HHV-8 seroprevalence: a global view

BACKGROUND Human herpes virus 8 (HHV-8) is the underlying infectious cause of Kaposi sarcoma (KS) and other proliferative diseases; that is, primary effusion lymphoma and multicentric Castleman disease. In regions with high HHV-8 seroprevalence in the general population, KS accounts for a major burden of disease. Outside these endemic regions, HHV-8 prevalence is high in men who have sex with men (MSM) and in migrants from endemic regions. We aim to conduct a systematic literature review and meta-analysis in order 1) to define the global distribution of HHV-8 seroprevalence (primary objective) and 2) to identify risk factors for HHV-8 infection, with a focus on HIV status (secondary objective). METHODS/DESIGN We will include observational studies reporting data on seroprevalence of HHV-8 in children and/or adults from any region in the world. Case reports and case series as well as any studies with fewer than 50 participants will be excluded. We will search MEDLINE, EMBASE, and relevant conference proceedings without language restriction. Two reviewers will independently screen the identified studies and extract data on study characteristics and quality, study population, risk factors, and reported outcomes, using a standardized form. For the primary objective we will pool the data using a fully bayesian approach for meta-analysis, with random effects at the study level. For the secondary objective (association of HIV and HHV-8) we aim to pool odds ratios for the association of HIV and HHV-8 using a fully bayesian approach for meta-analysis, with random effects at the study level. Sub-group analyses and meta-regression analyses will be used to explore sources of heterogeneity, including factors such as geographical region, calendar years of recruitment, age, gender, ethnicity, socioeconomic status, different risk groups for sexually and parenterally transmitted infections (MSM, sex workers, hemophiliacs, intravenous drug users), comorbidities such as organ transplantation and malaria, test(s) used to measure HHV-8 infection, study design, and study quality. DISCUSSION Using the proposed systematic review and meta-analysis, we aim to better define the global seroprevalence of HHV-8 and its associated risk factors. This will improve the current understanding of HHV-8 epidemiology, and could suggest measures to prevent HHV-8 infection and to reduce its associated cancer burden.

Tenofovir or zidovudine in second-line antiretroviral therapy after stavudine failure in southern Africa

BACKGROUND There is debate over using tenofovir or zidovudine alongside lamivudine in second-line antiretroviral therapy (ART) following stavudine failure. We analyzed outcomes in cohorts from South Africa, Zambia and Zimbabwe METHODS: Patients aged ≥16 years who switched from a first-line regimen including stavudine to a ritonavir-boosted lopinavir-based second-line regimen with lamivudine or emtricitabine and zidovudine or tenofovir in seven ART programs in southern Africa were included. We estimated the causal effect of receiving tenofovir or zidovudine on mortality and virological failure using Cox proportional hazards marginal structural models. Its parameters were estimated using inverse probability of treatment weights. Baseline characteristics were age, sex, calendar year and country. CD4 cell count, creatinine and hemoglobin levels were included as time-dependent confounders. RESULTS 1,256 patients on second-line ART, including 958 on tenofovir, were analyzed. Patients on tenofovir were more likely to have switched to second-line ART in recent years, spent more time on first-line ART (33 vs. 24 months) and had lower CD4 cell counts (172 vs. 341 cells/μl) at initiation of second-line ART. The adjusted hazard ratio comparing tenofovir with zidovudine was 1.00 (95% confidence interval 0.59-1.68) for virologic failure and 1.40 (0.57-3.41) for death. CONCLUSIONS We did not find any difference in treatment outcomes between patients on tenofovir or zidovudine; however, the precision of our estimates was limited. There is an urgent need for randomized trials to inform second-line ART strategies in resource-limited settings.

