Publications by authors named "Rupak Shivakoti"

28 Publications

  • Page 1 of 1

Host Lipidome and Tuberculosis Treatment Failure.

Eur Respir J 2021 Jun 17. Epub 2021 Jun 17.

National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.

Introduction: Host lipids play important roles in Tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well-characterised. We utilised unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.

Methods: A case-control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls.

Results: Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters (CE) and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two CE lipids combined in a unique classifier model provided an AUC of 0.79 (0.65-0.93) in the test dataset for prediction of TB treatment failure.

Conclusions: We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. A lipid signature with prognostic accuracy for TB treatment failure was also identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.
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http://dx.doi.org/10.1183/13993003.04532-2020DOI Listing
June 2021

Impact of HIV status on systemic inflammation during pregnancy.

AIDS 2021 11;35(14):2259-2268

Department of Epidemiology, Columbia University Mailman School of Public Health.

Objective: There are limited studies on the association of HIV infection with systemic inflammation during pregnancy.

Design: A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India.

Methods: The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A, and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively.

Results: Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared with pregnant women without HIV, with some trimester-specific differences.

Conclusion: Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.
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http://dx.doi.org/10.1097/QAD.0000000000003016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563396PMC
November 2021

Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection.

Front Immunol 2020 27;11:587617. Epub 2021 Jan 27.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, United States.

Background: Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ . LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women.

Methods: We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFN, CRP, AGP, I-FABP, IFN, IL-1, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression.

Results: Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors.

Conclusions: Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.
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http://dx.doi.org/10.3389/fimmu.2020.587617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873478PMC
July 2021

Validation of New Interactive Nutrition Assistant - Diet in India Study of Health (NINA-DISH) FFQ with multiple 24-h dietary recalls among pregnant women in Pune, India.

Br J Nutr 2021 Oct 28;126(8):1247-1256. Epub 2020 Dec 28.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY10032, USA.

Adequate dietary intake is critical to prevent adverse pregnancy outcomes. India has a high burden of maternal and child morbidity and mortality, but there is a lack of adequate tools to assess dietary intake. We validate an FFQ, New Interactive Nutrition Assistant - Diet in India Study of Health (NINA-DISH), among pregnant women living with and without HIV in Pune, India. Women were selected from a cohort study investigating immune responses to HIV and latent tuberculosis during pregnancy. The FFQ was administered during the third trimester and validated against multiple 24-h dietary recalls (24-HDR) collected in second and third trimesters. Data for analysis were available from fifty-eight women out of seventy enrolled into this sub-study, after excluding those with incomplete data or implausible energy intake. The median (Q1, Q3) age of study participants was 23 (20, 25) years. Median (Q1, Q3) daily energy intakes were 10 552 (8000, 11 958) and 10 673 (8510, 13 962) kJ by 24-HDR and FFQ, respectively, with FFQ overestimating nutrient intake. Pearson correlations between log-transformed estimates from FFQ and 24-HDR for energy, protein, carbohydrate, fat, Fe and Zn were 0·47, 0·48, 0·45, 0·33, 0·4 and 0·54, respectively. Energy-adjusted and de-attenuated correlations ranged from 0·41 (saturated fat) to 0·73 (Na). The highest misclassification into extreme tertiles was observed for fat (22 %), saturated fat (21 %) and Na (21 %). Bias existed at higher intake levels as observed by Bland-Altman plots. In conclusion, NINA-DISH is a valid and feasible tool for estimating dietary intakes among urban pregnant women in Western India.
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http://dx.doi.org/10.1017/S0007114520005188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236492PMC
October 2021

Association of Vegetable and Animal Flesh Intake with Inflammation in Pregnant Women from India.

Nutrients 2020 Dec 8;12(12). Epub 2020 Dec 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.

