Prevalence and Predictors of Colposcopic-Histopathologically Confirmed Cervical Intraepithelial Neoplasia in HIV-Infected Women in India

Background

Prevalence estimates of cervical intraepithelial neoplasia (CIN) among HIV-infected women in India have been based on cervical cytology, which may have underestimated true disease burden. We sought to better establish prevalence estimates and evaluate risk factors of CIN among HIV-infected women in Pune, India using colposcopy and histopathology as diagnostic tools.

Methodology

Previously unscreened, non-pregnant HIV-infected women underwent cervical cancer screening evaluation including standardized diagnostic colposcopy by a gynecologist. Histopathologic confirmation was conducted among consenting women with clinical suspicion of CIN. The prevalence of CIN was evaluated by a composite diagnosis based on colposcopy and histopathology results. Multivariable ordinal logistic regression analysis was conducted to determine independent predictors of increasing severity of CIN.

Results

The median age of the n = 303 enrolled HIV-infected women was 30 years (interquartile range, 27–34). A majority of the participants were widowed or separated (187/303, 61.7%), more than one-third (114/302, 37.7%) were not educated beyond primary school, and nearly two-thirds (196/301, 64.7%) had a family per capita income of <1,000 Indian Rupees (∼US$22) per month. Cervical high-risk HPV-DNA was detected in 41.7% (124/297) of participants. The composite colposcopic-histopathologic diagnoses revealed no evidence of CIN in 220 out of 303 (72.6%) women, CIN1 in 33/303 (10.9%), CIN2 in 31/303 (10.2%), CIN3 in 18/303 (5.9%) and 1 (0.3%) woman was diagnosed with ICC. Thus, over a quarter of the participants [83/303: 27.7% (95% CI: 22.7–33.1)] had ≥CIN1 lesions and a sixth [50/303: 16.5% (95% CI: 12.2–21.9)] had evidence of advanced (≥CIN2) neoplastic disease. The independent predictors of increasing severity of CIN as revealed by a proportional odds model using multivariable ordinal logistic regression included (i) currently receiving antiretroviral therapy [adjusted odds ratios (aOR): 2.24 (1.17, 4.26), p = 0.01] and (ii) presence of cervical high-risk HPV-DNA [aOR: 1.93 (1.13, 3.28), p = 0.02].

Conclusions

HIV-infected women in Pune, India have a substantial burden of cervical precancerous lesions, which may progress to invasive cervical cancer unless appropriately detected and treated. Increased attention should focus on recognizing and addressing this entirely preventable cancer among HIV-infected women, especially in the context of increasing longevity due to antiretroviral therapy.     

Linking HIV-Infected TB Patients to Cotrimoxazole Prophylaxis and Antiretroviral Treatment in India

Background

HIV-infected persons suffering from tuberculosis experience high mortality. No programmatic studies from India have documented the delivery of mortality-reducing interventions, such as cotrimoxazole prophylactic treatment (CPT) and antiretroviral treatment (ART). To guide TB-HIV policy in India we studied the effectiveness of delivering CPT and ART to HIV-infected persons treated for tuberculosis in three districts in Andhra Pradesh, India, and evaluated factors associated with death.

Methods and Findings

We retrospectively abstracted data for all HIV-infected tuberculosis patients diagnosed from March 2007 through August 2007 using standard treatment outcome definitions. 734 HIV-infected tuberculosis patients were identified; 493 (67%) were males and 569 (80%) were between the ages of 24–44 years. 710 (97%) initiated CPT, and 351 (50%) collected >60% of their monthly cotrimoxazole pouches provided throughout TB treatment. Access to ART was documented in 380 (51%) patients. Overall 130 (17%) patients died during TB treatment. Patients receiving ART were less likely to die (adjusted hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.3–0.6), while males and those with pulmonary TB were more likely to die (HR 1.7, 95% CI 1.1–2.7, and HR 1.9, 95% CI 1.1–3.2 respectively).

