic response in North American institutions. Support for global health educational activities is a valuable component of medical training, as they build skills and perspectives that are critical to responding to a pandemic or other health system cataclysm. We frame our argument as consideration of three questions that required rapid, effective responses in our home institutions during the pandemic: How can our health system function with new limitations on essential resources? How do we work at high intensity and volume, on a new disease, within new and evolving systems, while still providing high-quality, patient-centered care? And, how do we help personnel manage an unprecedented level of morbidity and mortality, disproportionately affecting the poor and marginalized, including moral difficulties of perceived care rationing?

Essential Principles of Preoperative Assessment in Internal Medicine: A Case-Based Teaching Session.

Introduction: Preoperative assessment is a core competency for internal medicine residents, but one with limited educational resources available presently. Ideally, residencies would provide an introduction to this topic prior to their residents performing preoperative assessments in clinic or during internal medicine consultation rotations. Methods: We developed a 120-minute case-based teaching session on preoperative assessment for PGY 2 residents where they reviewed a series of cases, applied preoperative risk calculators, and made recommendations on medication management using the same online tools they employ while working clinically. Interspersed lecture sections reviewed guiding principles, detailed key trials, and explored nuances of the topic. We performed pre- and posttests of knowledge and also obtained learner feedback. Results: Thirty-three out of 40 participants completed the pre- and posttests. The session was rated highly (M = 4.0 out of 5) and was viewed as preferable to a lecture-based approach (M = 4.4 out of 5); mean participant knowledge improved from 11.7 to 17.5 (p < .001) out of 22 points possible. The most consistently offered feedback was to give more time for the session than the 120 minutes allotted. Discussion: A teaching session mixing lecture with review of composite cases and application of preoperative assessment tools with immediate feedback improved knowledge and was viewed as enjoyable and preferable to lecture alone by participants. We recommend providing more time for the teaching by increasing the session length from 120 minutes to 140 minutes.

Folate Deficiency in an Urban Safety Net Population.

PURPOSE: Since mandatory fortification of grain products with folic acid in the United States in 1998, folate deficiency has become rare. Some have suggested that serum folate levels should be tested rarely in countries with mandatory folic acid fortification, given low rates of deficiency, high cost per deficiency diagnosis, and low rates of supplementation for those diagnosed as deficient. Given persistent racial, ethnic, and socioeconomic disparities in folate deficiency, these suggestions may not apply to all populations. We examine the rate at which serum testing detected folate deficiency in an urban safety net hospital and the characteristics of folate-deficient patients. METHODS: We reviewed the charts of all inpatients and emergency department patients with low serum folate results at a safety net hospital in Boston in 2018. We collected data concerning demographics, social determinants of health, clinical factors, and whether folate supplementation was prescribed. Finally, we performed a cost analysis. RESULTS: Of 1368 patients tested, 76 (5.5%) met criteria for folate deficiency. Overall, 86.8% of these patients were anemic, and 17.1% had macrocytic anemia; 42% were diagnosed with malnutrition. Common social determinants in folate-deficient patients included birth outside of the United States, homelessness, and alcohol use disorder. Of folate-deficient patients, 88% were newly prescribed folic acid supplementation at discharge. The estimated charge per deficient test was $1278. CONCLUSION: Compared with a nearby institution, serum folate testing at our safety net hospital detected deficiency at a higher rate, incurred a lower charge per deficient test, and was more likely to impact management.

Rationale and Design of the Awake Prone Position for Early Hypoxemia in COVID-19 Study Protocol: A Clinical Trial.

The unprecedented public health burdens of coronavirus disease (COVID-19) have intensified the urgency of identifying effective, low-cost treatments that limit the need for advanced life support measures and improve clinical outcomes. However, personal protective equipment and staffing shortages, disease virulence, and infectivity have created significant barriers to traditional clinical trial practices. We present the novel design of a pragmatic, adaptive, multicenter, international, prospective randomized controlled clinical trial evaluating the safety and effectiveness of awake prone positioning in spontaneously breathing patients with COVID-19 (APPEX-19 [Awake Prone Position for Early Hypoxemia in COVID-19]). Key innovations of this trial include 1) a novel smartphone-based communication process that facilitates rapid enrollment and intervention delivery while allowing social distancing and conservation of personal protective equipment, 2) Bayesian response-adaptive randomization to allow preferential assignment to the most effective intervention and expedite trial completion compared with frequentist designs, 3) remote electronic collection of patient-reported outcomes and electronic medical record data, and 4) pragmatic prospective use of patient-reported data and data collected as part of routine clinical care. Clinical trial registered with www.clinicaltrials.gov (NCT04344587).

Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease in the United States. Approximately 30% to 40% of individuals with diabetes mellitus develop DKD, and the presence of DKD significantly elevates the risk for morbidity and mortality. Understanding of DKD has grown in recent years. This review describes the pathogenesis of DKD and expands on evidence-based strategies for DKD management, integrating traditional approaches for hyperglycemia, hypertension, and albuminuria management with emerging therapeutic options. Given the public health burden of DKD, it is essential to prioritize prevention, recognition, and management of DKD in the primary care setting.

Reconfiguring a One-Way Street: A Position Paper on Why and How to Improve Equity in Global Physician Training.

Large numbers of U.S. physicians and medical trainees engage in hands-on clinical global health experiences abroad, where they gain skills working across cultures with limited resources. Increasingly, these experiences are becoming bidirectional, with providers from low- and middle-income countries traveling to experience health care in the United States, yet the same hands-on experiences afforded stateside physicians are rarely available for foreign medical graduates or postgraduate trainees when they arrive. These physicians are typically limited to observership experiences where they cannot interact with patients in most U.S. institutions. In this article, the authors discuss this inequity in global medical education, highlighting the shortcomings of the observership training model and the legal and regulatory barriers prohibiting foreign physicians from engaging in short-term clinical training experiences. They provide concrete recommendations on regulatory modifications that would allow meaningful short-term clinical training experiences for foreign medical graduates, including the creation of a new visa category, the designation of a specific temporary licensure category by state medical boards, and guidance for U.S. host institutions supporting such experiences. By proposing this framework, the authors hope to improve equity in global health partnerships via improved access to meaningful and productive educational experiences, particularly for foreign medical graduates with commitment to using their new knowledge and training upon return to their home countries.

Health Information and Global Health Inequity: Point-of-Care Knowledge Systems as a Foundation for Progress.

Point-of-care clinical knowledge systems play an increasingly important role in providing information for health care providers in high-resource settings, and there is evidence of strong interest among providers within low-resource settings. Unfortunately, systems developed for high-resource settings have a range of elements that make them suboptimal for low-resource settings. We discuss what a point-of-care clinical knowledge system designed for low-resource settings would ideally contain, and argue that such a system is worthy of further study and funding, towards the overarching goal of reducing global health inequity.

Taking it Global: Structuring Global Health Education in Residency Training.

To meet the demand by residents and to provide knowledge and skills important to the developing physician, global health (GH) training opportunities are increasingly being developed by United States (U.S.) residency training programs. However, many residency programs face common challenges of developing GH curricula, offering safe and mentored international rotations, and creating GH experiences that are of service to resource-limiting settings. Academic GH partnerships allow for the opportunity to collaborate on education and research and improve health care and health systems, but must ensure mutual benefit to U.S. and international partners. This article provides guidance for incorporating GH education into U.S. residency programs in an ethically sound and sustainable manner, and gives examples and solutions for common challenges encountered when developing GH education programs.