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Background: Most new tuberculosis vaccines will be administered as a booster to subjects primed with bacille Calmette-Guérin (BCG) during childhood.Methods: We investigated in vivo and in vitro immune responses to mycobacteria in human immunodeficiency virus (HIV)-positive subjects in Tanzania primed with BCG during childhood and entering a tuberculosis booster vaccine trial. Tests included intradermal skin testing for Mycobacterium tuberculosis purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS); lymphocyte proliferation assays and interferon (IFN)-gamma levels after stimulation with Mycobacterium vaccae sonicate (MVS), M. tuberculosis early secreted antigen (ESAT)-6, M. tuberculosis antigen 85 (Ag85), or M. tuberculosis whole-cell lysate (WCL); and determination of serum antibody to lipoarabinomannin (LAM).Results: A total of 888 subjects with CD4 cell counts > or = 200 cells/mm3 were enrolled. PPD and MAS test results were positive in 34% and 30% of the subjects, respectively. Proliferative responses were detected as follows: MVS, 6%; Ag85, 24%; ESAT-6, 21%; and WCL, 59%. IFN-gamma responses were 2%, 6%, 12%, and 38%, respectively. LAM antibody was detected in 28% of the subjects. Subjects were more likely to have detectable proliferative and IFN-gamma responses if they had positive PPD test results or CD4 cell counts > or = 500 cells/mm3. Overall, 94% of the subjects had evidence of primed mycobacterial immune responses.Conclusion: Of HIV-positive BCG-immunized adults with CD4 cell counts > or = 200 cells/mm3 in Tanzania, 94% are primed for booster mycobacterial immunization. [ABSTRACT FROM AUTHOR]

Abstract Background The importance of depression as a complication of HIV infection is increasingly understood, and people living in rural areas are at increased risk for depression. However, it is not known whether living in rural areas amplifies the risk of depression in patients with HIV. Methods We compared the prevalence of depression between rural and metropolitan HIV patients seen at the Dartmouth-Hitchcock HIV Program in a retrospective cohort study. Using the validated Rural-Urban Commuting Area Score, we categorized patients as living in small town/rural areas, micropolitan or metropolitan towns. Then, using a multivariate logistic regression model to adjust for demographic factors that differed between rural and metropolitan patients, we estimated the impact of living in rural areas on the odds of depression. Results Among 646 patients with HIV (185 small town/rural, 145 micropolitan, 316 metropolitan), rural patients were older, white, male, and men who have sex with men (ANOVA, F-statistic < 0.05). The prevalence of depression was highest in rural patients (59.5 vs. 51.7 vs. 41.2%, F statistic < 0.001), particularly rural patients on antiretroviral therapy (72.4 vs. 53.5 vs. 38.2%, F-statistic < 0.001. A multivariate logistic regression model showed that the odds of depression in rural patients with HIV were 1.34 (P < 0.001). Conclusion HIV-infected patients living in rural areas, particularly those on antiretroviral therapy, are highly vulnerable to depression.

Abstract Background Identifying novel TB diagnostics is a major public health priority. We explored the diagnostic characteristics of antimycobacterial lymphocyte proliferation assays (LPA) in HIV-infected subjects with latent or active TB. Methods HIV-infected subjects with bacille Calmette Guérin (BCG) scars and CD4 counts ≥ 200 cells/mm3 entering a TB booster vaccine trial in Tanzania had baseline in vivo and in vitro immune tests performed: tuberculin skin tests (TST), LPA and five day assays of interferon gamma (IFN-γ) release. Assay antigens were early secreted antigenic target 6 (ESAT-6), antigen 85 (Ag85), and Mycobacterium tuberculosis whole cell lysate (WCL). Subjects were screened for active TB at enrollment by history, exam, sputum smear and culture. We compared antimycobacterial immune responses between subjects with and without latent or active TB at enrollment. Results Among 1885 subjects screened, 635 had latent TB and 13 had active TB. Subjects with latent TB were more likely than subjects without TB to have LPA responses to ESAT-6 (13.2% vs. 5.5%, P < 0.0001), Ag85 (18.7% vs. 3.1%, P < 0.0001), and WCL (45.7% vs. 17.1%, P < 0.0001). Subjects with active TB also were more likely than those without active TB to have detectable LPA responses to ESAT-6 (38.5% vs. 8.1%, P = 0.0001), Ag85 (46.2% vs. 8.5%, P < 0.0001), and WCL (61.5% vs. 27.0%, P = 0.0053). In subjects with a positive TST, LPA responses to ESAT-6, Ag85 and WCL were more common during active TB (p < 0.0001 for all tests). In diagnosing active TB, in vivo and in vitro tests of mycobacterial immune responses had sensitivity and specificity as follows: TST 84.6% and 65.5%, ESAT-6 LPA 38.5% and 92.0%, Ag85 LPA 46.2% and 91.5%, and WCL LPA 61.5% and 73.0%. Detectable LPA responses were more common in patients with higher CD4 counts, and higher HIV viral loads. Conclusion Lymphoproliferative responses to mycobacteria are detectable during HIV-associated active TB, and are less sensitive but more specific than TST. Trial registration ClinicalTrials.gov Identifier NCT00052195.