Conclusions

Among HIV-infected TB patients in India death was common despite the availability of free cotrimoxazole locally and ART from referral centres. Death was strongly associated with the absence of ART during TB treatment. To minimize death, programmes should promote high levels of ART uptake and closely monitor progress in implementation.     

Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population

Background

Longevity is a multifactorial trait with a genetic contribution, and mitochondrial DNA (mtDNA) polymorphisms were found to be involved in the phenomenon of longevity.

Methodology/Principal Findings

To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao – a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged ≥95 yr (EL group). Control subjects include 926 individuals aged 60–69 years (elderly group) and 463 individuals aged 40–49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p = 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p = 0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects (1.7%) in females (p = 0.045).

Conclusions

Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population.     

Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Na?ve Subjects in the CASTLE Study

Background

CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.

Objectives

Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.

Methods

A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.

Results

Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.

Conclusion

Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.     

Routine Laboratory Results and Thirty Day and One-Year Mortality Risk Following Hospitalization with Acute Decompensated Heart Failure

Introduction

Several blood tests are performed uniformly in patients hospitalized with acute decompensated heart failure and are predictive of the outcomes: complete blood count, electrolytes, renal function, glucose, albumin and uric acid. We sought to evaluate the relationship between routine admission laboratory tests results, patient characteristics and 30-day and one-year mortality of patients admitted for decompensated heart failure and to construct a simple mortality prediction tool.

Methods

A retrospective population based study. Data from seven tertiary hospitals on all admissions with a principal diagnosis of heart failure during the years 2002–2005 throughout Israel were captured.

Results

8,246 patients were included in the study cohort. Thirty day mortality rate was 8.5% (701 patients) and one-year mortality rate was 28.7% (2,365 patients). Addition of five routine laboratory tests results (albumin, sodium, blood urea, uric acid and WBC) to a set of clinical and demographic characteristics improved c-statistics from 0.76 to 0.81 for 30-days and from 0.72 to 0.76 for one-year mortality prediction (both p-values <0.0001). Three dichotomized abnormal laboratory results with highest odds ratio for one-year mortality (hypoalbuminaemia, hyponatremia and elevated blood urea) were used to construct a simple prediction score, capable of discriminating from 1.1% to 21.4% in 30-day and from 11.6% to 55.6% in one-year mortality rates between patients with a score of 0 (1,477 patients) vs. score of 3 (544 patients).

Discussion

A small set of abnormal routine laboratory results upon admission can risk-stratify and independently predict 30-day and one-year mortality in patients hospitalized with acute decompensated heart failure.     

Prospective Study of Chikungunya Virus Acute Infection in the Island of La Réunion during the 2005–2006 Outbreak

Background

Chikungunya virus (CHIKV) is a recently re-emerged arthropod borne virus responsible for a massive outbreak in the Indian Ocean and India, and extended to Southeast Asia as well as Italy. CHIKV has adapted to Aedes albopictus, an anthropophilic mosquito species widely distributed in Asia, Europe, Africa and America. Our objective was to determine the clinical and biological features of patients at the acute phase of CHIKV infection.

Methods and Findings

A prospective study enrolled 274 consecutive patients with febrile arthralgia recorded at the Emergency Department of the Groupe Hospitalier Sud-Réunion between March and May 2006. Three groups were defined: one group of 180 viremic patients (positive CHIKV RT-PCR), one group of 34 patients with acute post-viremic infection (negative CHIKV RT-PCR, positive anti-CHIKV IgM and negative IgG), and one group of 46 uninfected patients (negative CHIKV RT-PCR, anti-CHIKV IgM and IgG). Bivariate analyses of clinical and biological features between groups were performed. Patients with CHIKV viremia presented typically with asymmetrical bilateral polyarthralgia (96.5%) affecting the lower (98%) and small joints (74.8%), as well as asthenia (88.6%), headache (70%), digestive trouble (63.3%), myalgia (59%), exanthems (47.8%), conjunctival hyperhemia (23%) and adenopathy (8.9%). Vertigo, cutaneous dysesthesia, pharyngitis and haemorrhages were seldom observed. So far unreported symptoms such as chondrocostal arthralgia (20%), entesopathies (1.6%), talalgia (14%) were also noted. Prurit was less frequent during the viremic than post-viremic phase (13.9% vs. 41.2%; p<0.001), whereas lymphopenia was more frequent (87.6% vs. 39.4%; p<0.001). Others biological abnormalities included leukopenia (38.3%), thrombocytopenia (37.3%), increased ASAT and ALAT blood levels (31.6 and 7.3%, respectively) and hypocalcemia (38.7%). Lymphopenia <1,000/mm³ was very closely associated with viremic patients (Yule coefficient 0.82, positive predictive value 92.3%). Age under 65 was associated with a benign course, as no patients younger than 65 had to be hospitalized (Yule coefficient 0.78).

