Publications by authors named "Timothy Lahey"

49 Publications

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

BMC Med Educ 2021 Aug 20;21(1):442. Epub 2021 Aug 20.

Department of Medicine/Ethics, Larner College of Medicine, University of Vermont, Given Medical Bldg, E-126, 89 Beaumont Ave, Burlington, VT, 05405, USA.

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.
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http://dx.doi.org/10.1186/s12909-021-02885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376629PMC
August 2021

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

BMC Med Educ 2021 Feb 24;21(1):131. Epub 2021 Feb 24.

University of Vermont's Larner College of Medicine, UVMMC, 111 Colchester Ave, Smith 2, Burlington, VT, 05401, USA.

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.
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http://dx.doi.org/10.1186/s12909-021-02533-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903930PMC
February 2021

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

J Infect Dis 2021 Aug;224(4):695-704

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

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.
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http://dx.doi.org/10.1093/infdis/jiaa785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366433PMC
August 2021

Building an Organizational Ethics Program on a Clinical Ethics Foundation.

J Clin Ethics 2020 ;31(3):259-267

Healthcare Ethics, Ascension Health, St. Louis, Missouri USA.

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.
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November 2020

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

Camb Q Healthc Ethics 2020 01;29(1):156-162

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.
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http://dx.doi.org/10.1017/S0963180119000884DOI Listing
January 2020

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

J Gen Intern Med 2019 08 30;34(8):1641-1644. Epub 2019 May 30.

Larner College of Medicine, University of Vermont, Burlington, VT, USA.

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.
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http://dx.doi.org/10.1007/s11606-019-05063-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667566PMC
August 2019

CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

PLoS One 2019 23;14(5):e0217091. Epub 2019 May 23.

Geisel School of Medicine, Hanover, NH, United States of America.

Background: DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo.

Methods: We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining.

Results: DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses.

Conclusion: DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters.

Trial Registration: ClinicalTrials.gov NCT02063555.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532882PMC
January 2020

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

BMC Public Health 2018 04 23;18(1):535. Epub 2018 Apr 23.

Geisel School of Medicine, Dartmouth College, Hanover, USA.

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 .
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http://dx.doi.org/10.1186/s12889-018-5460-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914029PMC
April 2018

Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site.

JCI Insight 2018 03 8;3(5). Epub 2018 Mar 8.

Thayer School of Engineering and.

Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs-specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.
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http://dx.doi.org/10.1172/jci.insight.97018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922287PMC
March 2018

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

PLoS Genet 2017 Jun 19;13(6):e1006710. Epub 2017 Jun 19.

Centro di Ricerca, Ospedale San Pietro Fatebenefratelli, Rome, Italy.

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.
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http://dx.doi.org/10.1371/journal.pgen.1006710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495514PMC
June 2017

Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: A randomized, controlled trial of DAR-901.

PLoS One 2017 12;12(5):e0175215. Epub 2017 May 12.

Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Background: Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic.

Methods: We performed a single site, randomized, double-blind, controlled, Phase 1 dose escalation trial of DAR-901 at Dartmouth-Hitchcock Medical Center in the United States. Healthy adult subjects age 18-65 with prior BCG immunization and a negative interferon-gamma release assay (IGRA) were enrolled in cohorts of 16 subjects and randomized to three injections of DAR-901 (n = 10 per cohort), or saline placebo (n = 3 per cohort), or two injections of saline followed by an injection of BCG (n = 3 per cohort; 1-8 x 106 CFU). Three successive cohorts were enrolled representing DAR-901 at 0.1, 0.3, and 1 mg per dose. Randomization was performed centrally and treatments were masked from staff and volunteers. Subsequent open label cohorts of HIV-negative/IGRA-positive subjects (n = 5) and HIV-positive subjects (n = 6) received three doses of 1 mg DAR-901. All subjects received three immunizations at 0, 2 and 4 months administered as 0.1 mL injections over the deltoid muscle alternating between right and left arms. The primary outcomes were safety and immunogenicity. Subjects were followed for 6 months after dose 3 for safety and had phlebotomy performed for safety studies and immune assays before and after each injection. Immune assays using peripheral blood mononuclear cells included cell-mediated IFN-γ responses to DAR-901 lysate and to Mycobacterium tuberculosis (MTB) lysate; serum antibody to M. tuberculosis lipoarabinomannan was assayed by ELISA.