In pregnant women, studies are lacking on the relationship of vegetable and animal flesh (poultry, red meat and seafood) intake with inflammation, especially in low- and middle-income countries. We conducted a cohort study of pregnant women receiving antenatal care at BJ Medical College in Pune, India. The dietary intake of pregnant women was queried in the third trimester using a validated food frequency questionnaire. Twelve inflammatory markers were measured in plasma samples using immunoassays. Only 12% of the study population were vegetarians, although animal flesh intake levels were lower compared to Western populations. In multivariable models, higher intakes of total vegetables were associated with lower levels of the T-helper (Th) 17 cytokine interleukin (IL)-17a ( = 0.03) and the monocyte/macrophage activation marker soluble CD163 (sCD163) ( = 0.02). Additionally, higher intakes of poultry were negatively associated with intestinal fatty-acid binding protein (I-FABP) levels ( = 0.01), a marker of intestinal barrier dysfunction and Th2 cytokine IL-13 ( = 0.03), and higher seafood was associated with lower IL-13 ( = 0.005). Our data from pregnant women in India suggest that a higher quality diet emphasizing vegetables and with some animal flesh is associated with lower inflammation. Future studies should confirm these findings and test if modulating vegetables and animal flesh intake could impact specific aspects of immunity and perinatal health.
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http://dx.doi.org/10.3390/nu12123767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762525PMC
December 2020

Dietary macronutrient intake and molecular-bacterial vaginosis: Role of fiber.

Clin Nutr 2020 10 29;39(10):3066-3071. Epub 2020 Jan 29.

Institute for Genome Science, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Electronic address:

Background & Aims: Women with bacterial vaginosis (BV) have increased risk of sexually transmitted infections and other adverse health outcomes. Based on the composition of their vaginal microbiota, women can broadly be classified into low-Lactobacillus (termed molecular-BV) and Lactobacillus-dominated profiles. Our objective was to determine the association between dietary macronutrient intake and molecular-BV.

Methods: In a cross-sectional study of 104 reproductive-age women, dietary intake data were obtained using the Block Brief 2000 food frequency questionnaire. Vaginal microbiota composition was characterized by sequencing amplicons of the 16S rRNA gene V3-V4 regions and clustering into community state types (CST). Logistic regression was used to determine the association of macronutrient intake with molecular-BV (low-Lactobacillus vs. Lactobacillus-dominated CSTs combined).

Results: Participants had a median age of 25.9 (interquartile range: 21.9-29.6), 58% were white (30% black), 51% overweight/obese and 52% on hormonal contraception. In multivariable models, diets richer in fiber were inversely associated with molecular-BV (adjusted odds ratio: 0.49 per standard deviation increase in energy-adjusted fiber intake, 95% confidence interval: 0.24-0.99; p = 0.049).

Conclusions: Our results indicate that diets richer in fiber were associated with lower odds of molecular-BV. Further studies are needed to confirm these findings and to test whether increasing fiber intake can modulate the microbiota towards a more optimal Lactobacillus-dominant profile.
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http://dx.doi.org/10.1016/j.clnu.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387193PMC
October 2020

Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Recovery from measles results in life-long protective immunity. To understand induction of long-term immunity, rhesus macaques were studied for 6 months after infection with wild-type measles virus (MeV). Infection caused viremia and rash, with clearance of infectious virus by day 14. MeV RNA persisted in PBMCs for 30-90 days and in lymphoid tissue for 6 months most often in B cells but was rarely detected in BM. Antibody with neutralizing activity and binding specificity for MeV nucleocapsid (N), hemagglutinin (H), and fusion proteins appeared with the rash and avidity matured over 3-4 months. Lymph nodes had increasing numbers of MeV-specific antibody-secreting cells (ASCs) and germinal centers with late hyalinization. ASCs appeared in circulation with the rash and continued to appear along with peripheral T follicular helper cells for the study duration. ASCs in lymph nodes and PBMCs produced antibody against both H and N, with more H-specific ASCs in BM. During days 14-21, 20- to 100-fold more total ASCs than MeV-specific ASCs appeared in circulation, suggesting mobilization of preexisting ASCs. Therefore, persistence of MeV RNA in lymphoid tissue was accompanied by continued germinal center formation, ASC production, avidity maturation, and accumulation of H-specific ASCs in BM to sustain neutralizing antibody and protective immunity.
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http://dx.doi.org/10.1172/jci.insight.134992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098782PMC
February 2020

Lipid mediators of inflammation and Resolution in individuals with tuberculosis and tuberculosis-Diabetes.

Prostaglandins Other Lipid Mediat 2020 04 11;147:106398. Epub 2019 Nov 11.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Byramjee-Jeejeebhoy Medical College-Johns Hopkins University Clinical Research Site, Pune, India.

Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.
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http://dx.doi.org/10.1016/j.prostaglandins.2019.106398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067657PMC
April 2020

Associations between dietary micronutrient intake and molecular-Bacterial Vaginosis.

Reprod Health 2019 Oct 22;16(1):151. Epub 2019 Oct 22.

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.

Objectives: Bacterial vaginosis (BV), a clinical condition characterized by decreased vaginal Lactobacillus spp., is difficult to treat. We examined associations between micronutrient intake and a low-Lactobacillus vaginal microbiota as assessed by molecular methods (termed "molecular-BV").

Methods: This cross-sectional analysis utilized data collected at the baseline visit of the Hormonal Contraception Longitudinal Study, a cohort of reproductive-aged women followed over 2 years while initiating or ceasing hormonal contraception (HC). The Block Brief 2000 Food Frequency Questionnaire was administered and micronutrient intakes were ranked. Vaginal microbiota composition was assessed using 16S rRNA gene amplicon sequencing and clustered into community state types (CSTs) based on the types and relative abundance of bacteria detected. Associations between the lowest estimated quartile intake of nutrients and having a low-Lactobacillus CST (molecular-BV) were evaluated by logistic regression. Separate models were built for each nutrient controlling for age, body mass index, behavioral factors, HC use and total energy intake. We also conducted a literature review of existing data on associations between micronutrient intakes and BV.

Results: Samples from 104 women were included in this analysis. Their mean age was 25.8 years (SD 4.3), 29.8% were African American, 48.1% were using HC, and 25% had molecular-BV. In adjusted multivariable analyses, the lowest quartile of betaine intake was associated with an increased odds of molecular-BV (aOR 9.2, p value < 0.01, [CI 2.4-35.0]).

Conclusions: This is the first study to assess the association between estimated micronutrient intake and molecular-BV. Lower energy-adjusted intake of betaine was associated with an increased risk of molecular-BV. Betaine might have direct effects on the vaginal microenvironment or may be mediated through the gut microbiota. Additional research is needed to determine reproducibility of this finding and whether improved intake of select micronutrients such as betaine decreases the risk of BV and its sequelae.
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http://dx.doi.org/10.1186/s12978-019-0814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806504PMC
October 2019

Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study.

BMC Med 2018 09 24;16(1):161. Epub 2018 Sep 24.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB).

Methods: Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV-infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis).

Results: In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin-18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87).

Conclusion: Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation.
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http://dx.doi.org/10.1186/s12916-018-1150-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151930PMC
September 2018

Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial.

Clin Nutr 2019 06 29;38(3):1303-1309. Epub 2018 May 29.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address:

Background & Aims: Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation.

Methods: We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B, B, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation.

Results: In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status.

Conclusions: In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.
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http://dx.doi.org/10.1016/j.clnu.2018.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265110PMC
June 2019

Intestinal Barrier Dysfunction and Microbial Translocation in Human Immunodeficiency Virus-Infected Pregnant Women Are Associated With Preterm Birth.

Clin Infect Dis 2018 09;67(7):1103-1109

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Preterm birth (PTB) rates are high in human immunodeficiency virus (HIV)-infected populations, even when on treatment. Still, only a subset of all births in HIV-infected pregnant women result in PTB, suggesting that risk factors other than HIV infection itself are also important. Inflammation is a known risk factor in uninfected populations, but its role in HIV-infected population have not been studied; in addition, the immune pathways involved are not clear and noninvasive immune markers with predictive value are lacking. Our objective was to determine the association of select markers of inflammation with PTB in HIV-1-infected pregnant women.

Methods: Within a randomized trial of pregnant women receiving nevirapine (Six-Week Extended-Dose Nevirapine [SWEN] trial), we nested a case-control study (n = 107; 26 cases, 81 controls) to determine the association of maternal inflammation with PTB. Cases were defined as PTB (<37 weeks' gestational age). We assessed inflammation by measuring plasma levels of markers of general inflammation (C-reactive protein [CRP]), intestinal barrier dysfunction (intestinal fatty acid binding protein [I-FABP]), and microbial translocation/monocyte activation (soluble CD14 [sCD14] and CD163 [sCD163]). Multivariable logistic regression was used to determine the odds of PTB per log2 increase of each marker.