Organizational ethics-defined as the alignment of an institution's practices with its mission, vision, and values-is a growing field in health care not well characterized in empirical literature. To capture the scope and context of organizational ethics work in United States healthcare institutions, we conducted a nationwide convenience survey of ethicists regarding the scope of organizational ethics work, common challenges faced, and the organizational context in which this work is done. In this article, we report substantial variability in the structure of organizational ethics programs and the settings in which it is conducted. Notable findings included disagreement about the activities that comprise organizational ethics and a lack of common metrics used to assess organizational ethics activities. A frequently cited barrier to full engagement in these activities was poor institution-wide understanding about the role and function of organizational ethics resources. These data suggest a tension in the trajectory of organizational ethics' professionalization: while some variability is appropriate to the field's relative youth, inadequate attention to definitions of organizational ethics practice and metrics for success can impede discussions about appropriate institutional support, leadership context, and training for practitioners., Competing Interests: Declarations. Conflict of Interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

In response to a burgeoning pediatric mental health epidemic, recent guidelines have instructed pediatricians to regularly screen their patients for mental health disorders with consistency and standardization. Yet, gold-standard screening surveys to evaluate mental health problems in children typically rely solely on reports given by caregivers, who tend to unintentionally under-report, and in some cases over-report, child symptomology. Digital phenotype screening tools (DPSTs), currently being developed in research settings, may help overcome reporting bias by providing objective measures of physiology and behavior to supplement child mental health screening. Prior to their implementation in pediatric practice, however, the ethical dimensions of DPSTs should be explored. Herein, we consider some promises and challenges of DPSTs under three broad categories: accuracy and bias, privacy, and accessibility and implementation. We find that DPSTs have demonstrated accuracy, may eliminate concerns regarding under- and over-reporting, and may be more accessible than gold-standard surveys. However, we also find that if DPSTs are not responsibly developed and deployed, they may be biased, raise privacy concerns, and be cost-prohibitive. To counteract these potential shortcomings, we identify ways to support the responsible and ethical development of DPSTs for clinical practice to improve mental health screening in children.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence., Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength., Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches., Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions., Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Background: Dismantling structural inequities in health care requires that physicians understand the impacts of social determinants of health (SDH). Although many medical schools incorporate SDH education, integration of these principles into the preclinical curriculum remains challenging., Methods: Students and faculty at the University of Vermont, Larner College of Medicine developed the Social Medicine Theme of the Week (SMTW), a peer-teaching approach to integrating SDH topics across the preclinical curriculum as part of a broader social medicine curriculum. Students created objectives to link SDH-related topics to the weekly curriculum and presented them to the class. Student innovation led to the incorporation of creative online infographics that were published in the curriculum calendar. First year medical students and faculty members were surveyed to assess preferences and educational impact of the SMTW announcements with accompanying infographics., Results: Of the 40 student respondents, 77.5% reported that their knowledge of SDH had improved due to the SMTW. Most students (82.5%) preferred the infographic modality over traditional teaching modalities. Faculty respondents reported limited engagement with the SMTW and, although they supported the need for these objectives, many (61%) found it difficult to integrate SDH content into their class materials., Conclusion: Student-led infographics are a popular method of integrating SDH content in the preclinical curriculum that can be optimized through faculty orientation and support. Success for this type of instruction requires opportunities for student developers, integration and formal assessment of objectives, faculty engagement and training, and institutional support for creating and delivering a robust social medicine curriculum., (© 2023. The Author(s).)

