Disruption of Neural Homeostasis as a Model of Relapse and Recurrence in Late-Life Depression.

The significant public health burden associated with late-life depression (LLD) is magnified by the high rates of recurrence. In this manuscript, we review what is known about recurrence risk factors, conceptualize recurrence within a model of homeostatic disequilibrium, and discuss the potential significance and challenges of new research into LLD recurrence. The proposed model is anchored in the allostatic load theory of stress. We review the allostatic response characterized by neural changes in network function and connectivity and physiologic changes in the hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system, and circadian rhythm. We discuss the role of neural networks' instability following treatment response as a source of downstream disequilibrium, triggering and/or amplifying abnormal stress response, cognitive dysfunction and behavioral changes, ultimately precipitating a full-blown recurrent episode of depression. We propose strategies to identify and capture early change points that signal recurrence risk through mobile technology to collect ecologically measured symptoms, accompanied by automated algorithms that monitor for state shifts (persistent worsening) and variance shifts (increased variability) relative to a patient's baseline. Identifying such change points in relevant sensor data could potentially provide an automated tool that could alert clinicians to at-risk individuals or relevant symptom changes even in a large practice.

Differential immunoglobulin and complement levels in leprosy prior to development of reversal reaction and erythema nodosum leprosum.

BACKGROUND: Leprosy is a treatable infectious disease caused by Mycobacterium leprae. However, there is additional morbidity from leprosy-associated pathologic immune reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. There is currently no predictive marker in use to indicate which people with leprosy will develop these debilitating immune reactions. Our peripheral blood mononuclear cell (PBMC) transcriptome analysis revealed that activation of the classical complement pathway is common to both RR and ENL. Additionally, differential expression of immunoglobulin receptors and B cell receptors during RR and ENL support a role for the antibody-mediated immune response during both RR and ENL. In this study, we investigated B-cell immunophenotypes, total and M. leprae-specific antibodies, and complement levels in leprosy patients with and without RR or ENL. The objective was to determine the role of these immune mediators in pathogenesis and assess their potential as biomarkers of risk for immune reactions in people with leprosy. METHODOLOGY/FINDINGS: We followed newly diagnosed leprosy cases (n = 96) for two years for development of RR or ENL. They were compared with active RR (n = 35), active ENL (n = 29), and healthy household contacts (n = 14). People with leprosy who subsequently developed ENL had increased IgM, IgG1, and C3d-associated immune complexes with decreased complement 4 (C4) at leprosy diagnosis. People who developed RR also had decreased C4 at leprosy diagnosis. Additionally, elevated anti-M. leprae antibody levels were associated with subsequent RR or ENL. CONCLUSIONS: Differential co-receptor expression and immunoglobulin levels before and during immune reactions intimate a central role for humoral immunity in RR and ENL. Decreased C4 and elevated anti-M. leprae antibodies in people with new diagnosis of leprosy may be risk factors for subsequent development of leprosy immune reactions.

Amazon plant diversity revealed by a taxonomically verified species list.

Recent debates on the number of plant species in the vast lowland rain forests of the Amazon have been based largely on model estimates, neglecting published checklists based on verified voucher data. Here we collate taxonomically verified checklists to present a list of seed plant species from lowland Amazon rain forests. Our list comprises 14,003 species, of which 6,727 are trees. These figures are similar to estimates derived from nonparametric ecological models, but they contrast strongly with predictions of much higher tree diversity derived from parametric models. Based on the known proportion of tree species in neotropical lowland rain forest communities as measured in complete plot censuses, and on overall estimates of seed plant diversity in Brazil and in the neotropics in general, it is more likely that tree diversity in the Amazon is closer to the lower estimates derived from nonparametric models. Much remains unknown about Amazonian plant diversity, but this taxonomically verified dataset provides a valid starting point for macroecological and evolutionary studies aimed at understanding the origin, evolution, and ecology of the exceptional biodiversity of Amazonian forests.

Live with the Disease Like You Used to Before You Knew You Were Infected: A Qualitative Study Among 10-Year Survivors Living with HIV in Haiti.