Conclusions

The diagnosis of CHIKV infection in acute phase is based on commonly accepted clinical criteria (fever and arthralgia), however clinical and biological diffrences exist in acute phase depending on whether or not the patient is within the viremic phase of the infection.     

Prevalence of Depression in a Large Urban South Indian Population — The Chennai Urban Rural Epidemiology Study (Cures – 70)

Background

In India there are very few population based data on prevalence of depression. The aim of the study was to determine the prevalence of depression in an urban south Indian population.

Methods and Findings

Subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), involving 26,001 subjects randomly recruited from 46 of the 155 corporation wards of Chennai (formerly Madras) city in South India. 25,455 subjects participated in this study (response rate 97.9%). Depression was assessed using a self-reported and previously validated instrument, the Patient Health Questionnaire (PHQ) – 12. Age adjustment was made according to the 2001 census of India. The overall prevalence of depression was 15.1% (age-adjusted, 15.9%) and was higher in females (females 16.3% vs. males 13.9%, p<0.0001). The odds ratio (OR) for depression in female subjects was 1.20 [Confidence Intervals (CI): 1.12–1.28, p<0.001] compared to male subjects. Depressed mood was the most common symptom (30.8%), followed by tiredness (30.0%) while more severe symptoms such as suicidal thoughts (12.4%) and speech and motor retardation (12.4%) were less common. There was an increasing trend in the prevalence of depression with age among both female (p<0.001) and male subjects (p<0.001). The prevalence of depression was higher in the low income group (19.3%) compared to the higher income group (5.9%, p<0.001). Prevalence of depression was also higher among divorced (26.5%) and widowed (20%) compared to currently married subjects (15.4%, p<0.001).

Conclusions

This is the largest population-based study from India to report on prevalence of depression and shows that among urban south Indians, the prevalence of depression was 15.1%. Age, female gender and lower socio-economic status are some of the factors associated with depression in this population.     

The Effect of Rural-to-Urban Migration on Obesity and Diabetes in India: A Cross-Sectional Study

Background

Migration from rural areas of India contributes to urbanisation and may increase the risk of obesity and diabetes. We tested the hypotheses that rural-to-urban migrants have a higher prevalence of obesity and diabetes than rural nonmigrants, that migrants would have an intermediate prevalence of obesity and diabetes compared with life-long urban and rural dwellers, and that longer time since migration would be associated with a higher prevalence of obesity and of diabetes.

Methods and Findings

The place of origin of people working in factories in north, central, and south India was identified. Migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by interview, examination, and fasting blood samples. Obesity, diabetes, and other cardiovascular risk factors were compared. A total of 6,510 participants (42% women) were recruited. Among urban, migrant, and rural men the age- and factory-adjusted percentages classified as obese (body mass index [BMI] >25 kg/m²) were 41.9% (95% confidence interval [CI] 39.1–44.7), 37.8% (95% CI 35.0–40.6), and 19.0% (95% CI 17.0–21.0), respectively, and as diabetic were 13.5% (95% CI 11.6–15.4), 14.3% (95% CI 12.2–16.4), and 6.2% (95% CI 5.0–7.4), respectively. Findings for women showed similar patterns. Rural men had lower blood pressure, lipids, and fasting blood glucose than urban and migrant men, whereas no differences were seen in women. Among migrant men, but not women, there was weak evidence for a lower prevalence of both diabetes and obesity among more recent (≤10 y) migrants.