Introduction: Transfer of trauma patients whose injuries are deemed unsurvivable, often results in early death or transition to comfort care and could be considered misuse of health care resources. This is particularly true where tertiary care resources are limited. Identifying riskfactors for and predicting futile transfers could reduce this impact and help to optimize triage and management., Methods: A retrospective study of interfacility trauma transfers to a single rural Level I rauma center from 2014 to 2019. Futility was defined as death, hospice, or declaration of comfort measures within 48 h of transfer without procedural or radiographic intervention at the accepting center. Multiple logistic regressions identified independent predictors of futile transfers. The predictive power of Mechanism,Glasgow coma scale, Age, and Arterial pressure (MGAP), an injury severity score based on Mechanism, Glasgow coma scale, Age, and systolic blood Pressure, were evaluated., Results: Of the 3368 trauma transfers, 37 (1.1%) met criteria as futile. Futile transfers occurred among patients who were significantly older with falls as the most common mechanism. Age, Glasgow coma scale, systolic blood Pressure and Injury Severity Score were significant (P < 0.05) independent predictors of futile transfer. MGAP had a high predictive power area under the receiver operating characteristic (AUROC 0.864, 95% confidence interval 0.803-0.925) for futility., Conclusions: A small proportion (1.1%) of transfers to a rural Level I trauma center met criteria for futility. Predictive tools, such as MGAP scoring, can provide objective criteria for evaluation of transfer necessity and prompt care pathways that involve pre-transfer communications, telemedicine, and/or patient centered goals of care discussions. Such tools could be used in conjunction with a more granular assessment regarding potential operational barriers to reduce futile transfers and to enhance optimization of resource utilization in low-resource service areas., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence., Methods: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples., Results: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here., Conclusions: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies., (© 2022. The Author(s).)

Purpose: Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR)., Methods: This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested., Results: The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care., Conclusion: Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact., Competing Interests: Steven AdesResearch Funding: Lilly, EMD Serono Alissa A. ThomasResearch Funding: Novocure, Spectrum Pharmaceuticals, Spectrum Pharmaceuticals Julian SpragueStock and Other Ownership Interests: Gilead Sciences, Johnson and Johnson, Merk and Company, Roche/Genentech, Pfizer Peter A. KaufmanStock and Other Ownership Interests: AmgenHonoraria: Lilly, Polyphor, Macrogenics, EisaiConsulting or Advisory Role: Polyphor, Roche/Genentech, Lilly, Eisai, Macrogenics, Pfizer, Merck, AstraZenecaSpeakers' Bureau: LillyResearch Funding: Eisai, Polyphor, Roche/Genentech, Lilly, Novartis, Macrogenics, Pfizer, SanofiTravel, Accommodations, Expenses: Lilly, Polyphor, MacrogenicsNo other potential conflicts of interest were reported.

Background: To support the development of social medicine curricula that empower medical school graduates to redress health inequities, we conducted a mixed methods student and faculty evaluation of an expanded and innovative preclinical social medicine curriculum., Methods: We implemented a longitudinal, interactive preclinical social medicine curriculum that was closely integrated with foundational science teaching then conducted a survey-based mixed methods student and faculty curriculum evaluation. Based on these results, we propose a novel conceptual roadmap for social medicine curriculum design., Results: Student and faculty evaluations of an expanded and innovative longitudinal preclinical social medicine curriculum were strongly favorable. Both student and faculty respondents indicated a particular desire for deeper coverage of race and poverty among other social medicine domains. Qualitative student evaluations highlighted the importance of faculty champions to social medicine teaching as well as the educational impact of stories that exemplify the practical impact of the social determinants of health on specific patient experiences. Qualitative faculty evaluations pointed to the challenges of curriculum integration and the need for faculty career development in social medicine teaching., Conclusions: Based on mixed methods student and faculty curriculum evaluation data, we propose a novel conceptual roadmap for the design of social medicine curricula at other institutions., (© 2021. The Author(s).)

