Emirates Heart Health Project (EHHP): A protocol for a stepped-wedge family-cluster randomized-controlled trial of a health-coach guided diet and exercise intervention to reduce weight and cardiovascular risk in overweight and obese UAE nationals.

INTRODUCTION: Cardiovascular disease (CVD) is the most common cause of death both globally and in the United Arab Emirates. Despite public health measures and health education, the rates of death from CVD remain stable. Barriers previously identified to lifestyle changes include cultural reasons, boredom, and lack of family support. The Emirates Heart Health Project (EHHP) seeks to support healthy lifestyle changes through a family-based intervention using a health coach and fitness tracker. METHODS AND ANALYSIS: The EHHP is a stepped-wedge cluster-randomized trial with each cluster comprised of members of an extended family. Eligible participants will be ≥ 18 years of age, with BMI ≥ 25, have Emirati citizenship and be able to give informed consent for study participation. The cluster will have 16 weekly teaching sessions in the participants' family home by a health coach who will review individual weight, diet and exercise (monitored by a wearable fitness tracker). The clusters will have pre-intervention assessments of their weight and CVD risk profile and enter the intervention in randomized order. Each cluster will have a post-intervention assessment of the same measures. The primary outcome is weight reduction from baseline. Secondary outcomes will include change in CVD risk factors such as systolic and diastolic blood pressure, hemoglobin A1c, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, waist circumference, and BMI. A mixed linear model will be used for analysis, where the parameters measured at the end of each 16-week episode will be the outcome values. These will be analyzed such that baseline values (measured just prior to the start of an episode) will be fixed covariables. Random effects are the family units. This trial has been registered with the NIH at clinicaltrials.gov (NCT04688684) and is being reported using the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and TIDieR (Template for intervention description and replication) framework. TRIAL REGISTRATION: Clinicaltrials.gov NCT04688684.

Mapping and characterising areas with high levels of HIV transmission in sub-Saharan Africa: A geospatial analysis of national survey data.

BACKGROUND: In the generalised epidemics of sub-Saharan Africa (SSA), human immunodeficiency virus (HIV) prevalence shows patterns of clustered micro-epidemics. We mapped and characterised these high-prevalence areas for young adults (15-29 years of age), as a proxy for areas with high levels of transmission, for 7 countries in Eastern and Southern Africa: Kenya, Malawi, Mozambique, Tanzania, Uganda, Zambia, and Zimbabwe. METHODS AND FINDINGS: We used geolocated survey data from the most recent United States Agency for International Development (USAID) demographic and health surveys (DHSs) and AIDS indicator surveys (AISs) (collected between 2008-2009 and 2015-2016), which included about 113,000 adults-of which there were about 53,000 young adults (27,000 women, 28,000 men)-from over 3,500 sample locations. First, ordinary kriging was applied to predict HIV prevalence at unmeasured locations. Second, we explored to what extent behavioural, socioeconomic, and environmental factors explain HIV prevalence at the individual- and sample-location level, by developing a series of multilevel multivariable logistic regression models and geospatially visualising unexplained model heterogeneity. National-level HIV prevalence for young adults ranged from 2.2% in Tanzania to 7.7% in Mozambique. However, at the subnational level, we found areas with prevalence among young adults as high as 11% or 15% alternating with areas with prevalence between 0% and 2%, suggesting the existence of areas with high levels of transmission Overall, 15.6% of heterogeneity could be explained by an interplay of known behavioural, socioeconomic, and environmental factors. Maps of the interpolated random effect estimates show that environmental variables, representing indicators of economic activity, were most powerful in explaining high-prevalence areas. Main study limitations were the inability to infer causality due to the cross-sectional nature of the surveys and the likely under-sampling of key populations in the surveys. CONCLUSIONS: We found that, among young adults, micro-epidemics of relatively high HIV prevalence alternate with areas of very low prevalence, clearly illustrating the existence of areas with high levels of transmission. These areas are partially characterised by high economic activity, relatively high socioeconomic status, and risky sexual behaviour. Localised HIV prevention interventions specifically tailored to the populations at risk will be essential to curb transmission. More fine-scale geospatial mapping of key populations,-such as sex workers and migrant populations-could help us further understand the drivers of these areas with high levels of transmission and help us determine how they fuel the generalised epidemics in SSA.

Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men.