Results: In multivariable models, there was increased odds of PTB per unit increase of log2 sCD14 (adjusted odds ratio [aOR], 2.45; 95% confidence interval [CI], 1.24-4.86), log2 sCD163 (aOR, 3.87; 95% CI, 1.43-10.49), and log2 I-FABP (aOR, 2.28; 95% CI, 1.18-4.41) but not log2 CRP (aOR, 0.72; 95% CI, .48-1.09).

Conclusions: Our results show that select immune markers can identify women at higher risk for PTB in HIV-1-infected populations and suggest that modulating gut barrier integrity and microbial translocation may affect PTB.

Clinical Trials Registration: NCT00061321.
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http://dx.doi.org/10.1093/cid/ciy253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137119PMC
September 2018

Vitamin A and D Deficiencies Associated With Incident Tuberculosis in HIV-Infected Patients Initiating Antiretroviral Therapy in Multinational Case-Cohort Study.

J Acquir Immune Defic Syndr 2017 07;75(3):e71-e79

*Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA; Departments of †International Health; ‡Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; §Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; ‖Department of Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, CT; ¶Department of Medicine, University of Witwatersrand, Johannesburg, South Africa; #UNC Lilongwe, Lilongwe, Malawi; **Durban International Clinical Research Site, Durban University of Technology, Durban, South Africa; ††University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; ‡‡Hospital Nossa Senhora de Conceição, Porto Alegre, Brazil; §§YR Gaitonde Centre for AIDS Research and Education, Chennai, India; ‖‖National AIDS Research Institute, Pune, India; ¶¶Les Centres GHESKIO, Port-Au-Prince, Haiti; ##Malawi College of Medicine, Johns Hopkins University Research Project, Blantyre, Malawi; ***Liverpool School of Tropical Medicine, Liverpool, United Kingdom; †††Asociacion Civil Impacta Salud y Educacion, Lima, Peru; ‡‡‡STD/AIDS Clinical Research Laboratory, Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil; §§§Research Institute for Health Sciences, Chiang Mai, Thailand; ‖‖‖Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD; and ¶¶¶Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.

Introduction: Numerous micronutrients have immunomodulatory roles that may influence risk of tuberculosis (TB), but the association between baseline micronutrient deficiencies and incident TB after antiretroviral therapy (ART) initiation in HIV-infected individuals is not well characterized.

Methods: We conducted a case-cohort study (n = 332) within a randomized trial comparing 3 ART regimens in 1571 HIV treatment-naive adults from 9 countries. A subcohort of 30 patients was randomly selected from each country (n = 270). Cases (n = 77; main cohort = 62, random subcohort = 15) included patients diagnosed with TB by 96 weeks post-ART initiation. We determined pretreatment concentrations of vitamin A, carotenoids, vitamin B6, vitamin B12, vitamin D, vitamin E, and selenium. We measured associations between pretreatment micronutrient deficiencies and incident TB using Breslow-weighted Cox regression models.

Results: Median pretreatment CD4 T-cell count was 170 cells/mm; 47.3% were women; and 53.6% Black. In multivariable models after adjusting for age, sex, country, treatment arm, previous TB, baseline CD4 count, HIV viral load, body mass index, and C-reactive protein, pretreatment deficiency in vitamin A (adjusted hazard ratio, aHR 5.33, 95% confidence interval, CI: 1.54 to 18.43) and vitamin D (aHR 3.66, 95% CI: 1.16 to 11.51) were associated with TB post-ART.

Conclusions: In a diverse cohort of HIV-infected adults from predominantly low- and middle-income countries, deficiencies in vitamin A and vitamin D at ART initiation were independently associated with increased risk of incident TB in the ensuing 96 weeks. Vitamin A and D may be important modifiable risk factors for TB in high-risk HIV-infected patients starting ART in resource-limited highly-TB-endemic settings.
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http://dx.doi.org/10.1097/QAI.0000000000001308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472489PMC
July 2017

Association of HIV infection with extrapulmonary tuberculosis: a systematic review.

Infection 2017 Feb 9;45(1):11-21. Epub 2016 Nov 9.

Johns Hopkins School of Medicine, Baltimore, MD, USA.

Purpose: HIV/AIDS is a known risk factor for the development of pulmonary tuberculosis (PTB). However, the association is less clear between HIV and extrapulmonary tuberculosis (EPTB). We conducted a systematic review to determine the association between HIV and EPTB.