Results: DAR-901 had an acceptable safety profile and was well-tolerated at all dose levels in all treated subjects. No serious adverse events were reported. Median (range) 7-day erythema and induration at the injection site for 1 mg DAR-901 were 10 (4-20) mm and 10 (4-16) mm, respectively, and for BCG, 30 (10-107) mm and 38 (15-55) mm, respectively. Three mild AEs, all headaches, were considered possibly related to DAR-901. No laboratory or vital signs abnormalities were related to immunization. Compared to pre-vaccination responses, three 1 mg doses of DAR-901 induced statistically significant increases in IFN-γ response to DAR-901 lysate and MTB lysate, and in antibody responses to M. tuberculosis lipoarabinomannan. Ten subjects who received 1 mg DAR-901 remained IFN-γ release assay (IGRA) negative after three doses of vaccine.

Conclusions: A three-injection series of DAR-901 was well-tolerated, had an acceptable safety profile, and induced cellular and humoral immune responses to mycobacterial antigens. DAR-901 is advancing to efficacy trials.

Trial Registration: ClinicalTrials.gov NCT02063555.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429024PMC
September 2017

Endogenous Endophthalmitis: A Novel Harbinger of the Injection Drug Epidemic in the United States.

Case Rep Infect Dis 2017 5;2017:9686353. Epub 2017 Apr 5.

Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Endogenous endophthalmitis is a rare but feared infectious ocular complication of injection drug use (IDU). The recent opioid epidemic in the United States threatens to increase the incidence of this disease. We report the first case of endogenous endophthalmitis in the United States caused by the emerging fungal pathogen in an injection drug user which led to no light perception vision (NLP). Worldwide experience with endogenous endophthalmitis is limited, but existing cases suggest infection by this particular fungal genus has a grim prognosis.
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http://dx.doi.org/10.1155/2017/9686353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396434PMC
April 2017

Immunogenicity and Protective Efficacy of the DAR-901 Booster Vaccine in a Murine Model of Tuberculosis.

PLoS One 2016 20;11(12):e0168521. Epub 2016 Dec 20.

Dartmouth's Geisel School of Medicine, 1 Medical Center Drive, Lebanon, NH, United States of America.

Background: The development of a novel tuberculosis vaccine is a leading global health priority. SRL172, an inactivated, whole-cell mycobacterial vaccine, was safe, immunogenic and reduced the incidence of culture-confirmed tuberculosis in a phase III trial in HIV-infected and BCG immunized adults in Tanzania. Here we describe the immunogenicity and protective efficacy of DAR-901, a booster vaccine against tuberculosis manufactured from the same seed strain using a new scalable method.

Methods: We evaluated IFN-γ responses by ELISpot and antibody responses by enzyme linked immunosorbent assay in C57BL/6 and BALB/c mice after three doses of DAR-901. In an aerosol challenge model, we evaluated the protective efficacy of the DAR-901 booster in C57BL/6 mice primed with BCG and boosted with two doses of DAR-901 at 4 dosage levels in comparison with homologous BCG boost.

Results: DAR-901 vaccination elicited IFN-γ responses to mycobacterial antigen preparations derived from both DAR-901 and Mycobacterium tuberculosis. DAR-901 immunization enhanced antibody responses to DAR-901 but not Mycobacterium tuberculosis lysate or purified protein derivative. Among animals primed with BCG, boosting with DAR-901 at 1 mg provided greater protection against aerosol challenge than a homologous BCG boost (lungs P = 0.036, spleen P = 0.028).

Conclusions: DAR-901 induces cellular and humoral immunity and boosts protection from M. tuberculosis compared to a homologous BCG boost.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173179PMC
June 2017

Mycobacterium bovis BCG and New Vaccines for the Prevention of Tuberculosis.

Microbiol Spectr 2016 10;4(5)

Dartmouth's Geisel School of Medicine.

