Association of COVID-19 Visitor Limitations and Goals of Care Discussions in the Intensive Care Unit.

INTRODUCTION: The COVID-19 pandemic led to visitor restrictions in many hospitals. Since care in the surgical intensive care unit (SICU) often engages visitors as surrogate decision-makers, we investigated whether there was an association between COVID-19-related visitor restrictions, goals of care discussions (GOCD), and patient outcomes in SICU patients. METHODS: We conducted a retrospective review of trauma and emergency general surgery (EGS) patients admitted to a rural tertiary SICU between July 2019 and April 2021, dividing patients into those admitted during COVID-19 visitor restrictions and those admitted at other times. Using univariate and multivariate logistic regression analyses, we compared the primary outcome, incidence of GOCD, and incidence of prolonged hospital (> 14 d) and intensive care unit length of stay (LOS, > 7 d) between the two groups. RESULTS: One hundred seventy nine of 368 study patients (48.6%) presented during restricted visitation. The proportion of GOCD was 38.0% and 36.5% in the restricted and nonrestricted visitation cohorts, respectively (P = 0.769). GOCD timing and outcomes were similar in both groups. The use of telecommunication increased during restricted visitation, as did the proportion of trauma patients admitted to the SICU. On multivariable logistic regression, age and patient category were independent predictors of GOCD. On outcomes analysis, visitor restriction was associated with prolonged hospital LOS for EGS patients (odds ratio 2.44, 95% confidence interval 1.01-5.91, P value 0.048). CONCLUSIONS: Restricted visitation was not associated with changes in frequency or outcome of GOCD, but was associated with prolonged hospital LOS among EGS patients who had SICU admissions. Further investigation of patient/surrogate satisfaction with virtual GOCD in the SICU setting is needed.

Using Wearable Digital Devices to Screen Children for Mental Health Conditions: Ethical Promises and Challenges.

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.

Integrating social determinants of health principles into the preclinical medical curriculum via student-led pedagogical modalities.

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.

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data.

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 1ß, 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.

Frequency and Predictors of Trauma Transfer Futility to a Rural Level I Trauma Center.

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.

Methylome-wide Analysis Reveals Epigenetic Marks Associated With Resistance to Tuberculosis in Human Immunodeficiency Virus-Infected Individuals From East Africa.

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 design and implementation of a longitudinal social medicine curriculum at the University of Vermont's Larner College of Medicine.

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.

A new roadmap for social medicine curriculum design based on mixed methods student and faculty evaluations of the preclinical curriculum.

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.

A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa.

One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an "experiment of nature" design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.

Building an Organizational Ethics Program on a Clinical Ethics Foundation.

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.

A Dashboard to Improve the Alignment of Healthcare Organization Decisionmaking to Core Values and Mission Statement.

The mission and value statements of healthcare organizations serve as the foundational philosophy that informs all aspects of the organization. The ultimate goal is seamless alignment of values to mission in a way that colors the overall life and culture of the organization. However, full alignment between healthcare organizational values and mission in a fashion that influences the daily life and culture of healthcare organizations does not always occur. Grounded in the belief that a lack of organizational alignment to explicit organizational mission and value statements often stems from the failure to develop processes that enable realization of the leadership's good intentions, the authors propose an organizational ethics dashboard to empower leaders of healthcare organizations to assess the adequacy of systems in place to support alignment with the stated ethical mission.

A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals.

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

Just a Game: the Dangers of Quantifying Medical Student Professionalism.

A medical student on her internal medicine clerkship says her numerical medical professionalism grade was "just a game." Building on this anecdote, we suggest there is good reason to believe that numerical summative assessments of medical student professionalism can, paradoxically, undermine medical student professionalism by sapping internal motivation and converting conversations about core professional values into just another hurdle to residency. We suggest better ways of supporting medical student professional development, including a portfolio comprised of written personal reflection and periodic 360° formative assessment in the context of longitudinal faculty coaching.

