Publications

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

A diagnosis of brucellosis can be difficult because routine culture and serological methods exhibit variable sensitivity and specificity. We present the use of a metagenomic next- generation sequencing assay to diagnose a case of neurobrucellosis from cerebrospinal fluid, resulting in the institution of appropriate antibiotic treatment and a favorable clinical outcome.

BACKGROUND

Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters. Thus, we investigated the chronic inflammatory state associated with HIV-infection as a source of pharmacokinetic variability of atazanavir. We also explored the association of total bilirubin concentrations with markers of inflammation and endothelial activation.

METHODS

Apparent oral clearance (CL/F) of atazanavir was estimated from plasma samples collected from participants in AIDS Clinical Trials Group Study A5202. Several inflammatory and endothelial activation biomarkers were measured at baseline and weeks 24 and 96 as part of metabolic sub-study A5224s: high-sensitivity C-reactive protein (hsCRP), interleukin-6, tumor necrosis factor alpha and its soluble receptors, soluble vascular cellular and intracellular adhesion molecules, and total bilirubin. Statistical analysis was performed by a matrix of correlation coefficients between atazanavir CL/F and biomarker concentrations measured at week 24. The correlation between atazanavir clearance and percentage change in bilirubin from baseline to weeks 24 and 96, and between biomarkers and bilirubin concentrations at each week were also evaluated.

RESULTS

Among 107 participants, there were no significant correlations observed between atazanavir CL/F and inflammatory and endothelial activation biomarkers measured at week 24 (P ≥ 0.24). As expected, bilirubin increased with increasing exposure to atazanavir (rho = - 0.25, P = 0.01). Bilirubin concentrations were inversely correlated (P < 0.01) with each of the biomarkers except hsCRP.

CONCLUSIONS

Atazanavir CL/F did not correlate with the inflammatory biomarkers changes. Inflammatory-mediated inhibition of cytochrome P450 3A may have been attenuated due to atazanavir-associated increases of bilirubin, which has known anti-inflammatory properties.

BACKGROUND

Although HIV and injury contribute substantially to disease burdens in lowand middle-income countries (LMIC), their intersection is poorly characterized.

OBJECTIVE

This systematic review assessed the prevalence and associated mortality impact of HIVseropositivity among injured patients in LMIC.

METHODS

A systematic search of PubMed, EMBASE, Global Health, CINAHL, POPLINE and Cochrane databases through August 2016 was performed. Prospective and cross-sectional reports of injured patients from LMIC that evaluated HIV-serostatus were included. Two reviewers identified eligible records (kappa=0.83); quality was assessed using GRADE criteria. HIV-seroprevalence and mortality risks were summarized and pooled estimates were calculated using random-effects models with heterogeneity assessed.

RESULTS

Of 472 retrieved records, sixteen met inclusion. All reports were of low or very low quality and derived from sub-Saharan Africa. HIV-serostatus was available for 3,994 patients. Individual report and pooled HIV-seroprevalence estimates were uniformly greater than temporally matched national statistics (range: 4.5-35.0%). Pooled reports from South Africa were three-fold greater than matched national prevalence (32.0%, 95% CI, 28.0-37.0%). Mortality data were available for 1,398 patients. Heterogeneity precluded pooled mortality analysis. Among individual reports, 66.7% demonstrated significantly increased relative risks (RR) of death; none found reduced risk of death among HIV-seropositive patients. Increased mortality risk among HIV-seropositive patients ranged from 1.86 (95% CI, 1.11-3.09) in Malawi to 10.7 (95% CI, 1.32-86.1) in South Africa.

CONCLUSION

The available data indicate that HIV-seropositivity among the injured is high relative to national rates and may increase mortality, suggesting that integrated HIV-injury programming could be beneficial. Given the data limitations, further study of the HIV-injury intersection is crucially needed.

OBJECTIVE

Otologic methicillin-resistant (MRSA) infection has historically been rare, but given the rise in community-acquired MRSA carriage and infection at other body sites, prevalence rates may be changing. The goal of this study was to determine the prevalence of MRSA in recent otologic cultures from patients with acute otitis externa (AOE).

STUDY DESIGN

Retrospective review of an institutional microbiologic database.

METHODS

A retrospective analysis was performed on serial culture isolates taken from the ear at a quaternary care hospital from January 2014 to April 2016. The causative pathogen and antibiotic sensitivity was determined by culture isolation and end point mean inhibitory concentration (MIC) testing. Medical records were reviewed to document patient characteristics, chronicity of infection, symptomatology, and previous treatments.

RESULTS

Over the study period, 173 patients were diagnosed with AOE and underwent otologic cultures of the ear. Fifty-three (30.6%) of cultures grew (SA). Of SA infections, 15 (28.3%) were identified as MRSA. MRSA patients were typically older than patients with methicillin-sensitive SA (MSSA) (mean age 46.7 ± 17.9 29 ± 19.4,  = 0.003) and had more medical comorbidities (4 1.7,  = 0.001). Compared to patients with MSSA, patients with MRSA were significantly more likely to have had prior ototopical antibiotic exposure (37% 73%,  = 0.019).

CONCLUSION

Contemporary ear culture isolates at quaternary care center show higher rates of MRSA compared to historical reports in the literature. Clinicians should consider ear cultures to identify MRSA AOE.

LEVEL OF EVIDENCE

IV.