Methods: We searched the electronic databases Medline, Embase, and relevant conference literature using defined search terms for EPTB and HIV. Only publications in English and only studies reporting adjusted estimates were included, while our search criteria did not include restriction by age or geographic location of study participants. Qualitative and quantitative analyses (including I test for heterogeneity) were performed.

Results: Sixteen studies (15 cross-sectional and 1 case-control) conducted from 1984 to 2016 were included in the final analyses after screening 5163 articles and conference abstracts. Our qualitative analysis showed heterogeneity in study design and study population characteristics along with a medium/high risk of bias in the majority of studies. While most of the individual studies showed increased odds of EPTB compared with PTB among HIV-infected individuals, we did not provide an overall pooled estimate, as the I value was high at 93% for the cross-sectional studies.

Conclusions: While an association between HIV and EPTB is observed in most individual studies, the high heterogeneity and risk of bias in these studies highlight the need for further well-designed prospective cohort studies to assess the true risk of EPTB in the HIV-infected patient population.
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http://dx.doi.org/10.1007/s15010-016-0960-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303538PMC
February 2017

Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort.

Open Forum Infect Dis 2016 Sep 27;3(3):ofw118. Epub 2016 Jul 27.

Johns Hopkins University School of Medicine , Baltimore, Maryland.

 We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings.  We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4 T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis.  Among 99 cases and 234 controls, median baseline CD4 T-cell count was 181 cells/µL, and HIV RNA was 5.05 log cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27-7.20), sCD14 (IRR, 2.17; 95% CI, 1.02-4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01-0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated.  Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.
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http://dx.doi.org/10.1093/ofid/ofw118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084713PMC
September 2016

Persistently Elevated C-Reactive Protein Level in the First Year of Antiretroviral Therapy, Despite Virologic Suppression, Is Associated With HIV Disease Progression in Resource-Constrained Settings.

J Infect Dis 2016 Apr 29;213(7):1074-8. Epub 2015 Nov 29.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies.
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http://dx.doi.org/10.1093/infdis/jiv573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779305PMC
April 2016

Measles Virus Neutralizing Antibody Response, Cell-Mediated Immunity, and Immunoglobulin G Antibody Avidity Before and After Receipt of a Third Dose of Measles, Mumps, and Rubella Vaccine in Young Adults.

J Infect Dis 2016 Apr 23;213(7):1115-23. Epub 2015 Nov 23.

Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring.

Background: Two doses of measles, mumps, and rubella (MMR) vaccine are 97% effective against measles, but waning antibody immunity to measles and failure of the 2-dose vaccine occur. We administered a third MMR dose (MMR3) to young adults and assessed immunogenicity over 1 year.

Methods: Measles virus (MeV) neutralizing antibody concentrations, cell-mediated immunity (CMI), and immunoglobulin G (IgG) antibody avidity were assessed at baseline and 1 month and 1 year after MMR3 receipt.

Results: Of 662 subjects at baseline, 1 (0.2%) was seronegative for MeV-neutralizing antibodies (level, <8 mIU/mL), and 23 (3.5%) had low antibody levels (8-120 mIU/mL). One month after MMR3 receipt, 1 subject (0.2%) was seronegative, and 6 (0.9%) had low neutralizing antibodies, with only 21 of 662 (3.2%) showing a ≥ 4-fold rise in neutralizing antibodies. One year after MMR3 receipt, no subject was seronegative, and 10 of 617 (1.6%) had low neutralizing antibody levels. CMI analyses showed low levels of spot-forming cells after stimulation, suggesting the presence of T-cell memory, but the response was minimal after MMR3 receipt. MeV IgG avidity did not correlate with findings of neutralization analyses.

Conclusions: Most subjects were seropositive before MMR3 receipt, and very few had a secondary immune response after MMR3 receipt. Similarly, CMI and avidity analyses showed minimal qualitative improvements in immune response after MMR3 receipt. We did not find compelling data to support a routine third dose of MMR vaccine.
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http://dx.doi.org/10.1093/infdis/jiv555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729920PMC
April 2016

Soluble CD14: An Independent Biomarker for the Risk of Mother-to-Child Transmission of HIV in a Setting of Preexposure and Postexposure Antiretroviral Prophylaxis.

