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Approximately 90% of tuberculosis (TB) cases among non-US-born persons in the United States are attributable to progression of latent TB infection to TB disease. Using survival analysis, we investigated whether birthplace is associated with time to disease progression among non-US-born persons in whom TB disease developed. We derived a Cox regression model comparing differences in time to TB diagnosis after US entry among 19 birth regions, adjusting for sex, birth year, and age at entry. After adjusting for age at entry and birth year, the median time to TB diagnosis was lowest among persons from Middle Africa, 128 months (95% CI 116-146 months) for male persons and 121 months (95% CI 108-136 months) for female persons. We found time to TB diagnosis among non-US-born persons varied by birth region, which represents a prognostic indicator for progression of latent TB infection to TB disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common cause of primary liver cancer deaths worldwide. The major risk factors for liver cancer development are cirrhosis, hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and chronic alcohol abuse. HCC displays heterogeneity in terms of biology, etiology, and epidemiology. In Southeast Asia and Africa, chronic HBV infection is a major risk factor for HCC, whereas chronic HCV infection is a risk factor for HCC in western countries and Japan. Environmental and genetic conditions also play a role in the regional and temporal variations in the incidence of HCC. In this study, we used the ESTIMATE (ESTIMATE, Estimation of stromal and immune cells in malignant tumor tissues using expression data) algorithm and the CIBERSOFT tool to analyze gene expression profiles and infiltrating immune cells in HCC between Asian and non-Asian patients. The results showed that stromal and immune scores were dependent on overall survival (OS) in non-Asian patients but not in Asian patients. Kaplan-Meier survival analysis revealed four differentially expressed genes (DEGs) that were significantly associated with OS in non-Asian patients only. CIBERSORT (CIBERSORT, Cell type identification by estimating relative subsets of known RNA transcripts) analysis indicated that the composition of infiltrating immune cells was significantly different between Asian and non-Asian patients. By parsing the subclasses of HCC, the ability to predict prognosis and guide therapeutic targets for potentially actionable HCC may be improved.

Background: Survival analyses methods (SAMs) are central to analysing time-to-event outcomes. Appropriate application and reporting of such methods are important to ensure correct interpretation of the data. In this study, we systematically review the application and reporting of SAMs in studies of tuberculosis (TB) patients in Africa. It is the first review to assess the application and reporting of SAMs in this context., Methods: Systematic review of studies involving TB patients from Africa published between January 2010 and April 2020 in English language. Studies were eligible if they reported use of SAMs. Application and reporting of SAMs were evaluated based on seven author-defined criteria., Results: Seventy-six studies were included with patient numbers ranging from 56 to 182,890. Forty-three (57%) studies involved a statistician/epidemiologist. The number of published papers per year applying SAMs increased from two in 2010 to 18 in 2019 (P = 0.004). Sample size estimation was not reported by 67 (88%) studies. A total of 22 (29%) studies did not report summary follow-up time. The survival function was commonly presented using Kaplan-Meier survival curves (n = 51, (67%) studies) and group comparisons were performed using log-rank tests (n = 44, (58%) studies). Sixty seven (91%), 3 (4.1%) and 4 (5.4%) studies reported Cox proportional hazard, competing risk and parametric survival regression models, respectively. A total of 37 (49%) studies had hierarchical clustering, of which 28 (76%) did not adjust for the clustering in the analysis. Reporting was adequate among 4.0, 1.3 and 6.6% studies for sample size estimation, plotting of survival curves and test of survival regression underlying assumptions, respectively. Forty-five (59%), 52 (68%) and 73 (96%) studies adequately reported comparison of survival curves, follow-up time and measures of effect, respectively., Conclusion: The quality of reporting survival analyses remains inadequate despite its increasing application. Because similar reporting deficiencies may be common in other diseases in low- and middle-income countries, reporting guidelines, additional training, and more capacity building are needed along with more vigilance by reviewers and journal editors.

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences ( P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.)., (Copyright © 2017 Gargano et al.)

Objectives: To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS)., Design, Setting: Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010., Subjects, Participants: 36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55-2.27)., Outcome Measures: Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation., Results: There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21-5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97-2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74-4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80-3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80-3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi's sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates., Conclusions: A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes., (© 2012 Wiley Periodicals, Inc.)

Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART., Methods and Findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF., Conclusions: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3)., Trial Registration: ClinicalTrials.gov NCT00089505.