Altruism, Scepticism, and collective decision-making in foreign-born U.S. residents in a tuberculosis vaccine trial.

BACKGROUND: The current vaccine against tuberculosis, BCG, is effective when given in most TB-endemic countries at birth but has diminished efficacy against pulmonary TB after 15-20 years. As a result, new booster vaccines for adolescents and adults are being developed to realize the World Health Organization target of global elimination of TB by 2035. Multiple TB candidates thus are in active clinical development. METHODS: One of these, DAR-901, is advancing in human clinical trials. These clinical trials are conducted in BCG immunized adults with and without HIV infection in order to assess safety and efficacy among the people most in need of a new vaccine. A Phase I dose escalation trial of DAR-901 in BCG-immunized adults with or without HIV infection was conducted between 2014 and 2016. This offered an unusual opportunity to qualitatively examine why foreign-born adults living in the United States - a poorly studied population - decide to participate, or not, in clinical trials. RESULTS: We conducted a qualitative study of individuals who were recruited to participate in this Phase I vaccine trial, interviewing those who agreed and declined to participate. We found diverse motivations for participation or refusal; varied understandings of tuberculosis and vaccines; and complex views about how 'informed consent' can be at odds with cultural understandings of power, authority, and medical decision-making. These dynamics included: knowledge (direct or indirect) of tuberculosis, a desire to be altruistic and simultaneous hopes for personal gain as well as concerns over what remuneration for participation could mean, the importance of personal relationships with care providers in shaping volunteerism, concerns over privacy, and evidence of how culture and history shape medical decision-making. CONCLUSIONS: This US-based trial, aimed at addressing a crucible global health issue, raises productive questions about the interface between altruism and scepticism regarding clinical research participation. TRIAL REGISTRATION: NCT02063555 .

Greater preexisting interferon γ responses to mycobacterial antigens and lower bacillary load during HIV-associated tuberculosis.

The role of preexisting interferon (IFN) γ responses in controlling bacillary burden in human immunodeficiency virus (HIV)-associated tuberculosis is not known. Among BCG-immunized HIV-infected adults who developed tuberculosis in a phase III trial of an investigational tuberculosis vaccine, greater baseline IFN-γ responses to early secretory antigenic target 6 and Mycobacterium tuberculosis whole-cell lysate were associated with reduced bacillary burden on sputum smear grade, days to culture positivity on agar, and sputum culture grade during subsequent tuberculosis. This association was most consistent among recipients of the investigational vaccine. When HIV-associated tuberculosis develops, greater preexisting IFN-γ responses to mycobacterial antigens are associated with reduced tuberculosis bacillary burden. ClinicalTrials.gov Identifier. NCT0052195.

Recurrent tuberculosis risk among HIV-infected adults in Tanzania with prior active tuberculosis.

BACKGROUND: Active tuberculosis is common among human immunodeficiency virus (HIV)-infected persons living in tuberculosis-endemic areas, but the hazard of subsequent tuberculosis disease has not been quantified in a single prospective cohort. METHODS: Among HIV-infected, BCG-immunized adults with CD4 counts ≥200 cells/µL who received placebo in the DarDar tuberculosis vaccine trial in Tanzania, we compared the prospective risk of active tuberculosis between subjects who did and who did not report prior active tuberculosis. All subjects with a positive tuberculin skin test without prior active tuberculosis were offered isoniazid preventive treatment. Definite or probable tuberculosis was diagnosed during active follow-up using rigorous published criteria. RESULTS: We diagnosed 52 cases of definite and 92 cases of definite/probable tuberculosis among 979 subjects during a median follow-up of 3.2 years. Among the 80 subjects who reported prior active tuberculosis, 11 (13.8%) subsequently developed definite tuberculosis and 17 (21.3%) developed definite/probable tuberculosis, compared with 41 (4.6%) and 75 (8.3%), respectively, of 899 subjects without prior active tuberculosis (definite tuberculosis risk ratio [RR], 3.01; 95% confidence interval [CI], 1.61-5.63, P < .001; definite/probable tuberculosis RR, 2.55; 95% CI, 1.59-4.09, P < .001). In a Cox regression model adjusting for age, CD4 count, and isoniazid receipt, subjects with prior active tuberculosis had substantially greater hazard of subsequent definite tuberculosis (hazard radio [HR], 3.69; 95% CI, 1.79-7.63, P < .001) and definite/probable tuberculosis (HR, 2.78; 95% CI, 1.58-4.87, P < .001). CONCLUSIONS: Compared to subjects without prior tuberculosis, the hazard of active tuberculosis is increased 3-fold among HIV-infected adults with prior active tuberculosis. Clinical Trials Registration. NCT0052195.