J Infect Dis 2016 Mar 6;213(5):762-5. Epub 2015 Oct 6.

Johns Hopkins University Medical Institutions, Baltimore, Maryland.

Elevated soluble CD14 (sCD14) concentrations, a marker of monocyte activation, predicts adverse outcomes in human immunodeficiency virus (HIV)-infected adults. To examine the association of sCD14 concentrations with the risk of mother-to-child transmission (MTCT) of HIV, we nested a case-control study (49 pairs of infants and their HIV-infected mothers) within the Six-Week Extended-Dose Nevirapine trial. Median peripartum maternal log2 sCD14 concentration was higher among transmitters (defined as pairs in which maternally transmitted HIV infection occurred by 12 months of age) than nontransmitters (20.29 pg/mL vs 19.41 pg/mL; P = .005). There was an increased odds of MTCT for every log2 increase in maternal sCD14 concentration, after adjustment for maternal HIV load, CD4 count and cART exposure (adjusted odds ratio, 3.51; 95% confidence interval, 1.21-10.21). Maternal monocyte activation may adversely influence the risk of MTCT of HIV.
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http://dx.doi.org/10.1093/infdis/jiv479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747613PMC
March 2016

Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation.

Clin Infect Dis 2015 Jul 31;61(1):102-10. Epub 2015 Mar 31.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART.

Methods: A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models.

Results: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation.

Conclusions: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening.
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http://dx.doi.org/10.1093/cid/civ265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542913PMC
July 2015

Prevalence and risk factors of micronutrient deficiencies pre- and post-antiretroviral therapy (ART) among a diverse multicountry cohort of HIV-infected adults.

Clin Nutr 2016 Feb 10;35(1):183-189. Epub 2015 Feb 10.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Background & Aims: HIV-infected adults have increased risk of several individual micronutrient deficiencies. However, the prevalence and risk factors of concurrent and multiple micronutrient deficiencies and whether micronutrient concentrations change after antiretroviral therapy (ART) initiation have not been well described. The objective of this study was to determine the prevalence and risk factors of individual, concurrent and multiple micronutrient deficiencies among ART-naïve HIV-infected adults from nine countries and assess change in micronutrient status 48 weeks post-ART initiation.

Methods: A random sub-cohort (n = 270) stratified by country was selected from the multinational PEARLS clinical trial (n = 1571 ART-naïve, HIV-infected adults). We measured serum concentrations of vitamins A, D (25-hydroxyvitamin), E, carotenoids and selenium pre-ART and 48 weeks post-ART initiation, and measured vitamins B6, B12, ferritin and soluble transferrin receptor at baseline only. Prevalence of single micronutrient deficiencies, concurrent (2 coexisting) or conditional (a deficiency in one micronutrient given a deficiency in another) and multiple (≥3) were determined using defined serum concentration cutoffs. We assessed mean changes in micronutrient concentrations from pre-ART to week 48 post-ART initiation using multivariable random effects models.

Results: Of 270 participants, 13.9%, 29.2%, 24.5% and 32.4% had 0, 1, 2 and multiple deficiencies, respectively. Pre-ART prevalence was the highest for single deficiencies of selenium (53.2%), vitamin D (42.4%), and B6 (37.3%) with 12.1% having concurrent deficiencies of all three micronutrients. Deficiency prevalence varied widely by country. 48 weeks post-ART initiation, mean vitamin A concentration increased (p < 0.001) corresponding to a 9% decrease in deficiency. Mean concentrations also increased for other micronutrients assessed 48 weeks post-ART (p < 0.001) but with minimal change in deficiency status.

Conclusions: Single and multiple micronutrient deficiencies are common among HIV-infected adults pre-ART initiation but vary between countries. Importantly, despite increases in micronutrient concentrations, prevalence of individual deficiencies remains largely unchanged after 48 weeks on ART. Our results suggest that ART alone is not sufficient to improve micronutrient deficiency.
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http://dx.doi.org/10.1016/j.clnu.2015.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531105PMC
February 2016

Limited in vivo production of type I or type III interferon after infection of macaques with vaccine or wild-type strains of measles virus.

J Interferon Cytokine Res 2015 Apr 17;35(4):292-301. Epub 2014 Dec 17.