BACKGROUND: This study was done to characterize parameters associated with semen human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) viral load (VL) variability in HIV-infected, therapy-naive men. METHODS: Paired blood and semen samples were collected from 30 HIV-infected, therapy-naive men who have sex with men, and 13 participants were observed longitudinally for up to 1 year. Human immunodeficiency virus RNA, bacterial load by 16S RNA, herpesvirus (Epstein-Barr virus and cytomegalovirus [CMV]) shedding, and semen cytokines/chemokines were quantified, and semen T-cell subsets were assessed by multiparameter flow cytometry. RESULTS: Semen HIV RNA was detected at 93% of visits, with >50% of men shedding high levels of virus (defined as >5000 copies/mL). In the baseline cross-sectional analysis, an increased semen HIV VL correlated with local CMV reactivation, the semen bacterial load, and semen inflammatory cytokines, particularly interleukin (IL)-8. T cells in semen were more activated than blood, and there was an increased frequency of Th17 cells and γδ-T-cells. Subsequent prospective analysis demonstrated striking interindividual variability in HIV and CMV shedding patterns, and only semen IL-8 levels and the blood VL were independently associated with semen HIV levels. CONCLUSIONS: Several clinical and immune parameters were associated with increased HIV semen levels in antiretroviral therapy-naive men, with induction of local proinflammatory cytokines potentially acting as a common pathway.

Impact of Ramadan fasting on glucose levels in women with gestational diabetes mellitus treated with diet alone or diet plus metformin: a continuous glucose monitoring study.

OBJECTIVE: Women with gestational diabetes mellitus (GDM) are categorized as at high risk for adverse events during Ramadan fasting. However, this is largely based on clinical opinion. In this study, we shed some light on what happens to glucose levels during Ramadan fasting. METHODS: This is a prospective observational study. A total of 32 patients with GDM were recruited; 10 patients, treated with diet only (group 1), to observe their glucose levels before fasting and 22 patients who insisted on fasting the month of Ramadan, 13 treated with diet only (group 2) and nine treated with diet plus metformin 500 mg twice daily (group 3), to evaluate their glucose levels during fasting. Interstitial glucose was monitored in all by using the iPro2 Professional continuous glucose monitoring (CGM) system. RESULTS: Mean glucose level was 116±21 mg/dL (6.16±1.16 mmol/L), 106±9 mg/dL (5.88±0.49 mmol/L) and 99±7 mg/dL (5.49±0.34 mmol/L) in groups 1, 2 and 3, respectively. Patients in group 1 had the lowest rate of hypoglycemia (50%), followed by patients in group 2 (60%), whereas patients in group 3 had the highest rate of hypoglycemia (78%). CONCLUSIONS: CGM data indicates that Ramadan fasting in women with GDM treated with diet alone or with diet plus metformin was associated with lower mean glucose levels and higher rates of hypoglycemia when compared with non-fasting glucose levels. Women with GDM should be advised against fasting during Ramadan until further data is available.

Concerted Efforts to Control or Eliminate Neglected Tropical Diseases: How Much Health Will Be Gained?

BACKGROUND: The London Declaration (2012) was formulated to support and focus the control and elimination of ten neglected tropical diseases (NTDs), with targets for 2020 as formulated by the WHO Roadmap. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma) are to be controlled by preventive chemotherapy (PCT), and four (Chagas' disease, human African trypanosomiasis, leprosy and visceral leishmaniasis) by innovative and intensified disease management (IDM). Guinea worm, virtually eradicated, is not considered here. We aim to estimate the global health impact of meeting these targets in terms of averted morbidity, mortality, and disability adjusted life years (DALYs). METHODS: The Global Burden of Disease (GBD) 2010 study provides prevalence and burden estimates for all nine NTDs in 1990 and 2010, by country, age and sex, which were taken as the basis for our calculations. Estimates for other years were obtained by interpolating between 1990 (or the start-year of large-scale control efforts) and 2010, and further extrapolating until 2030, such that the 2020 targets were met. The NTD disease manifestations considered in the GBD study were analyzed as either reversible or irreversible. Health impacts were assessed by comparing the results of achieving the targets with the counterfactual, construed as the health burden had the 1990 (or 2010 if higher) situation continued unabated. PRINCIPLE FINDINGS/CONCLUSIONS: Our calculations show that meeting the targets will lead to about 600 million averted DALYs in the period 2011-2030, nearly equally distributed between PCT and IDM-NTDs, with the health gain amongst PCT-NTDs mostly (96%) due to averted disability and amongst IDM-NTDs largely (95%) from averted mortality. These health gains include about 150 million averted irreversible disease manifestations (e.g. blindness) and 5 million averted deaths. Control of soil-transmitted helminths accounts for one third of all averted DALYs. We conclude that the projected health impact of the London Declaration justifies the required efforts.