COVID-19 infection and a repeated false positivity effect in HIV testing: A case report.

Several reports in the literature have described the association between SARS-CoV-2 infection and false positive HIV testing results. We present a case of a cisgender male who has sex with men with a false positive HIV test after fully recovering from COVID-19 14 days prior. Initial 4th generation HIV 1 and 2 antibody/antigen testing was positive twice, but confirmatory antibody testing was negative. HIV viral load was persistently undetectable. Most of the previously published case reports describe concurrent testing and positivity for HIV and COVID-19. Our report stands out due to the implication of a potentially prolonged association that could persist for several weeks.

Molecular epidemiology of HIV-associated tuberculosis in Dar es Salaam, Tanzania: strain predominance, clustering, and polyclonal disease.

Molecular typing of Mycobacterium tuberculosis can be used to elucidate the epidemiology of tuberculosis, including the rates of clustering, the frequency of polyclonal disease, and the distribution of genotypic families. We performed IS6110 typing and spoligotyping on M. tuberculosis strains isolated from HIV-infected subjects at baseline or during follow-up in the DarDar Trial in Tanzania and on selected community isolates. Clustering occurred in 203 (74%) of 275 subjects: 124 (80%) of 155 HIV-infected subjects with baseline isolates, 56 (69%) of 81 HIV-infected subjects with endpoint isolates, and 23 (59%) of 39 community controls. Overall, 113 (41%) subjects had an isolate representing the East Indian "GD" family. The rate of clustering was similar among vaccine and placebo recipients and among subjects with or without cellular immune responses to mycobacterial antigens. Polyclonal disease was detected in 6 (43%) of 14 patients with multiple specimens typed. Most cases of HIV-associated tuberculosis among subjects from this study in Dar es Salaam resulted from recently acquired infection. Polyclonal infection was detected and isolates representing the East Indian GD strain family were the most common.

Semen protects CD4+ target cells from HIV infection but promotes the preferential transmission of R5 tropic HIV.

Sexual intercourse is the major means of HIV transmission, yet the impact of semen on HIV infection of CD4(+) T cells remains unclear. To resolve this conundrum, we measured CD4(+) target cell infection with X4 tropic HIV IIIB and HC4 and R5 tropic HIV BaL and SF162 after incubation with centrifuged seminal plasma (SP) from HIV-negative donors and assessed the impact of SP on critical determinants of target cell susceptibility to HIV infection. We found that SP potently protects CD4(+) T cells from infection with X4 and R5 tropic HIV in a dose- and time-dependent manner. SP caused a diminution in CD4(+) T cell surface expression of the HIVR CD4 and enhanced surface expression of the HIV coreceptor CCR5. Consequently, SP protected CD4(+) T cells from infection with R5 tropic HIV less potently than it protected CD4(+) T cells from infection with X4 tropic HIV. SP also reduced CD4(+) T cell activation and proliferation, and the magnitude of SP-mediated suppression of target cell CD4 expression, activation, and proliferation correlated closely with the magnitude of the protection of CD4(+) T cells from infection with HIV. Taken together, these data show that semen protects CD4(+) T cells from HIV infection by restricting critical determinants of CD4(+) target cell susceptibility to HIV infection. Further, semen contributes to the selective transmission of R5 tropic HIV to CD4(+) target cells.