In 2003, the Haitian Study Group on Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), a nonprofit organization, began administering antiretroviral therapy (ART) to its patients. This practice transformed HIV from a fatal disease to a more manageable chronic condition. However, relatively few studies focus on the experiences of survivors. This study provided a unique opportunity to interview patients who survived at least 10 years after being treated with ART at GHESKIO. The goal of the study was to elicit from patients their perspectives on what enabled them to survive with AIDS. Grounded Theory, a qualitative research method was used to guide data collection, coding, and analysis. Individual interviews were conducted, audio-taped, transcribed and analyzed in Creole, and translated into English. Data saturation was reached at 25 participants. Of which, 64% were women, the mean age was 49, range of 43-55 years, 24% were married, 44% had not completed elementary school, and 72% had no income, the remaining participants had incomes ranging from $1000 to $5000 annually. Qualitative analysis resulted in 681 codes, which were grouped into six categories: being spiritually grounded, having supportive interactions with providers, caring for children, setting personal goals, persevering and living life as usual, and maintaining strict medication adherence practices. The overarching theory was that having a reason to live despite one's circumstances and living life as usual enabled one to survive. Having a strong spiritual foundation coupled with supportive family and providers motivated participants to live and adhere to their ART. As the number of patients who are living longer with HIV in Haiti increases, results from this study will be important in helping tailor interventions that enhance their overall quality of life.

Impact of a youth-friendly HIV clinic: 10 years of adolescent outcomes in Port-au-Prince, Haiti.

INTRODUCTION: Adolescents account for over 40% of new HIV infections in Haiti. This analysis compares outcomes among HIV-positive adolescents before and after implementation of an adolescent HIV clinic in Port-au-Prince, Haiti. METHODS: We conducted a cohort study using programmatic data among HIV-positive adolescents aged 13 to 19. Data from 41,218 adolescents who were HIV tested from January 2003 to December 2012 were included. Outcomes across the HIV care cascade were assessed before and after implementation of an adolescent clinic (2009), including HIV testing, enrolment in care, assessment for antiretroviral therapy (ART) eligibility, ART initiation and 12-month retention. Pre-ART outcomes were assessed 12 months after HIV testing. Factors associated with pre-ART and ART attrition were identified through multivariable competing risk and Cox proportional hazards regression modelling. RESULTS: Cumulatively, 1672 (4.1%) adolescents tested HIV positive (80% female, median age 16 years). Retention by cascade step comparing pre- and post-clinic included the following: 86% versus 87% of patients enrolled in care, 61% versus 79% were assessed for ART eligibility, 85% versus 92% initiated ART and 68% versus 66% were retained 12 months after ART initiation. Pre-ART attrition decreased from 61% pre-clinic to 50% post-clinic (p<0.001). Pre-ART attrition was associated with being female (sub-distributional hazard ratio (sHR): 1.59; CI: 1.31-1.93), syphilis diagnosis (sHR: 1.47; CI: 1.16-1.85) and slum residence (sHR: 0.84; CI: 0.72-0.97). ART attrition was associated with syphilis diagnosis (hazard ratio (HR): 2.23; CI: 1.35-3.68) and CD4 <50 cells/µL (HR: 1.88; CI: 1.15-3.06). CONCLUSIONS: Implementation of a youth-friendly adolescent clinic improved retention in HIV care among adolescents, particularly in the assessment of ART eligibility and ART initiation. Additional interventions are needed to improve retention among pre-ART patients and support long-term retention among ART patients.

Viral Co-infection and Leprosy Outcomes: A Cohort Study.

BACKGROUND: The role of the host immunity in determining leprosy clinical forms and complications is well recognized, implying that changes in the immune status may interfere with several aspects of the disease. Therefore, we hypothesized that the presence of viral co-infections and associated immunological changes will have a clinical impact on leprosy outcomes. The aim of our study was to determine the clinical impact of human immunodeficiency virus (HIV), human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection on the development of reactions, neuritis, neuropathy and relapses. METHODOLOGY/PRINCIPAL FINDINGS: Cohort study in 245 leprosy subjects from Bahia, Brazil. Patients were followed from the time of diagnosis until at least the end of multidrug therapy. Viral co-infection was detected in 36 out of the 245 patients (14.7%). Specific co-infection rates were 10.6% for HBV, 2.9% for HIV, 2.5% for HTLV-1 and 0.8% for HCV. All four groups of co-infected patients had higher rates of neuritis and nerve function impairment compared to non co-infected leprosy subjects. The relapse rate was also higher in the co-infected group (8.3%) versus patients without co-infection (1.9%); relative risk 4.37, 95% confidence interval 1.02-18.74. CONCLUSIONS/SIGNIFICANCE: Leprosy patients should be screened for HBV, HCV, HIV and HTLV-1 co-infections. Besides contributing to better health care, this measure will facilitate the early detection of severe complications through targeting of higher risk patients.

Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis.

Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine ß-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.

"I am proud of myself, just the way I am" (Mwen fyé de tét mwen, jan mwen ye ya): a qualitative study among young Haitian women seeking care for sexually transmitted infections (STIs) in Haiti.