Tuberculosis infects millions of people worldwide and remains a leading global killer despite widespread neonatal administration of the tuberculosis vaccine, bacillus Calmette-Guérin (BCG). BCG has clear and sustained efficacy, but after 10 years, its efficacy appears to wane, at least in some populations. Fortunately, there are many new tuberculosis vaccines in development today, some in advanced stages of clinical trial testing. Here we review the epidemiological need for tuberculosis vaccination, including evolving standards for administration to at risk individuals in developing countries. We also examine proven sources of immune protection from tuberculosis, which to date have exclusively involved natural or vaccine exposure to whole cell mycobacteria. After summarizing evidence for the use and efficacy of BCG, we detail the most promising new candidate vaccines against tuberculosis. The global need for a new tuberculosis vaccine is acute and huge, but clinical trials to be completed in the coming few years are likely either to identify a new tuberculosis vaccine or to substantially reframe how we understand immune protection from this historical scourge.
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http://dx.doi.org/10.1128/microbiolspec.TNMI7-0003-2016DOI Listing
October 2016

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

Am J Hum Genet 2016 Mar;98(3):514-524

Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajhg.2016.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800052PMC
March 2016

An ethical framework for global psychiatry.

Ann Glob Health 2014 Mar-Apr;80(2):146-51

Dartmouth College, Hanover, NH. Electronic address:

Existing literature addresses the ethical considerations of global health work and how medical school curricula can help prepare students for them, but little has been written regarding an ethical approach to global psychiatry. In this paper we summarize prominent ethical issues that arise in global health psychiatry in order to provide a foundation for a framework in global health psychiatry. These issues include obtaining informed consent in the face of language barriers, diagnosing and treating for mental illnesses while navigating communities where such conditions are heavily stigmatized, and justifying the cessation of proving care to current patients for the sake of providing care to new patients abroad. To help prepare psychiatrists and students for work that engages these issues, we propose a multi-step process to assist the practicing global psychiatrist in recognizing ethical dilemmas and evaluating potential courses of action based on their respective ethical merits.
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http://dx.doi.org/10.1016/j.aogh.2014.04.002DOI Listing
March 2016

Question: Can you identify this condition? Acute retinal necrosis.

Can Fam Physician 2013 Dec;59(12):1307; 1308-10

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December 2013

The ethics of clinical research in low- and middle-income countries.

Authors:
Timothy Lahey

Handb Clin Neurol 2013 ;118:301-13

Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover; Section of Infectious Diseases and International Health, Department of Medicine, Lebanon and Bioethics Committee, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. Electronic address:

The increasing conduct of clinical research in low- and middle-income countries (LMIC) is motivated by the desire to promote host country access to biomedical research, to enhance LMIC access to modern clinical care, and opportunities to conduct research with simpler regulatory requirements and at lower cost. Yet clinical research in LMIC is associated with ethical risks beyond those of clinical research conducted in high-income countries (HIC). Ethical challenges particular to clinical research in LMIC include the conduct of placebo-controlled clinical trials in LMIC despite HIC availability of effective comparator interventions, obtaining informed consent despite power inequities, and the obligation of HIC researchers to redress health disparities in LMIC. This chapter covers these and additional ethical challenges of clinical research in LMIC, and proposes ways to navigate these challenges through awareness, regulatory oversight, consultation, and collaboration with LMIC investigators and community representatives. With its ethical challenges properly managed, clinical research in LMIC provides historic opportunities to bring biomedical research and better healthcare infrastructure to countries previously left behind in the modern rush to biomedical innovation.
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http://dx.doi.org/10.1016/B978-0-444-53501-6.00025-1DOI Listing
April 2014

The design of a medical school social justice curriculum.