The rise and fall of HIV in high-prevalence countries: a challenge for mathematical modeling.

Several countries with generalized, high-prevalence HIV epidemics, mostly in sub-Saharan Africa, have experienced rapid declines in transmission. These HIV epidemics, often with rapid onsets, have generally been attributed to a combination of factors related to high-risk sexual behavior. The subsequent declines in these countries began prior to widespread therapy or implementation of any other major biomedical prevention. This change has been construed as evidence of behavior change, often on the basis of mathematical models, but direct evidence for behavior changes that would explain these declines is limited. Here, we look at the structure of current models and argue that the common "fixed risk per sexual contact" assumption favors the conclusion of substantial behavior changes. We argue that this assumption ignores reported non-linearities between exposure and risk. Taking this into account, we propose that some of the decline in HIV transmission may be part of the natural dynamics of the epidemic, and that several factors that have traditionally been ignored by modelers for lack of precise quantitative estimates may well hold the key to understanding epidemiologic trends.

The individualistic fallacy, ecological studies and instrumental variables: a causal interpretation.

The validity of ecological studies in epidemiology for inferring causal relationships has been widely challenged as observed associations could be biased by the Ecological Fallacy. We reconsider the important design components of ecological studies, and discuss the conditions that may lead to spurious associations. Ecological associations are useful and valid when the ecological exposures can be interpreted as Instrumental Variables. A suitable example may be a time series analysis of environmental pollution (e.g. particulate matter with an aerodynamic diameter of <10 micrometres; PM10) and health outcomes (e.g. hospital admissions for acute myocardial infarction) as environmental pollution levels are a cause of individual exposure levels and not just an aggregate measurement. Ecological exposures may also be employed in situations (perhaps rare) where individual exposures are known but their associations with health outcomes are confounded by unknown or unquantifiable factors. Ecological associations have a notorious reputation in epidemiology and individualistic associations are considered superior to ecological associations because of the "ecological fallacy". We have argued that this is incorrect in situations in which ecological or aggregate exposures can serve as an instrumental variable and associations between individual exposure and outcome are likely to be confounded by unmeasured variables.

High HIV risk in a cohort of male sex workers from Nairobi, Kenya.

OBJECTIVES: Men who have sex with men (MSM) are at high risk of HIV-1 acquisition and transmission, yet there remains limited data in the African context, and for men who sell sex to men (MSM SW) in particular. METHODS: We enrolled 507 male sex workers in a Nairobi-based prospective cohort study during 2009-2012. All participants were offered HIV/STI screening, counselling and completed a baseline questionnaire. RESULTS: Baseline HIV prevalence was 40.0% (95% CI 35.8% to 44.3%). Prevalent HIV infection was associated with age, less postsecondary education, marijuana use, fewer female partners and lower rates of prior HIV testing. Most participants (73%) reported at least two of insertive anal, receptive anal and insertive vaginal sex in the past 3 months. Vaginal sex was reported by 37% of participants, and exclusive MSM status was associated with higher HIV rates. Condom use was infrequent, with approximately one-third reporting 100% condom use during anal sex. HIV incidence was 10.9 per 100 person-years (95% CI 7.4 to 15.6). Predictors of HIV risk included history of urethral discharge (aHR 0.29, 95% CI 0.08 to 0.98, p=0.046), condom use during receptive anal sex (aHR 0.05, 95% CI 0.01 to 0.41, p=0.006) and frequency of sex with male partners (aHR 1.33/sex act, 95% CI 1.01 to 1.75, p=0.04). CONCLUSIONS: HIV prevalence and incidence were extremely high in Nairobi MSM SW; a combination of interventions including increasing condom use, pre-exposure prophylaxis and access to effective treatment is urgently needed to decrease HIV transmission in this key population.

Epstein-Barr virus infection correlates with the expression of COX-2, p16(INK4A) and p53 in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL), a germinal-center related B cell neoplasm in almost all cases, is characterized by scarcity of the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 95 cases of cHL were studied. Five-micrometer sections were prepared and stained with hematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, COX-2, p53, p16, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS. There were 49 nodular sclerosis, 32 mixed cellularity, 8 lymphocyte-rich, and 6 lymphocyte-depleted subtypes in this series of cases. EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins.