Haitian women are twice as likely as men to have HIV/AIDs. Factors underlying the feminization of HIV are complex. Self-esteem is an important correlate of sexual behavior. However, its meaning and impact on health behaviors may be influenced by cultural factors. This qualitative study took place in Haiti 4 months after the 2010 earthquake and examines the meaning of self-esteem among young Haitian women seeking treatment for a recurrent sexually transmitted infection (STI). The meaning of self-esteem was derived from a sense of gratitude and was rooted in their ability to provide for family. This may have led to behaviors such as not using condoms or having sex with partners in concurrent relationships. This article highlights the resilience and resourcefulness of Haitian women, provides insight into how women with apparent positive self-images were led to make choices that placed them at high risk for contracting HIV, and concludes with recommendations for future interventions.

The Haiti research-based model of international public health collaboration: the GHESKIO Centers.

For 3 decades, GHESKIO (the Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes), the Haitian Ministry of Health, and Weill Cornell have pursued a tripartite mission of service, training, and translational research. The initial focus was on AIDS and tuberculosis. The mission has expanded to include the local community and now provides maternal-child health, family planning, cancer prevention and treatment, immunizations (including human papillomavirus, cholera), and primary education through vocational and microcredit programs. Outcome measures include a reduction in HIV prevalence from 6.2% to the current 2.2%, extensive tuberculosis and cholera prevention and treatment programs, and national training programs for biomedical and community health workers.

Use of Luminex MagPlex magnetic microspheres for high-throughput spoligotyping of Mycobacterium tuberculosis isolates in Port-au-Prince, Haiti.

Genotyping of Mycobacterium tuberculosis strains became indispensable for understanding tuberculosis transmission dynamics and designing measures to combat the disease. Unfortunately, typing involves sophisticated laboratory analysis, is expensive, and requires a high level of technical expertise, which limited its use in the resource-poor countries where the majority of tuberculosis cases occur. Spoligotyping is a PCR-based M. tuberculosis complex genotyping method with advantages of technical simplicity, numerical output, and high reproducibility. It is based on the presence or absence of 43 distinct "spacers" separating insertion elements in the direct repeat region of the M. tuberculosis genome. The spoligotyping assay involves reverse hybridization of PCR products to the capture spacers attached to nitrocellulose membranes or to microspheres. Here we report modification of the classic 43-spacer method using the new generation of Luminex multiplexing technology with magnetic microspheres. The method was successfully established and validated on strains with known spoligotypes in our laboratory in Haiti. The distribution of spoligotypes determined in a collection of 758 recent M. tuberculosis isolates was in accordance with previous data for Haitian isolates in the SITWITWEB international database, which were obtained with the traditional membrane-based method. In the present form, spoligotyping may be suitable as a high-throughput, first-line tool for genotyping of Mycobacterium tuberculosis in countries with limited resources.

Lives saved by expanding HIV treatment availability in resource-limited settings: the example of Haiti.

BACKGROUND: Guidelines recommend antiretroviral therapy (ART) initiation at CD4 <350 cells per microliter for HIV-infected individuals in resource-limited settings. However, funding for treatment expansion remains uncertain. We forecast the mortality impact of ART expansion alternatives in Haiti. METHODS: We used data from Haiti to develop a country-specific model of HIV disease. The model projects the mortality, total number of HIV-infected individuals, and number and coverage (percentage of those eligible) on ART by simulating cohorts of HIV-infected individuals over 10 years. Five ART expansion scenarios, ranging from fully expanded ART (best case) to No New ART (worst case), were assessed. RESULTS: By 2010, the model predicts 103,500 individuals living with HIV in Haiti, of whom 27,300 were estimated to receive ART. Continuing ART initiation at current rates requires increasing the number on ART to 43,300 by 2020 (56% coverage), with 89,700 deaths estimated between 2010 and 2020. The number on ART could increase by 7400 (+17.1%, best case) or decrease by 25,600 (-59.1%, worst case), resulting in 19,500 deaths averted and 9900 fewer in care awaiting ART (best versus worst case). Results are sensitive to untreated disease progression and pre-ART loss from care. Increased HIV testing, linkage to care, and retention in care can avert additional deaths and achieve nearly 80% ART coverage with optimal policy improvements. CONCLUSIONS: In resource-limited settings, continued improvements in HIV treatment access will save lives. Efforts to efficiently expand ART access should remain a global priority.