Acad Med 2013 Oct;88(10):1442-9

Ms. Coria is a medical student, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Mr. McKelvey is a medical student, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Mr. Charlton is a medical student, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Dr. Woodworth is a recent graduate, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, and internal medicine resident, Duke University Medical Center, Durham, North Carolina. Dr. Lahey is associate professor of medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

The acquisition of skills to recognize and redress adverse social determinants of disease is an important component of undergraduate medical education. In this article, the authors justify and define "social justice curriculum" and then describe the medical school social justice curriculum designed by the multidisciplinary Social Justice Vertical Integration Group (SJVIG) at the Geisel School of Medicine at Dartmouth. The SJVIG addressed five goals: (1) to define core competencies in social justice education, (2) to identify key topics that a social justice curriculum should cover, (3) to assess social justice curricula at other institutions, (4) to catalog institutionally affiliated community outreach sites at which teaching could be paired with hands-on service work, and (5) to provide examples of the integration of social justice teaching into the core (i.e., basic science) curriculum. The SJVIG felt a social justice curriculum should cover the scope of health disparities, reasons to address health disparities, and means of addressing these disparities. The group recommended competency-based student evaluations and advocated assessing the impact of medical students' social justice work on communities. The group identified the use of class discussion of physicians' obligation to participate in social justice work as an educational tool, and they emphasized the importance of a mandatory, longitudinal, immersive, mentored community outreach practicum. Faculty and administrators are implementing these changes as part of an overall curriculum redesign (2012-2015). A well-designed medical school social justice curriculum should improve student recognition and rectification of adverse social determinants of disease.
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http://dx.doi.org/10.1097/ACM.0b013e3182a325beDOI Listing
October 2013

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

J Infect Dis 2013 Nov 1;208(10):1629-33. Epub 2013 Aug 1.

Geisel School of Medicine at Dartmouth.

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.
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http://dx.doi.org/10.1093/infdis/jit396DOI Listing
November 2013

Children's medicines in Tanzania: a national survey of administration practices and preferences.

PLoS One 2013 6;8(3):e58303. Epub 2013 Mar 6.

Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

Objective: The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics.

Patients And Methods: We surveyed children aged 6-12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre.

Results: Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take.

Conclusions: There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058303PLOS
September 2013

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

Clin Infect Dis 2013 Jan 12;56(1):151-8. Epub 2012 Sep 12.

Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.

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.
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http://dx.doi.org/10.1093/cid/cis798DOI Listing
January 2013

Human seminal plasma fosters CD4(+) regulatory T-cell phenotype and transforming growth factor-β1 expression.

Am J Reprod Immunol 2012 Oct 17;68(4):322-30. Epub 2012 Jul 17.

Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.

Problem: Semen mediates expansion of CD4(+) regulatory T cells (Treg) in the murine female reproductive tract. The impact of semen on Treg in humans, however, remains unclear.

Method Of Study: Using seminal plasma (SP) from 20 healthy donors, we investigated the impact of human semen on CD4(+) T-cell expression of CD127 and CD49d as well as CD4(+) CD127(low) CD49d(low) Treg proliferation, apoptosis, and intracellular expression of FoxP3, TGF-β1, and IL-10.

Results: SP reduced CD4(+) T-cell expression of CD127 and CD49d and increased the proportion of CD127(low) CD49d(low) Treg. This increase was non-proliferative, mediated in part via the conversion of CD4(+) helper T cells into FoxP3(-) but not FoxP3(+) Treg. Additionally, SP induced an increase in intracellular expression of the immunosuppressive cytokine TGF-β1 by the FoxP3(-) but not FoxP3(+) Treg. SP had no impact on Treg intracellular expression of IL-10.

Conclusion: Human seminal plasma fosters the non-proliferative increase in the proportion and immunoregulatory activity of FoxP3(-) Treg.
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http://dx.doi.org/10.1111/j.1600-0897.2012.01176.xDOI Listing
October 2012

Selective impact of HIV disease progression on the innate immune system in the human female reproductive tract.

PLoS One 2012 4;7(6):e38100. Epub 2012 Jun 4.

Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.

Background: We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.

Methods: CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.

Results: CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains. Although there was broad CVL inhibition of most both laboratory-adapted and T/F virus strains, there was practically no inhibition of T/F strain RHPA.c, which was isolated from a woman newly infected via heterosexual intercourse. HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor. HIV disease progress predicted decreased CVL anti-HIV activity against both laboratory-adapted and T/F strains of HIV. Anti-HIV activity exhibited close associations with CVL levels of fourteen cytokines and chemokines.