Prediction of the origin of French Legionella pneumophila strains using a mixed-genome microarray.

BACKGROUND: Legionella is a water and soil bacterium that can infect humans, causing a pneumonia known as Legionnaires' disease. The pneumonia is almost exclusively caused by the species L. pneumophila, of which serogroup 1 is responsible for 90% of patients. Within serogroup 1, large differences in prevalence in clinical isolates have been described. A recent study, using a Dutch Legionella strain collection, identified five virulence associated markers. In our study, we verify whether these five Dutch markers can predict the patient or environmental origin of a French Legionella strain collection. In addition, we identify new potential virulence markers and verify whether these can predict better. A total of 219 French patient isolates and environmental strains were compared using a mixed-genome micro-array. The micro-array data were analysed to identify predictive markers, using a Random Forest algorithm combined with a logistic regression model. The sequences of the identified markers were compared with eleven known Legionella genomes, using BlastN and BlastX; the functionality for each of the predictive markers was checked in the literature. RESULTS: The five Dutch markers insufficiently predicted the patient or environmental origin of the French Legionella strains. Subsequent analyses identified four predictive markers for the French collection that were used for the logistic regression model. This model showed a negative predictive value of 91%. Three of the French markers differed from the Dutch markers, one showed considerable overlap and was found in one of the Legionella genomes (Lorraine strain). This marker encodes for a structural toxin protein RtxA, described for L. pneumophila as a factor involved in virulence and entry in both human cells and amoebae. CONCLUSIONS: The combination of a mixed-genome micro-array and statistical analysis using a Random Forest algorithm has identified virulence markers in a consistent way. The Lorraine strain and related Dutch and French Legionella strains contain a marker that encodes a RtxA protein which probably is involved in the increased prevalence in clinical isolates. The current set of predictive markers is insufficient to justify its use as a reliable test in the public health field in France. Our results suggest that genetic differences in Legionella strains exist between geographically distinct entities. It may be necessary to develop region-specific mixed-genome microarrays that are constantly adapted and updated.

Female sex work interventions and changes in HIV and syphilis infection risks from 2003 to 2008 in India: a repeated cross-sectional study.

OBJECTIVES: We examined if increased spending and coverage of female sex worker (FSW) interventions were associated with declines in HIV or syphilis risk among young pregnant women (as a proxy for new infections in the general population) in the high-burden southern states of India. DESIGN: Repeated cross-sectional analysis. SETTING: We used logistic regression to relate district-level spending, number of sexually transmitted infections (STIs) treated, FSWs reached or condoms distributed to the declines in the annual risk of HIV and syphilis from 2003 to 2008 among prenatal clinic attendees in the four high-HIV burden states of Andhra Pradesh, Karnataka, Maharashtra and Tamil Nadu. PARTICIPANTS: 386 961 pregnant women aged 15-24 years (as a proxy for incident infections in the adult population). INTERVENTIONS: We examined National AIDS Control Organisation (NACO) data on 868 FSW intervention projects implemented between 1995 and 2008. PRIMARY AND SECONDARY OUTCOME MEASURES: HIV or syphilis infection. RESULTS: HIV and syphilis prevalence declined substantially among young pregnant women. Each additional STI treated (per 1000 people) reduced the annual risk of HIV infection by -1.7% (95% CI -3.3 to -0.1) and reduced the annual risk of syphilis infection by -10.9% (95%CI -15.9 to -5.8). Spending, FSWs reached or condoms distributed did not reduce HIV risk, but each was significantly associated with reduced annual risk of syphilis infection. There were no major differences between the NACO-funded and Avahan-funded districts in the annual risk of either STI. CONCLUSIONS: Targeted FSW interventions are associated with reductions in syphilis risk and STI treatment is associated with reduced HIV risk. Both more and less costly FSW interventions have comparable effectiveness.

HIV-1 clade D is associated with increased rates of CD4 decline in a Kenyan cohort.

HIV-1 is grouped phylogenetically into clades, which may impact rates of HIV-1 disease progression. Clade D infection in particular has been shown to be more pathogenic. Here we confirm in a Nairobi-based prospective female sex worker cohort (1985-2004) that Clade D (n = 54) is associated with a more rapid CD4 decline than clade A1 (n = 150, 20.6% vs 13.4% decline per year, 1.53-fold increase, p = 0.015). This was independent of "protective" HLA and country of origin (p = 0.053), which in turn were also independent predictors of the rate of CD4 decline (p = 0.026 and 0.005, respectively). These data confirm that clade D is more pathogenic than clade A1. The precise reason for this difference is currently unclear, and requires further study. This is first study to demonstrate difference in HIV-1 disease progression between clades while controlling for protective HLA alleles.