Exploring the periodicity of cardiovascular events in Switzerland: Variation in deaths and hospitalizations across seasons, day of the week and hour of the day

Purpose The purpose of this study is to explore the periodical patterns of events and deaths related to cardiovascular disease (CVD), acute myocardial infarction (AMI) and stroke in Swiss adults (≥18years). Methods Mortality data for period 1969–2007 (N=869,863 CVD events) and hospitalization data for period 1997–2008 (N=959,990 CVD events) were used. The annual, weekly and circadian distribution of CVD-related deaths and events were assessed. Multivariate analysis was conducted using multinomial logistic regression adjusting for age, gender and calendar year and considering deaths from respiratory diseases, accidents or other causes as competitive events. Results CVD deaths and hospitalizations occurred less frequently in the summer months. Similar patterns were found for AMI and stroke. No significant weekly variation for CVD deaths was found. Stratification by age and gender showed subjects aged <65years to present a higher probability of dying on Mondays and Saturday, only for men. This finding was confirmed after multivariate adjustment. Finally, a circadian variation in CVD mortality was observed, with a first peak in the morning (8–12am) and a smaller second peak in the late afternoon (2–6pm). This pattern persisted after multivariate adjustment and was more pronounced for AMI than for stroke. Conclusion There is a periodicity of hospitalizations and deaths related to CVD, AMI and stroke in Switzerland. This pattern changes slightly according to the age and sex of the subjects. Although the underlying mechanisms are not fully identified, preventive measures should take into account these aspects to develop better strategies of prevention and management of CVD.

Correlating the Ancient Maya and Modern European Calendars with High-Precision AMS 14C Dating

The reasons for the development and collapse of Maya civilization remain controversial and historical events carved on stone monuments throughout this region provide a remarkable source of data about the rise and fall of these complex polities. Use of these records depends on correlating the Maya and European calendars so that they can be compared with climate and environmental datasets. Correlation constants can vary up to 1000 years and remain controversial. We report a series of high-resolution AMS C-14 dates on a wooden lintel collected from the Classic Period city of Tikal bearing Maya calendar dates. The radiocarbon dates were calibrated using a Bayesian statistical model and indicate that the dates were carved on the lintel between AD 658-696. This strongly supports the Goodman-Martinez-Thompson (GMT) correlation and the hypothesis that climate change played an important role in the development and demise of this complex civilization.

Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries

OBJECTIVE To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries. METHODS Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed. RESULTS In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/μL between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/μL (76% increase), 88 to 135 cells/μL (53%), and 209 to 274 cells/μL (31%). In 2009, compared with LIC, median counts were 13 cells/μL [95% confidence interval (CI): -56 to +30] lower in LMIC, 22 cells/μL (-62 to +18) lower in UMIC, and 112 cells/μL (+75 to +149) higher in HIC. They were 23 cells/μL (95% CI: +18 to +28 cells/μL) higher in women than men. Median counts were 88 cells/μL (95% CI: +35 to +141 cells/μL) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage. CONCLUSIONS Median CD4 cell counts at the start of cART increased 2000-2009 but remained below 200 cells/μL in LIC and MIC and below 300 cells/μL in HIC. Earlier start of cART will require substantial efforts and resources globally.

Case-control analysis on metformin and cancer of the esophagus

PURPOSE Metformin use has been associated with decreased cancer risks, though data on esophageal cancer are scarce. We explored the relation between use of metformin or other anti-diabetic drugs and the risk of esophageal cancer. METHODS We conducted a case-control analysis in the UK-based general practice research database (GPRD, now clinical practice research datalink, CPRD). Cases were individuals with an incident diagnosis of esophageal cancer between 1994 and 2010 at age 40-89 years. Ten controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Various potential confounders including diabetes mellitus, gastro-esophageal reflux, and use of proton-pump inhibitors were evaluated in univariate models, and the final results were adjusted for BMI and smoking. Results are presented as odds ratios (ORs) with 95 % confidence intervals (CI). RESULTS Long-term use (≥30 prescriptions) of metformin was not associated with a materially altered risk of esophageal cancer (adj. OR 1.23, 95 % CI 0.92-1.65), nor was long-term use of sulfonylureas (adj. OR 0.93, 95 % CI 0.70-1.23), insulin (adj. OR 0.87, 95 % CI 0.60-1.25), or of thiazolidinediones (adj. OR 0.71, 95 % CI 0.37-1.36). CONCLUSION In our population-based study, use of metformin was not associated with an altered risk of esophageal cancer.