Background: Human Immunodeficiency Virus (HIV) infection predisposes to tuberculosis (TB). We described incidence, risk factors and prognosis of TB in HIV-1 infected patients during pre (1995-1996), early (1997-1999), and late Highly Active Antiretroviral Therapy (HAART) (2000-2007) periods., Methods: We included patients from a population-based, multicenter, nationwide cohort. We calculated incidence rates (IRs) and mortality rates (MRs). Cox's regression analysis was used to estimate risk factors for TB infection with HAART initiation included as time updated variable. Kaplan-Meier was used to estimate mortality after TB., Results: Among 2,668 patients identified, 120 patients developed TB during the follow-up period. The overall IR was 8.2 cases of TB/1,000 person-years of follow-up (PYR). IRs decreased during the pre-, early and late-HAART periods (37.1/1000 PYR, 12.9/1000 PYR and 6.5/1000 PYR respectively). African and Asian origin, low CD4 cell count and heterosexual and injection drug user route of HIV transmission were risk factors for TB and start of HAART reduced the risk substantially. The overall MR in TB patients was 34.4 deaths per 1,000 PYR (95% Confidence Interval: 22.0-54.0) and was highest in the first two years after the diagnosis of TB., Conclusions: Incidence of TB still associated with conventional risk factors as country of birth, low CD4 count and route of HIV infection while HAART reduces the risk substantially. The mortality in this patient population is high in the first two years after TB diagnosis.

Background: Prostate cancer mortality rates for African-Americans are much higher than Caucasians and a similar trend is observed for prostate cancer survival. Data on recently immigrated African-descent men are lacking., Methods: Using cancer registry data from Brooklyn, NY and two countries in the Caribbean (Guyana and Trinidad and Tobago), survival rates were estimated. We also examined whether Black race or Caribbean birthplace predict prostate cancer survival among males living in the United States (US)., Results: The Caribbean cases were diagnosed at a later age than those in the US (Guyana: 74.5 years, Trinidad and Tobago: 72.4 years, Brooklyn: 65.8 years). Patients in the Caribbean had a worse 5-year survival rate compared to those in the US (41.6% vs. 84.4%) but for immigrant Caribbean-born males living in the US the 5-year survival rate was not significantly different from African-Americans (78.1%, 95% CI: 70.9-83.7% vs. 81.4%, 95% CI: 69.5-89.1%, P = 0.792). The risk of death for Caribbean-born was more than three times higher than US-born men (HR: 3.43, 95% CI: 2.17-5.44, adjusted for ethnicity, stage, and mean age of diagnosis). A mean age of diagnosis >65 years old and stage IV disease, but not ethnicity, were found to be independently associated with the risk of death., Conclusion: The survival disadvantage for Caribbean-born patients may be partly due to later diagnosis. Interventions focused on screening, education about the disease and early detection could potentially reduce cancer mortality in this population.

Object: In the setting of a developing country where preoperative imaging may be limited, the authors wished to determine whether cisternal scarring or aqueduct patency at the time of surgery was sufficiently predictive of the failure of endoscopic third ventriculostomy (ETV) to justify shunt placement at the time of the initial operation., Methods: The status of the prepontine cistern and aqueduct at the time of ventriculoscopy was prospectively recorded in 403 children in whom an ETV had been completed. Kaplan-Meier methods were used to construct survival curves. A Cox proportional hazards model was used to provide estimates of HRs for the time to ETV failure. Several independent variables were tested in a single multivariable model, including those previously shown to be associated with ETV survival, that is, age, hydrocephalus etiology, and extent of choroid plexus cauterization (CPC). In addition, intraoperative variables of particular interest were included in the analysis: status of the aqueduct at surgery (closed vs open) and status of the prepontine cistern at surgery (scarred vs clean/unscarred). Multicollinearity was not a concern since the variance inflation factors for all variables were < 2. The examination of stratified survival curves confirmed the appropriateness of the proportional hazards assumption for each variable., Results: Overall actuarial 3-year success was 57%. Consistent with previous results, age, hydrocephalus etiology, and extent of CPC were significantly associated with ETV success. A closed aqueduct and an unscarred cistern were each independently associated with significantly better ETV success (HRs of 0.66 and 0.44, respectively). The presence of cisternal scarring more than doubled the risk of ETV failure, and an open aqueduct increased the risk of failure by 50%., Conclusions: Intraoperative observations of the aqueduct and prepontine cistern are independent predictors of the risk of ETV failure and can be used to further refine outcome predictions based on age, hydrocephalus etiology, and extent of CPC. Further studies will test validity in several African centers and determine what threshold of failure risk should prompt shunt placement at the initial operation.