Background: Tuberculosis (TB) is the most deadly infectious disease globally and is highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb who remain disease free carry epigenetic changes that strongly protect them from active TB., Methods: We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS., Results: We identified 3 regions of interest that included markers that were differentially methylated between TB cases and controls with latent TB infection: chromosome 1 (RNF220, P = 4 × 10-5), chromosome 2 (between COPS8 and COL6A3, P = 2.7 × 10-5), and chromosome 5 (CEP72, P = 1.3 × 10-5). These methylation results co-localized with associated single-nucleotide polymorphisms (SNPs), methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung., Conclusions: Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

This commentary examines the appropriateness of a clinician's deceiving a patient who will not discuss lifesaving therapy through the lens of solidarity, a key professional ethical value. Clinicians' awareness of social determinants of many patients' increased vulnerability to HIV infection is needed to promote equitable HIV intervention outcomes at both individual and community levels., (© 2021 American Medical Association. All Rights Reserved.)

Background: Despite an abundant literature advocating that social determinants of health (SDH) be taught during undergraduate medical education, there are few detailed descriptions of how to design and implement longitudinal core curricula that is delivered to all students and accomplishes this goal., Methods: In this paper, we describe the design and implementation of a social medicine curriculum at the University of Vermont's Larner College of Medicine (UVM Larner). Using Kern's principles, we designed a longitudinal curriculum that extends through both preclinical and clinical training for all students and focused on integrating SDH material directly into basic science and clinical training., Results: We successfully developed and implemented two primary tools, a "Social Medicine Theme of the Week" (SMTW) in preclinical training, and SDH rounds in the clinical setting to deliver SDH content to all learners at UVM Larner., Conclusions: Extensive student-faculty partnerships, robust needs assessment, and focusing on longitudinal and integrated SDH content delivery to all students were key features that contributed to successful design and implementation.

Competing Interests: Competing interests: None declared.

The current coronavirus disease 2019 (COVID-19) pandemic has triggered an intense global research effort to inform the life-saving work of frontline clinicians who need reliable information as soon as possible. Yet research done in pressured circumstances can lead to ethical dilemmas, especially for vulnerable research subjects. We present the case of a child with neurocognitive impairment who is diagnosed with COVID-19 infection after presenting with fever and a seizure. The child lives in a group home and is in the custody of the state; her parents lost parental rights many years ago. Some members of the health care team want to enroll her in a randomized clinical trial evaluating an experimental treatment of COVID-19. For minor patients to enroll in this clinical trial, the institutional review board requires assent of patients and consent of guardians. An ethics consult is called to help identify relevant concerns in enrollment. In the accompanying case discussion, we address historical perspectives on research involving people with disabilities; proper management of research participation for people with disabilities including consent by proxy, therapeutic misconception, and other threats to the ethical validity of clinical trials; and the potentially conflicting obligations of researchers and clinicians., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Organizational ethics programs often are created to address tensions in organizational values that have been identified through repeated clinical ethics consultation requests. Clinical ethicists possess some core competencies that are suitable for the leadership of high-quality organizational ethics programs, but they may need to develop new skills to build these programs, such as familiarity with healthcare delivery science, healthcare financing, and quality improvement methodology. To this end, we suggest that clinical ethicists build organizational ethics programs incrementally and via quality improvement projects undertaken in collaboration with senior clinical leaders. Organizational ethics programs often differ from clinical ethics programs in their membership and processes, and likely will require ethicists to forge new partnerships with a wide array of organizational leaders. With attention to the ways that organizational ethics programs differ from clinical ethics programs, and investment in quality improvement methodology and formal institutional needs assessments, clinical ethics leaders can position an organizational ethics program to advocate effectively for visible and compelling alignment of leadership decision making with the values of the organization., (Copyright 2020 The Journal of Clinical Ethics. All rights reserved.)

Shared decision making honors patient autonomy, particularly for preference-sensitive care decisions. Shared decision making can be challenging, however, when patients have impaired decision-making capacity. Here, after presenting an illustrative case example, this paper proposes a capacity-adjusted "sliding scale" approach to shared decision making., (© 2020 American Medical Association. All Rights Reserved.)

Shared decision making honors patient autonomy and improves patient comprehension and therefore should be a part of every clinical decision a patient makes. Use of shared decision making in research informed consent conversations is more complicated due to diverse and potentially divergent investigator and patient interests, along with the presence of clinical equipoise. This article clarifies these different interests and discusses ways in which shared decision making can be applied in research. Provided there is transparency about competing interests, patient-centered and values-focused communication approaches embodied in shared decision making can support the ethical recruitment of patients for clinical research., (© 2020 American Medical Association. All Rights Reserved.)