Metformin and the risk of endometrial cancer: a case-control analysis

OBJECTIVE To explore the risk of endometrial cancer in relation to metformin and other antidiabetic drugs. METHODS We conducted a case-control analysis to explore the association between use of metformin and other antidiabetic drugs and the risk of endometrial cancer using the UK-based General Practice Research Database (GPRD). Cases were women with an incident diagnosis of endometrial cancer, and up to 6 controls per case were matched in age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated and results were adjusted by multivariate logistic regression analyses for BMI, smoking, a recorded diagnosis of diabetes mellitus, and diabetes duration. RESULTS A total of 2554 cases with incident endometrial cancer and 15,324 matched controls were identified. Ever use of metformin compared to never use of metformin was not associated with an altered risk of endometrial cancer (adj. OR 0.86, 95% CI 0.63-1.18). Stratified by exposure duration, neither long-term (≥25 prescriptions) use of metformin (adj. OR 0.79, 95% CI 0.54-1.17), nor long-term use of sulfonylureas (adj. OR 0.96, 95% CI 0.65-1.44), thiazolidinediones (≥15 prescriptions; adj. OR 1.22, 95% CI 0.67-2.21), or insulin (adj. OR 1.05 (0.79-1.82) was associated with the risk of endometrial cancer. CONCLUSION Use of metformin and other antidiabetic drugs were not associated with an altered risk of endometrial cancer.

LGM Summer Climate on the Southern Margin of the Laurentide Ice Sheet: Wet Or Dry?

Regional climate simulations are conducted using the Polar fifth-generation Pennsylvania State University (PSU)-NCAR Mesoscale Model (MM5) with a 60-km horizontal resolution domain over North America to explore the summer climate of the Last Glacial Maximum (LGM: 21 000 calendar years ago), when much of the continent was covered by the Laurentide Ice Sheet (LIS). Output from a tailored NCAR Community Climate Model version 3 (CCM3) simulation of the LGM climate is used to provide the initial and lateral boundary conditions for Polar MM5. LGM boundary conditions include continental ice sheets, appropriate orbital forcing, reduced CO2 concentration, paleovegetation, modified sea surface temperatures, and lowered sea level. The simulated LGM summer climate is characterized by a pronounced low-level thermal gradient along the southern margin of the LIS resulting from the juxtaposition of the cold ice sheet and adjacent warm ice-free land surface. This sharp thermal gradient anchors the midtropospheric jet stream and facilitates the development of synoptic cyclones that track over the ice sheet, some of which produce copious liquid precipitation along and south of the LIS terminus. Precipitation on the southern margin is orographically enhanced as moist southerly low-level flow (resembling a contemporary, Great Plains low-level jet configuration) in advance of the cyclone is drawn up the ice sheet slope. Composites of wet and dry periods on the LIS southern margin illustrate two distinctly different atmospheric flow regimes. Given the episodic nature of the summer rain events, it may be possible to reconcile the model depiction of wet conditions on the LIS southern margin during the LGM summer with the widely accepted interpretation of aridity across the Great Plains based on geological proxy evidence.

Polar MM5 Simulations of the Winter Climate of the Laurentide Ice Sheet at the LGM