Conclusions: Amid a multifaceted immune defense against HIV-1 and other sexually transmitted pathogens, HIV disease progression is associated with selective disturbances in both CVL anti-HIV activity and specific innate immune defenses in the human female reproductive tract (FRT). Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038100PLOS
October 2012

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

J Clin Microbiol 2012 Aug 30;50(8):2645-50. Epub 2012 May 30.

Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

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.
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http://dx.doi.org/10.1128/JCM.00624-12DOI Listing
August 2012

Test characteristics of urinary lipoarabinomannan and predictors of mortality among hospitalized HIV-infected tuberculosis suspects in Tanzania.

PLoS One 2012 8;7(3):e32876. Epub 2012 Mar 8.

Dartmouth Medical School, Hanover, New Hampshire, United States of America.

Background: Tuberculosis is the most common cause of death among patients with HIV infection living in tuberculosis endemic countries, but many cases are not diagnosed pre-mortem. We assessed the test characteristics of urinary lipoarabinomannan (LAM) and predictors of mortality among HIV-associated tuberculosis suspects in Tanzania.

Methods: We prospectively enrolled hospitalized HIV-infected patients in Dar es Salaam, with ≥2 weeks of cough or fever, or weight loss. Subjects gave 2 mLs of urine to test for LAM using a commercially available ELISA, ≥2 sputum specimens for concentrated AFB smear and solid media culture, and 40 mLs of blood for culture.

Results: Among 212 evaluable subjects, 143 (68%) were female; mean age was 36 years; and the median CD4 count 86 cells/mm(3). 69 subjects (33%) had culture confirmation of tuberculosis and 65 (31%) were LAM positive. For 69 cases of sputum or blood culture-confirmed tuberculosis, LAM sensitivity was 65% and specificity 86% compared to 36% and 98% for sputum smear. LAM test characteristics were not different in patients with bacteremia but showed higher sensitivity and lower specificity with decreasing CD4 cell count. Two month mortality was 64 (53%) of 121 with outcomes available. In multivariate analysis there was significant association of mortality with absence of anti-retroviral therapy (p = 0.004) and a trend toward association with a positive urine LAM (p = 0.16). Among culture-negative patients mortality was 9 (75%) of 12 in LAM positive patients and 27 (38%) of 71 in LAM negative patients (p = 0.02).

Conclusions: Urine LAM is more sensitive than sputum smear and has utility for the rapid diagnosis of culture-confirmed tuberculosis in this high-risk population. Mortality data raise the possibility that urine LAM may also be a marker for culture-negative tuberculosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032876PLOS
August 2012

Perspective: a proposed medical school curriculum to help students recognize and resolve ethical issues of global health outreach work.

Authors:
Timothy Lahey

Acad Med 2012 Feb;87(2):210-5

Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.

Medical students' interest in global health outreach work is intense and growing. Yet, medical students' global health outreach work is fraught with ethical complexity: Students must make challenging resource allocation decisions in an unfamiliar setting while providing complicated care with evolving expertise across power gradients and geographical as well as cultural boundaries. Inadequate training in the recognition and resolution of the ethical issues inherent in this work likely endangers future service work participation and undercuts the efficacy of medical students' global health outreach work. The author describes how the medical school curriculum can empower medical students to recognize and resolve ethical issues encountered in global health outreach work. To achieve this goal, he proposes a curriculum in the ethics of global health outreach to train students to understand (1) the ethical justifications for global health outreach work, (2) the drivers of global health disparities, (3) the key ethical issues raised by global health outreach, and (4) how to resolve ethical quandaries encountered during global health outreach work through collaboration. Beyond specific topical content, a medical school curriculum in the ethics of global health outreach should emphasize the importance of local collaboration and longitudinal mentorship of medical students. Medical school training in the recognition and resolution of the ethical issues attendant on global health outreach work prepares students not only for more sophisticated work in international settings but also for the ethical complexities of medical practice closer to home.
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http://dx.doi.org/10.1097/ACM.0b013e31823f3fb1DOI Listing
February 2012
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