Conclusions

Migration into urban areas is associated with increases in obesity, which drive other risk factor changes. Migrants have adopted modes of life that put them at similar risk to the urban population. Gender differences in some risk factors by place of origin are unexpected and require further exploration. Please see later in the article for the Editors'' Summary     

Leptospirosis outbreak following severe flooding: a rapid assessment and mass prophylaxis campaign; Guyana, January-February 2005

Background

Leptospirosis is a zoonosis usually transmitted through contact with water or soil contaminated with urine from infected animals. Severe flooding can put individuals at greater risk for contracting leptospirosis in endemic areas. Rapid testing for the disease and large-scale interventions are necessary to identify and control infection. We describe a leptospirosis outbreak following severe flooding and a mass chemoprophylaxis campaign in Guyana.

Methodology/Principal Findings

From January–March 2005, we collected data on suspected leptospirosis hospitalizations and deaths. Laboratory testing included anti-leptospiral dot enzyme immunoassay (DST), immunohistochemistry (IHC) staining, and microscopic agglutination testing (MAT). DST testing was conducted for 105 (44%) of 236 patients; 52 (50%) tested positive. Four (57%) paired serum samples tested by MAT were confirmed leptospirosis. Of 34 total deaths attributed to leptospirosis, postmortem samples from 10 (83%) of 12 patients were positive by IHC. Of 201 patients interviewed, 89% reported direct contact with flood waters. A 3-week doxycycline chemoprophylaxis campaign reached over 280,000 people.

Conclusions

A confirmed leptospirosis outbreak in Guyana occurred after severe flooding, resulting in a massive chemoprophylaxis campaign to try to limit morbidity and mortality.     

T. cruzi OligoC-TesT: A Simplified and Standardized Polymerase Chain Reaction Format for Diagnosis of Chagas Disease

Background

PCR has evolved into one of the most promising tools for T. cruzi detection in the diagnosis and control of Chagas disease. However, general use of the technique is hampered by its complexity and the lack of standardization.

Methodology

We here present the development and phase I evaluation of the T. cruzi OligoC-TesT, a simple and standardized dipstick format for detection of PCR amplified T. cruzi DNA. The specificity and sensitivity of the assay were evaluated on blood samples from 60 Chagas non-endemic and 48 endemic control persons and on biological samples from 33 patients, 7 reservoir animals, and 14 vectors collected in Chile.

Principal Findings

The lower detection limits of the T. cruzi OligoC-TesT were 1 pg and 1 to 10 fg of DNA from T. cruzi lineage I and II, respectively. The test showed a specificity of 100% (95% confidence interval [CI]: 96.6%–100%) on the control samples and a sensitivity of 93.9% (95% CI: 80.4%–98.3%), 100% (95% CI: 64.6%–100%), and 100% (95% CI: 78.5%–100%) on the human, rodent, and vector samples, respectively.

Conclusions

The T. cruzi OligoC-TesT showed high sensitivity and specificity on a diverse panel of biological samples. The new tool is an important step towards simplified and standardized molecular diagnosis of Chagas disease.     

Early Experience in the Treatment of Intra-Cranial Aneurysms by Endovascular Flow Diversion: A Multicentre Prospective Study

Introduction

Flow diversion is a new approach to the endovascular treatment of intracranial aneurysms which uses a high density mesh stent to induce sac thrombosis. These devices have been designed for the treatment of complex shaped and large size aneurysms. So far published safety and efficacy data on this approach is sparse.

Material and Methods

Over 8 months, standardized clinical and angiographic data were collected on 70 patients treated with a flow diverter device (SILK flow diverter (SFD)) in 18 centres worldwide. Treatment and early follow up details were audited centrally. SFDs were deployed alone in 57 (81%) or with endosaccular coils in 10 (14%) aneurysms, which included: 44 (63%) saccular, 26 (37%) fusiform shapes and 18 (26%) small, 37 (53%) large, 15 (21%) giant sizes. Treatment outcome data up to 30 days were reported for all patients, with clinical (50 patients) and imaging (49 patients) follow up (median 119 days) data available.