Genome analysis of Legionella pneumophila strains using a mixed-genome microarray.

BACKGROUND: Legionella, the causative agent for Legionnaires' disease, is ubiquitous in both natural and man-made aquatic environments. The distribution of Legionella genotypes within clinical strains is significantly different from that found in environmental strains. Developing novel genotypic methods that offer the ability to distinguish clinical from environmental strains could help to focus on more relevant (virulent) Legionella species in control efforts. Mixed-genome microarray data can be used to perform a comparative-genome analysis of strain collections, and advanced statistical approaches, such as the Random Forest algorithm are available to process these data. METHODS: Microarray analysis was performed on a collection of 222 Legionella pneumophila strains, which included patient-derived strains from notified cases in The Netherlands in the period 2002-2006 and the environmental strains that were collected during the source investigation for those patients within the Dutch National Legionella Outbreak Detection Programme. The Random Forest algorithm combined with a logistic regression model was used to select predictive markers and to construct a predictive model that could discriminate between strains from different origin: clinical or environmental. RESULTS: Four genetic markers were selected that correctly predicted 96% of the clinical strains and 66% of the environmental strains collected within the Dutch National Legionella Outbreak Detection Programme. CONCLUSIONS: The Random Forest algorithm is well suited for the development of prediction models that use mixed-genome microarray data to discriminate between Legionella strains from different origin. The identification of these predictive genetic markers could offer the possibility to identify virulence factors within the Legionella genome, which in the future may be implemented in the daily practice of controlling Legionella in the public health environment.

A systematic review and meta-analysis of risk factors for sexual transmission of HIV in India.

BACKGROUND: Approximately 2.4 million people are living with HIV in India. This large disease burden, and potential for epidemic spread in some areas, demands a full understanding of transmission in that country. We wished to quantify the effects of key sexual risk factors for HIV infection for each gender and among high- and low-HIV risk populations in India. METHODOLOGY: We conducted a systematic review of sexual risk factors for HIV infection from 35 published studies. Risk factors analyzed were: male circumcision/religion, Herpes Simplex Virus 2, syphilis, gonorrhoea, genital ulcer, multiple sexual partners and commercial sex. Studies were included if they met predetermined criteria. Data were extracted and checked by two researchers and random-effects meta analysis of effects was conducted. Heterogeneity in effect estimates was examined by I(2) statistic. Publication bias was tested by Begg's test and funnel plots. Meta regression was used to assess effect modification by various study attributes. RESULTS: All risk factors were significantly associated with HIV status. The factor most strongly associated with HIV for both sexes was HSV-2 infection (OR(men): 5.87; 95%CI: 2.46-14.03; OR(women): 6.44; 95%CI: 3.22-12.86). The effect of multiple sexual partners was similar among men (OR = 2.46; 95%CI: 1.91-3.17,) and women (OR = 2.02; 95%CI: 1.43-2.87) and when further stratified by HIV-risk group. The association between HSV-2 and HIV prevalence was consistently stronger than other STIs or self-reported genital ulcer. If the strong associations between HSV-2 and HIV were interpreted causally, these results implied that approximately half of the HIV infections observed in our study population were attributable to HSV-2 infection. CONCLUSIONS: The risk factors examined in our analysis should remain targets of HIV prevention programs. Our results confirm that sexual risk factors for HIV infection continue to be an important part of Indian HIV epidemic 26 years after it began.

Comparing pandemic to seasonal influenza mortality: moderate impact overall but high mortality in young children.