Optimized regional climate simulations are conducted using the Polar MM5, a version of the fifth-generation Pennsylvania State University-NCAR Mesoscale Model (MM5), with a 60-km horizontal resolution domain over North America during the Last Glacial Maximum (LGM, 21 000 calendar years ago), when much of the continent was covered by the Laurentide Ice Sheet (LIS). The objective is to describe the LGM annual cycle at high spatial resolution with an emphasis on the winter atmospheric circulation. Output from a tailored NCAR Community Climate Model version 3 (CCM3) simulation of the LGM climate is used to provide the initial and lateral boundary conditions for Polar MM5. LGM boundary conditions include continental ice sheets, appropriate orbital forcing, reduced CO2 concentration, paleovegetation, modified sea surface temperatures, and lowered sea level. Polar MM5 produces a substantially different atmospheric response to the LGM boundary conditions than CCM3 and other recent GCM simulations. In particular, from November to April the upper-level flow is split around a blocking anticyclone over the LIS, with a northern branch over the Canadian Arctic and a southern branch impacting southern North America. The split flow pattern is most pronounced in January and transitions into a single, consolidated jet stream that migrates northward over the LIS during summer. Sensitivity experiments indicate that the winter split flow in Polar MM5 is primarily due to mechanical forcing by LIS, although model physics and resolution also contribute to the simulated flow configuration. Polar MM5 LGM results are generally consistent with proxy climate estimates in the western United States, Alaska, and the Canadian Arctic and may help resolve some long-standing discrepancies between proxy data and previous simulations of the LGM climate.

Relative survival is an adequate estimate of cancer-specific survival: baseline mortality-adjusted 10-year survival of 771 rectal cancer patients.

BACKGROUND The objective of the present investigation is to assess the baseline mortality-adjusted 10-year survival of rectal cancer patients. METHODS Ten-year survival was analyzed in 771 consecutive American Joint Committee on Cancer (AJCC) stage I-IV rectal cancer patients undergoing open resection between 1991 and 2008 using risk-adjusted Cox proportional hazard regression models adjusting for population-based baseline mortality. RESULTS The median follow-up of patients alive was 8.8 years. The 10-year relative, overall, and cancer-specific survival were 66.5% [95% confidence interval (CI) 61.3-72.1], 48.7% (95% CI 44.9-52.8), and 66.4% (95% CI 62.5-70.5), respectively. In the entire patient sample (stage I-IV) 47.3% and in patients with stage I-III 33.6 % of all deaths were related to rectal cancer during the 10-year period. For patients with AJCC stage I rectal cancer, the 10-year overall survival was 96% and did not significantly differ from an average population after matching for gender, age, and calendar year (p = 0.151). For the more advanced tumor stages, however, survival was significantly impaired (p < 0.001). CONCLUSIONS Retrospective investigations of survival after rectal cancer resection should adjust for baseline mortality because a large fraction of deaths is not cancer related. Stage I rectal cancer patients, compared to patients with more advanced disease stages, have a relative survival close to 100% and can thus be considered cured. Using this relative-survival approach, the real public health burden caused by rectal cancer can reliably be analyzed and reported.

Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND Treatment of patients with paediatric acute lymphoblastic leukaemia has evolved such that the risk of late effects in survivors treated in accordance with contemporary protocols could be different from that noted in those treated decades ago. We aimed to estimate the risk of late effects in children with standard-risk acute lymphoblastic leukaemia treated with contemporary protocols. METHODS We used data from similarly treated members of the Childhood Cancer Survivor Study cohort. The Childhood Cancer Survivor Study is a multicentre, North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. We included cohort members if they were aged 1·0-9·9 years at the time of diagnosis of acute lymphoblastic leukaemia and had received treatment consistent with contemporary standard-risk protocols for acute lymphoblastic leukaemia. We calculated mortality rates and standardised mortality ratios, stratified by sex and survival time, after diagnosis of acute lymphoblastic leukaemia. We calculated standardised incidence ratios and absolute excess risk for subsequent neoplasms with age-specific, sex-specific, and calendar-year-specific rates from the Surveillance, Epidemiology and End Results Program. Outcomes were compared with a sibling cohort and the general US population. FINDINGS We included 556 (13%) of 4329 cohort members treated for acute lymphoblastic leukaemia. Median follow-up of the survivors from 5 years after diagnosis was 18·4 years (range 0·0-33·0). 28 (5%) of 556 participants had died (standardised mortality ratio 3·5, 95% CI 2·3-5·0). 16 (57%) deaths were due to causes other than recurrence of acute lymphoblastic leukaemia. Six (1%) survivors developed a subsequent malignant neoplasm (standardised incidence ratio 2·6, 95% CI 1·0-5·7). 107 participants (95% CI 81-193) in each group would need to be followed-up for 1 year to observe one extra chronic health disorder in the survivor group compared with the sibling group. 415 participants (376-939) in each group would need to be followed-up for 1 year to observe one extra severe, life-threatening, or fatal disorder in the group of survivors. Survivors did not differ from siblings in their educational attainment, rate of marriage, or independent living. INTERPRETATION The prevalence of adverse long-term outcomes in children treated for standard risk acute lymphoblastic leukaemia according to contemporary protocols is low, but regular care from a knowledgeable primary-care practitioner is warranted. FUNDING National Cancer Institute, American Lebanese-Syrian Associated Charities, Swiss Cancer Research.