The fungal pathogen Neozygites floridana Weiser and Muma has been evaluated as a classical biological candidate for introduction into Africa against the invasive tomato red spider mite Tetranychus evansi Baker and Pritchard. In this study, the effect of temperature on sporulation, germination and virulence of three isolates of N. floridana collected from T. evansi in three climatically distinct regions of Brazil and Argentina was determined. Six constant temperatures of 13 degrees C, 17 degrees C, 21 degrees C, 25 degrees C, 29 degrees C and 33 degrees C were tested for their effect on the ability of the three fungal isolates to sporulate, germinate and kill the mites. Six alternating-temperature regimes of 17-13 degrees C, 21-13 degrees C, 29-13 degrees C, 33-13 degrees C, 33-23 degrees C, 33-28 degrees C under a 12h photophase were also tested to estimate virulence of the three isolates against T. evansi. The Vipos isolate discharged more conidia than isolates from Recife or Piracicaba at all temperatures and sporulation was strongly temperature dependent. Optimal sporulation rates were observed at 25 degrees C while optimal germination rates were observed at 25 degrees C and 29 degrees C. At 29 degrees C, the shortest mean survival time of T. evansi (3.16 days, 95% CI of 3.05-3.27) was observed for the isolate from Vipos, while the longest LT(50) (3.47 days, 95% CI 3.34-3.59) was observed for the isolate from Piracicaba. Mortality of mites increased as the differences between alternating day and night temperatures increased from 8 degrees C (21-13 degrees C), to 10 degrees C (33-23 degrees C), to 16 degrees C (29-13 degrees C), with smallest and highest temperature differences of 4 degrees C (17-13 degrees C) and 20 degrees C (33-13 degrees C), both producing low mortalities. The overall results suggest that the Vipos isolate is better adapted to a wider range of temperatures than the other isolates tested.

Background: Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences., Methods: Data from studies conducted in Africa and Thailand were compiled and the risk estimates of treatment failure, adjusted and unadjusted by genotyping, were derived by three methods (intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP)) and then compared., Results: 29 clinical trials (15 from Africa and 14 from Thailand) with a total of 65 treatment arms (38 from Africa and 27 from Thailand) were included in the analysis. Of the 15,409 patients enrolled, 2,637 (17.1%) had incomplete follow up for the unadjusted analysis and 4,489 (33.4%) for the adjusted analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach. In the unadjusted analyses the median difference between the ITT and mITT estimates was greater in Thai studies (11.4% [range 2.1-31.8]) compared to African Studies (1.8% [range 0-11.7]). In the adjusted analyses the median difference between PP and mITT estimates was 1.7%, but ranged from 0 to 30.9%. The discrepancy between estimates was correlated significantly with the proportion of patients with incomplete follow-up; p < 0.0001. The proportion of studies with a major difference (> 5%) between adjusted PP and mITT was 28% (16/57), with the risk difference greater in African (37% 14/38) compared to Thai studies (11% 2/19). In the African studies, a major difference in the adjusted estimates was significantly more likely in studies in high transmission sites (62% 8/13) compared to studies in moderate transmission sites (24% 6/25); p = 0.035., Conclusion: Estimates of anti-malarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived. In order to monitor temporal and spatial trends in anti-malarial efficacy, standardized analytical tools need to be applied in a transparent and systematic manner.

We analyzed data from over 4500 elephants to show that animals in European zoos have about half the median life span of conspecifics in protected populations in range countries. This discrepancy is clearest in Asian elephants; unlike African elephants in zoos, this species' infant mortality is very high (for example, twice that seen in Burmese timber camps), and its adult survivorship in zoos has not improved significantly in recent years. One risk factor for Asian zoo elephants is being moved between institutions, with early removal from the mother tending to have additional adverse effects. Another risk factor is being born into a zoo rather than being imported from the wild, with poor adult survivorship in zoo-born Asians apparently being conferred prenatally or in early infancy. We suggest stress and/or obesity as likely causes of zoo elephants' compromised survivorship.

Background: Amodiaquine is frequently used as a partner drug in combination therapy or in some setting as monotherapy, but little is known about its effects on gametocyte production and sex ratio and its potential influence on transmission in Africa. The effects of amodiaquine on sexual stage parasites and gametocyte sex ratio, and the factors associated with a male-biased sex ratio were evaluated in 612 children with uncomplicated Plasmodium falciparum malaria who were treated with amodiaquine during the period 2000 - 2006 in an endemic area., Methods: Clinical, parasitological and laboratory parameters were evaluated before treatment and during follow-up for 28-42 days, and according to standard methods. Gametocyte sex ratio was defined as the proportion of peripheral gametocytes that are male., Results: Clinical recovery from illness occurred in all children. Gametocytaemia was detected in 66 patients (11%) before treatment and in another 56 patients (9%) after treatment. Gametocyte densities were significantly higher by days 3-7 following treatment compared with pre-treatment (P < 0.0001). Overall, mean gametocyte sex ratio increased significantly during follow-up and over the study periods from 2000-2006 (P < 0.001 in both cases), but was female-biased at enrolment throughout the study periods. Absence of fever, a haematocrit < 25%, asexual parasitaemia > 20,000/microL, gametocytaemia < 18/microL, and enrolment in 2006 were associated with a male-biased sex ratio pre-treatment. Anaemia and high parasitaemia were independent predictors of gametocyte maleness 7 days post treatment., Conclusion: Amodiaquine may significantly increase gametocyte carriage, density and sex ratio, and may potentially influence transmission. It is possible that anaemia could have contributed to the increased sex ratio. These findings may have implications for malaria control efforts in Africa.