Results

Difficulties in SFD deployment were reported in 15 (21%) and parent artery thrombosis in 8 (11%) procedures. Procedural complications caused stroke in 1 and serious extracranial bleeding in 3 patients; 2 of whom developed fatal pneumonias. Delayed worsening of symptoms occurred in 5 patients (3 transient, 1 permanent neurological deficit, and 1 death) and fatal aneurysm bleeding in 1 patient. Overall permanent morbidity rates were 2 (4%) and mortality 4 (8%). Statistical analysis revealed no significant association between complications and variables related to treated aneurysm morphology or rupture status.

Conclusion

This series is the largest reporting outcome of the new treatment approach and provides data for future study design. Procedural difficulties in SFD deployment were frequent and anti-thrombosis prophylaxis appears to reduce the resulting clinical sequelae, but at the cost of morbidity due to extracranial bleeding. Delayed morbidity appears to be a consequence of the new approach and warrants care in selecting patients for treatment and future larger studies.     

Result Publication of Chinese Trials in World Health Organization Primary Registries

Background

Result publication is the key step to improve the transparency of clinical trials.

Objective

To investigate the result publication rate of Chinese trials registered in World Health Organization (WHO) primary registries.

Method

We searched 11 WHO primary registries for Chinese trials records. The progress of each trial was analyzed. We searched for the full texts of result publications cited in the registration records. For completed trials without citations, we searched PubMed, Embase, Chinese Biomedical Literature Database (Chinese), China Knowledge Resource Integrated Database, and Chinese Science and Technology Periodicals Database for result publications. The search was conducted on July 14, 2009. We also called the investigators of completed trials to ask about results publication.

Results

We identified 1294 Chinese trials records (428 in ChiCTR,743 in clinicaltrials.gov,55 in ISRCTN, 21 in ACTRN). A total of 443 trials had been completed. The publication rate of the Chinese trials in WHO primary registries is 35.2%(156/443).The publication rate of Chinese trials in clinicaltrials.gov, ChiCTR, ISRCTN, and ACRTN was 36.5% (53/145), 36.3% (89/245), 26.0%(9/44), and 55.6%(5/9), respectively. The publication rate of trials sponsored by industry(23.8%) was lower than that of sponsored by central and local government(31.7%), hospital(35.1%), and universities (40.7%). The publication rate for randomized trials was higher than that of cohort study and case-control study (33.2% versus 16.7%, 22.2%). The publication rate for interventional studies and observational studies was similar(33.4% versus 33.3%).

Conclusion

The publication rate of the registered Chinese trials was low, with no significant difference between ChiCTR and clinicaltrials.gov. An effective mechanism is needed to promote publication of results for registered trials in China.     

Serotype-Specific Differences in the Risk of Dengue Hemorrhagic Fever: An Analysis of Data Collected in Bangkok,Thailand from 1994 to 2006

Background

It is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention in Bangkok, Thailand.

Methodology/Principal Findings

Prospective studies were conducted from 1994 to 2006. Univariate and multivariate logistic and multinomial logistic regressions were used to determine if dengue hemorrhagic fever (DHF) and signs of severe clinical disease (pleural effusion, ascites, thrombocytopenia, hemoconcentration) were associated with serotype. Crude and adjusted odds ratios were calculated. There were 162 (36%) cases with DENV-1, 102 (23%) with DENV-2, 123 (27%) with DENV-3, and 64 (14%) with DENV-4. There was no significant difference in the rates of DHF by serotype: DENV-2 (43%), DENV-3 (39%), DENV-1 (34%), DENV-4 (31%). DENV-2 was significantly associated with increased odds of DHF grade I compared to DF (OR 2.9 95% CI 1.1, 8.0), when using DENV-1 as the reference. Though not statistically significant, DENV-2 had an increased odds of total DHF and DHF grades II, III, and IV. Secondary serologic response was significantly associated with DHF (OR 6.2) and increased when considering more severe grades of DHF. DENV-2 (9%) and -4 (3%) were significantly less often associated with primary disease than DENV-1 (28%) and -3 (33%). Restricting analysis to secondary cases, we found DENV-2 and DENV-3 to be twice as likely to result in DHF as DEN-4 (p = 0.05). Comparing study years, we found the rate of DHF to be significantly less in 1999, 2000, 2004, and 2005 than in 1994, the study year with the highest percentage of DHF cases, even when controlling for other variables.