[Helminth control in the adult horse: the need for a re-orientation].

The epidemiological situation of strongyle infections in adult horses in Switzerland is characterized by a strong dominance of small strongyles (Cyathostominae) and an overall low level of egg shedding in the faeces. The prevailing attitude towards anthelmintic therapy considers neither husbandry conditions nor pasture hygiene measures. Instead, calendar-based routine medication, comprising usually 3 to 4 annual treatments, is the typical strategy. Such an approach, however, often results in an excessive administration of anthelmintics. With respect to the continuous spread of drug resistant cyathostomins a change of strategy seems inevitable. A consensus has been agreed on between equine parasitologists and clinicians of the Vetsuisse Faculty in Zurich and Berne to focus on the concept of a selective control approach, based on individual faecal egg counts as the central element. It is now recommended that clinically healthy horses (> 4 y) are treated only when their strongyle egg count is equal to or higher than 200 eggs per gram of faeces. A regular analysis of the strongyle population based on larval cultures, the control of drug efficacy, and quarantine measures for incoming horses are mandatory components of the concept. Recent experiences in several pilot farms have indicated that only 4 % of the McMaster analyses resulted in a deworming treatment. For horses that did not receive any nematicidal anthelmintic during the current season, a "safety" treatment is recommended at the end of the grazing period.

Incidence Rate of Kaposi Sarcoma in HIV-Infected Patients on Antiretroviral Therapy in Southern Africa: A Prospective Multicohort Study.

BACKGROUND The risk of Kaposi sarcoma (KS) among HIV-infected persons on antiretroviral therapy (ART) is not well defined in resource-limited settings. We studied KS incidence rates and associated risk factors in children and adults on ART in Southern Africa. METHODS We included patient data of 6 ART programs in Botswana, South Africa, Zambia, and Zimbabwe. We estimated KS incidence rates in patients on ART measuring time from 30 days after ART initiation to KS diagnosis, last follow-up visit, or death. We assessed risk factors (age, sex, calendar year, WHO stage, tuberculosis, and CD4 counts) using Cox models. FINDINGS We analyzed data from 173,245 patients (61% female, 8% children aged <16 years) who started ART between 2004 and 2010. Five hundred and sixty-four incident cases were diagnosed during 343,927 person-years (pys). The overall KS incidence rate was 164/100,000 pys [95% confidence interval (CI): 151 to 178]. The incidence rate was highest 30-90 days after ART initiation (413/100,000 pys; 95% CI: 342 to 497) and declined thereafter [86/100,000 pys (95% CI: 71 to 105), >2 years after ART initiation]. Male sex [adjusted hazard ratio (HR): 1.34; 95% CI: 1.12 to 1.61], low current CD4 counts (≥500 versus <50 cells/μL, adjusted HR: 0.36; 95% CI: 0.23 to 0.55), and age (5-9 years versus 30-39 years, adjusted HR: 0.20; 95% CI: 0.05 to 0.79) were relevant risk factors for developing KS. INTERPRETATION Despite ART, KS risk in HIV-infected persons in Southern Africa remains high. Early HIV testing and maintaining high CD4 counts is needed to further reduce KS-related morbidity and mortality.