1 W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland.

The innate immune response to viral infections often includes induction of types I and III interferons (IFNs) and production of antiviral proteins. Measles is a severe virus-induced rash disease, but in vitro studies suggest that in the absence of defective interfering RNAs, neither wild-type (WT) nor vaccine strains of measles virus (MeV) induce IFN. To determine whether IFN is produced in vivo, we studied tissues from macaques infected with vaccine or WT strains of MeV using quantitative reverse transcriptase-polymerase chain reaction to assess levels of IFN and IFN-stimulated gene (ISG) mRNAs and a flow cytometry-based bioassay to assess levels of biologically active IFN. There was little to no induction of type I IFN, type III IFN, Mx, or ISG56 mRNAs in monkeys infected with vaccine or WT MeV and no IFN detection by bioassay. Therefore, the innate responses to infection with vaccine or WT strains of MeV are not dependent on IFN production.
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http://dx.doi.org/10.1089/jir.2014.0122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390142PMC
April 2015

Pre-antiretroviral therapy serum selenium concentrations predict WHO stages 3, 4 or death but not virologic failure post-antiretroviral therapy.

Nutrients 2014 Nov 13;6(11):5061-78. Epub 2014 Nov 13.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28-99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86-95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30-9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium.
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http://dx.doi.org/10.3390/nu6115061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245580PMC
November 2014

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Lancet 2014 Sep 22;384(9947):1005-70. Epub 2014 Jul 22.

Institute of Community and Public Health-Birzeti University, Ramallah, West Bank, Occupied Palestinian Territory.

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

Findings: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

Interpretation: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(14)60844-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202387PMC
September 2014

The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.

JAMA 2013 Aug;310(6):591-608

Institute for Health Metrics and Evaluation, 2301 Fifth Ave., Suite 600, Seattle, WA, 98121, USA.

Importance: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy.

Objectives: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries.

Design: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages.

Results: US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th.

Conclusions And Relevance: From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.
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http://dx.doi.org/10.1001/jama.2013.13805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436627PMC
August 2013

Induction of dendritic cell production of type I and type III interferons by wild-type and vaccine strains of measles virus: role of defective interfering RNAs.

J Virol 2013 Jul 15;87(14):7816-27. Epub 2013 May 15.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

The innate immune response to viral infection frequently includes induction of type I interferons (IFN), but many viruses have evolved ways to block this response and increase virulence. In vitro studies of IFN production after infection of susceptible cells with measles virus (MeV) have often reported greater IFN synthesis after infection with vaccine than with wild-type strains of MeV. However, the possible presence in laboratory virus stocks of 5' copy-back defective interfering (DI) RNAs that induce IFN independent of the standard virus has frequently confounded interpretation of data from these studies. To further investigate MeV strain-dependent differences in IFN induction and the role of DI RNAs, monocyte-derived dendritic cells (moDCs) were infected with the wild-type Bilthoven strain and the vaccine Edmonston-Zagreb strain with and without DI RNAs. Production of type I IFN, type III IFN, and the interferon-stimulated genes (ISGs) Mx and ISG56 by infected cells was assessed with a flow cytometry-based IFN bioassay, quantitative reverse transcriptase PCR (RT-PCR), and immunoassays. Bilthoven infected moDCs less efficiently than Edmonston-Zagreb. Presence of DI RNAs in vaccine stocks resulted in greater maturation of moDCs, inhibition of virus replication, and induction of higher levels of IFN and ISGs. Production of type I IFN, type III IFN, and ISG mRNA and protein was determined by both the level of infection and the presence of DI RNAs. At the same levels of infection and in the absence of DI RNA, IFN induction was similar between wild-type and vaccine strains of MeV.
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http://dx.doi.org/10.1128/JVI.00261-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700182PMC
July 2013

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2224-60

Institute for Health Metrics and Evaluation, Seattle, WA 98121, USA.

Background: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.

Methods: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.

Findings: In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.

Interpretation: Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61766-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156511PMC
December 2012

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2197-223

Institute for Health Metrics and Evaluation, Seattle 98121, WA, USA.

Background: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time.

Methods: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights.

Findings: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions.

Interpretation: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61689-4DOI Listing
December 2012

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2163-96

School of Population Health, Brisbane, QLD, Australia.

Background: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs).

Methods: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis.

Findings: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa.

Interpretation: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61729-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350784PMC
December 2012
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