Conclusions/Significance

As in other studies, we find secondary disease to be strongly associated with DHF and with more severe grades of DHF. DENV-2 appears to be marginally associated with more severe dengue disease as evidenced by a significant association with DHF grade I when compared to DENV-1. In addition, we found non-significant trends with other grades of DHF. Restricting the analysis to secondary disease we found DENV-2 and -3 to be twice as likely to result in DHF as DEN-4. Differences in severity by study year may suggest that other factors besides serotype play a role in disease severity.     

HIV Prevalence and Associated Risk Factors among Individuals Aged 13-34 Years in Rural Western Kenya

Objectives

To estimate HIV prevalence and characterize risk factors among young adults in Asembo, rural western Kenya.

Design

Community-based cross-sectional survey.

Methods

From a demographic surveillance system, we selected a random sample of residents aged 13-34 years, who were contacted at home and invited to a nearby mobile study site. Consent procedures for non-emancipated minors required assent and parental consent. From October 2003 - April 2004, consenting participants were interviewed on risk behavior and tested for HIV and HSV-2. HIV voluntary counseling and testing was offered.

Results

Of 2606 eligible residents, 1822 (70%) enrolled. Primary reasons for refusal included not wanting blood taken, not wanting to learn HIV status, and partner/parental objection.Females comprised 53% of 1762 participants providing blood. Adjusted HIV prevalence was 15.4% overall: 20.5% among females and 10.2% among males. HIV prevalence was highest in women aged 25-29 years (36.5%) and men aged 30-34 years (41.1%). HSV-2 prevalence was 40.0% overall: 53% among females, 25.8% among males. In multivariate models stratified by gender and marital status, HIV infection was strongly associated with age, higher number of sex partners, widowhood, and HSV-2 seropositivity.

Conclusions

Asembo has extremely high HIV and HSV-2 prevalence, and probable high incidence, among young adults. Further research on circumstances around HIV acquisition in young women and novel prevention strategies (vaccines, microbicides, pre-exposure prophylaxis, HSV-2 prevention, etc.) are urgently needed.     

Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study

Background

Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).

Methods and Findings

A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).

Conclusions

Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia. Please see later in the article for the Editors'' Summary     

When Can Antibiotic Treatments for Trachoma Be Discontinued? Graduating Communities in Three African Countries

Background

Repeated mass azithromycin distributions are effective in controlling the ocular strains of chlamydia that cause trachoma. However, it is unclear when treatments can be discontinued. Investigators have proposed graduating communities when the prevalence of infection identified in children decreases below a threshold. While this can be tested empirically, results will not be available for years. Here we use a mathematical model to predict results with different graduation strategies in three African countries.

Methods

A stochastic model of trachoma transmission was constructed, using the parameters with the maximum likelihood of obtaining results observed from studies in Tanzania (with 16% infection in children pre-treatment), The Gambia (9%), and Ethiopia (64%). The expected prevalence of infection at 3 years was obtained, given different thresholds for graduation and varying the characteristics of the diagnostic test.

Results

The model projects that three annual treatments at 80% coverage would reduce the mean prevalence of infection to 0.03% in Tanzanian, 2.4% in Gambian, and 12.9% in the Ethiopian communities. If communities graduate when the prevalence of infection falls below 5%, then the mean prevalence at 3 years with the new strategy would be 0.3%, 3.9%, and 14.4%, respectively. Graduations reduced antibiotic usage by 63% in Tanzania, 56% in The Gambia, and 11% in Ethiopia.

Conclusion

Models suggest that graduating communities from a program when the infection is reduced to 5% is a reasonable strategy and could reduce the amount of antibiotic distributed in some areas by more than 2-fold.