BACKGROUND: We assessed the severity of the 2009 influenza pandemic by comparing pandemic mortality to seasonal influenza mortality. However, reported pandemic deaths were laboratory-confirmed - and thus an underestimation - whereas seasonal influenza mortality is often more inclusively estimated. For a valid comparison, our study used the same statistical methodology and data types to estimate pandemic and seasonal influenza mortality. METHODS AND FINDINGS: We used data on all-cause mortality (1999-2010, 100% coverage, 16.5 million Dutch population) and influenza-like-illness (ILI) incidence (0.8% coverage). Data was aggregated by week and age category. Using generalized estimating equation regression models, we attributed mortality to influenza by associating mortality with ILI-incidence, while adjusting for annual shifts in association. We also adjusted for respiratory syncytial virus, hot/cold weather, other seasonal factors and autocorrelation. For the 2009 pandemic season, we estimated 612 (range 266-958) influenza-attributed deaths; for seasonal influenza 1,956 (range 0-3,990). 15,845 years-of-life-lost were estimated for the pandemic; for an average seasonal epidemic 17,908. For 0-4 yrs of age the number of influenza-attributed deaths during the pandemic were higher than in any seasonal epidemic; 77 deaths (range 61-93) compared to 16 deaths (range 0-45). The ≥75 yrs of age showed a far below average number of deaths. Using pneumonia/influenza and respiratory/cardiovascular instead of all-cause deaths consistently resulted in relatively low total pandemic mortality, combined with high impact in the youngest age category. CONCLUSION: The pandemic had an overall moderate impact on mortality compared to 10 preceding seasonal epidemics, with higher mortality in young children and low mortality in the elderly. This resulted in a total number of pandemic deaths far below the average for seasonal influenza, and a total number of years-of-life-lost somewhat below average. Comparing pandemic and seasonal influenza mortality as in our study will help assessing the worldwide impact of the 2009 pandemic.

HIV-specific CD8+ T-cell proliferation is prospectively associated with delayed disease progression.

Human immunodeficiency virus (HIV)-specific CD8(+) T-cell proliferation is consistently correlated with enhanced host HIV immune control, but whether proliferative responses are a cause or consequence of immune protection is unclear. We measured Env-specific CD8(+) T-cell proliferation and interferon (IFN)-γ secretion in HIV-infected participants with CD4 counts >200, who then completed 121 person-years of prospective follow-up to monitor HIV disease progression. In all, 13 of 31 participants (42%) reached end point during longitudinal follow-up. Strong Env-specific CD8(+) T-cell proliferation (>10% of CD8(+) T cells) was observed in 14/31 participants at baseline, and this was associated with a longer time to HIV disease progression end point, stratified baseline CD4 count (P=0.016). No associations were observed for IFN-γ ELISPOT responses and progression (P>0.2). Strong proliferation remained significant in multivariate Cox regression analyses (P=0.044) as an independent predictor of delayed HIV disease progression, along with baseline CD4 count (P=0.04). Duration of HIV infection was associated with more rapid progression in univariate, but not multivariate, analysis (P=0.112). Age and baseline viral load were not predictive of progression. HIV-specific CD8(+) T-cell proliferation was a correlate of protective immunity in this prospective study; such responses may be important for HIV vaccine protection.

The potential impact of an HIV vaccine with limited protection on HIV incidence in Thailand: a modeling study.

BACKGROUND: The RV144 trial on the ALVAC/AIDSVAX candidate HIV vaccine, carried out in Thailand, showed short-lived protection against infection. METHODS: Using a deterministic compartmental model we explored the potential impact of this vaccine on heterosexual HIV transmission in Thailand. Both one-off vaccination strategies, as well as strategies with regular boosting, either annually or every two years, were explored. Both targeting the general adult population and prioritizing sex workers were modeled. The impact of risk compensation among high risk groups, as well as whether higher levels of safe sex in high risk groups could be an alternative to vaccination, was studied. RESULTS: One-off vaccination campaigns had only transient effects, and boosting appears to be a key component of successful vaccination campaigns. Intensive vaccination campaigns may reduce HIV incidence by up to 75% after 10 years of vaccination. Targeting only sex workers has a smaller impact but has a more favorable cost-benefit ratio. Risk compensation has the potential of undoing much of the benefits of a vaccination program and may even increase incidence. In contrast, higher levels of safe sex among sex workers would provide a viable alternative to vaccinating this group. DISCUSSION: The new vaccine holds promise for controlling HIV in Thailand and similar countries. In view of the short lived protection of the vaccine, regular boosting of immunity as well as avoidance of risk compensation are essential. Targeting sex workers would achieve the greatest reduction in incidence per vaccination and may be considered for expensive vaccines but its cost-effectiveness has to be compared to alternatives.

Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review.

BACKGROUND: The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data. METHODOLOGY AND PRINCIPAL FINDINGS: To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis. CONCLUSIONS: Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

Guidelines for conducting tuberculin skin test surveys in high-prevalence countries.

This Supplement provides an update on guidelines first published in 1996 on conducting a tuberculin skin test survey and analyzing the resulting data. The updated guidelines add experiences gained from community surveys, revisit the proposed sampling strategies, and provide additional information on ethical considerations.