The role of human T cell lymphotrophic virus type 1, hepatitis B virus and hepatitis C virus coinfections in leprosy

Leprosy spectrum and outcome is associated with the host immune response against Mycobacterium leprae. The role of coinfections in leprosy patients may be related to a depression of cellular immunity or amplification of inflammatory responses. Leprosy remains endemic in several regions where human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) or hepatitis C virus (HCV) are also endemic. We have evaluated the evidence for the possible role of these viruses in the clinical manifestations and outcomes of leprosy. HTLV-1, HBV and HCV are associated with leprosy in some regions and institutionalization is an important risk factor for these viral coinfections. Some studies show a higher prevalence of viral coinfection in lepromatous cases. Although HBV and HCV coinfection were associated with reversal reaction in one study, there is a lack of information about the consequences of viral coinfections in leprosy. It is not known whether clinical outcomes associated with leprosy, such as development of reactions or relapses could be attributed to a specific viral coinfection. Furthermore, whether the leprosy subtype may influence the progression of the viral coinfection is unknown. All of these important and intriguing questions await prospective studies to definitively establish the actual relationship between these entities.

Virologic, clinical and immunologic responses following failure of first-line antiretroviral therapy in Haiti.

BACKGROUND: Since HIV-1 RNA (viral load) testing is not routinely available in Haiti, HIV-infected patients receiving antiretroviral therapy (ART) are monitored using the World Health Organization (WHO) clinical and/or immunologic criteria. Data on survival and treatment outcomes for HIV-1 infected patients who meet criteria for ART failure are limited. We conducted a retrospective study to compare survival rates for patients who experienced failure on first-line ART by clinical and/or immunologic criteria and switched to second-line ART vs. those who failed but did not switch. METHODS: Patients receiving first-line ART at the GHESKIO Center in Port-au-Prince, Haiti, who met WHO clinical and immunologic criteria for failure were identified. Survival and treatment outcomes were compared in patients who switched their ART regimen and those who did not. Cox regression analysis was used to determine predictors of mortality after failure of first-line ART. RESULTS: Of 3126 patients who initiated ART at the GHESKIO Center between 1 March 2003 and 31 July 2008, 482 (15%) met WHO immunologic and/or clinical criteria for failure. Among those, 195 (41%) switched to second-line ART and 287 (59%) did not. According to Kaplan-Meier survival analysis, the probability of survival to 12 months after failure of first-line ART was 93% for patients who switched to second-line ART after failure and 88% for patients who did not switch. Predictors of mortality after failure of first-line ART were weight in the lowest quartile for sex, CD4 T cell count ≤ 100, adherence<90% at the time of failure and not switching to second-line ART. CONCLUSIONS: Patients who failed first-line ART based on clinical and/or immunologic criteria and did not switch to second-line therapy faced a higher mortality than those who switched after failure. To decrease mortality, interventions to identify patients in whom ART may be failing earlier are needed urgently. In addition, there is a major need to optimize second-line antiretroviral regimens for improved potency, lower toxicity and greater convenience for patients.

The role of human T cell lymphotrophic virus type 1, hepatitis B virus and hepatitis C virus coinfections in leprosy.

Leprosy spectrum and outcome is associated with the host immune response against Mycobacterium leprae. The role of coinfections in leprosy patients may be related to a depression of cellular immunity or amplification of inflammatory responses. Leprosy remains endemic in several regions where human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) or hepatitis C virus (HCV) are also endemic. We have evaluated the evidence for the possible role of these viruses in the clinical manifestations and outcomes of leprosy. HTLV-1, HBV and HCV are associated with leprosy in some regions and institutionalization is an important risk factor for these viral coinfections. Some studies show a higher prevalence of viral coinfection in lepromatous cases. Although HBV and HCV coinfection were associated with reversal reaction in one study, there is a lack of information about the consequences of viral coinfections in leprosy. It is not known whether clinical outcomes associated with leprosy, such as development of reactions or relapses could be attributed to a specific viral coinfection. Furthermore, whether the leprosy subtype may influence the progression of the viral coinfection is unknown. All of these important and intriguing questions await prospective studies to definitively establish the actual relationship between these entities.

Cost-effectiveness of early versus standard antiretroviral therapy in HIV-infected adults in Haiti.

BACKGROUND: In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm³ in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial. METHODS AND FINDINGS: Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS-US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS-US$5,537/YLS). CONCLUSIONS: Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm³ in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS <3 times gross domestic product per capita) after a maximum of 3 years, after excluding research-related laboratory tests. TRIAL REGISTRATION: ClinicalTrials.gov NCT00120510.

Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.

BACKGROUND: For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS: We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS: Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS: Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)