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Objective: Mild traumatic brain injury (mTBI) constitutes majority of TBI cases. A considerable portion of mTBI cases has intracranial imaging abnormalities (complicated mTBI), which pose challenges in the diagnosis and management to clinicians. Here, we aimed to evaluate the early clinical course and outcomes of pediatric complicated mTBI cases treated at a large-volume tertiary referral center. Materials and Methods: A single-center retrospective cohort study was conducted at a large-volume tertiary trauma referral center for 12-month period between 2017 and 2018. Pediatric mTBI cases with at least one of the following computed tomography (CT) findings were included a depressed skull fracture, pneumocephalus, intracranial hemorrhage, edema, or contusion. Demographic, clinical, and radiological data were collected and analyzed. Results: One hundred and twenty-four patients with complicated mTBI were identified. Falls were the leading mechanisms of trauma (71.8%). Most patients (90.3%) had a Glasgow coma score (GCS) of 15 at initial evaluation. Most frequent radiological findings on initial CT scan were epidural hematoma (EDH) (34.7%) and pneumocephalus (31.5%), followed by subdural hematoma (SDH) (19.4%), subarachnoid hemorrhage (16.9%), contusion (14.5%), and depressed skull fracture (8.1%). Radiological findings in the routine repeat CT scan were stable in 55.6% of the patients, whereas the findings progressed in 15.3% and improved in 29% of patients during this interval period (median 7 h). Neurosurgical operation was performed in 7 (5.6%) patients. Thirty-six (29%) patients were identified as having clinically important TBI (ciTBI). Average length of stay at emergency department was 9.7 ± 4.9 h, and the average length of hospital stay was 3.6 ± 2.3 days. Multivariate analysis revealed that age, GCS, pneumocephalus, depressed skull fracture, EDH, and SDH were independent predictors of ciTBI. Conclusion: Pediatric complicated mTBI is associated with higher rates of hospitalization and therefore ciTBI but relatively lower rates of need for neurosurgery. Effective decision-making tools and algorithms are needed to guide optimal management strategies of these patients.

BackgroundVisualizing and comprehending 3-dimensional (3D) neuroanatomy is challenging. Cadaver dissection is limited by low availability, high cost, and the need for specialized facilities. New technologies, including 3D rendering of neuroimaging, 3D pictures, and 3D videos, are filling this gap and facilitating learning, but they also have limitations. This proof-of-concept study explored the feasibility of combining the spatial accuracy of 3D reconstructed neuroimaging data with realistic texture and fine anatomical details from 3D photogrammetry to create high-fidelity cadaveric neurosurgical simulations.MethodsFour fixed and injected cadaver heads underwent neuroimaging. To create 3D virtual models, surfaces were rendered using magnetic resonance imaging (MRI) and computed tomography (CT) scans, and segmented anatomical structures were created. A stepwise pterional craniotomy procedure was performed with synchronous neuronavigation and photogrammetry data collection. All points acquired in 3D navigational space were imported and registered in a 3D virtual model space. A novel machine learning-assisted monocular-depth estimation tool was used to create 3D reconstructions of 2-dimensional (2D) photographs. Depth maps were converted into 3D mesh geometry, which was merged with the 3D virtual model’s brain surface anatomy to test its accuracy. Quantitative measurements were used to validate the spatial accuracy of 3D reconstructions of different techniques.ResultsSuccessful multilayered 3D virtual models were created using volumetric neuroimaging data. The monocular-depth estimation technique created qualitatively accurate 3D representations of photographs. When 2 models were merged, 63% of surface maps were perfectly matched (mean [SD] deviation 0.7 ± 1.9 mm; range −7 to 7 mm). Maximal distortions were observed at the epicenter and toward the edges of the imaged surfaces. Virtual 3D models provided accurate virtual measurements (margin of error

IntroductionSurgical clipping of superior hypophyseal artery (SHA) aneurysms is a challenging task for neurosurgeons due to their close anatomical relationships. The development of endovascular techniques and the difficulty in surgery have led to a decrease in the number of surgical procedures and thus the experience of neurosurgeons in this region. In this study, we aimed to reveal the microsurgical anatomy of the ipsilateral and contralateral approaches to SHA aneurysms and define their limitations via morphometric analyses of radiological anatomy, three-dimensional (3D) modeling, and surgical illustrations.MethodFive fixed and injected cadaver heads underwent dissections. In order to make morphometric measurements, 75 cranial MRI scans were reviewed. Cranial scans were rendered with a module and used to produce 3D models of different anatomical structures. In addition, a medical illustration was drawn that shows different sizes of aneurysms and surgical clipping approaches.ResultsFor the contralateral approach, pterional craniotomy and sylvian dissection were performed. The contralateral SHA was reached from the prechiasmatic area. The dissected SHA was approached with an aneurysm clip, and maneuverability was evaluated. For the ipsilateral approach, pterional craniotomy and sylvian dissection were performed. The ipsilateral SHA was reached by mobilizing the left optic nerve with left optic nerve unroofing and left anterior clinoidectomy. MRI measurements showed that the area of the prechiasm was 90.4 ± 36.6 mm2 (prefixed: 46.9 ± 10.4 mm2, normofixed: 84.8 ± 15.7 mm2, postfixed: 137.2 ± 19.5 mm2, p

Abstract Background Children living with HIV continue to be in urgent need of combined antiretroviral therapy (ART). Strategies to scale up and improve pediatric HIV care in resource-poor regions, especially in sub-Saharan Africa, require further research from these settings. We describe treatment outcomes in children treated in rural Uganda after 1 and 2 years of ART start. Methods Cross-sectional assessment of all children treated with ART for 12 (M12) and 24 (M24) months was performed. CD4 counts, HIV RNA levels, antiretroviral resistance patterns, and non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations were determined. Patient adherence and antiretroviral-related toxicity were assessed. Results Cohort probabilities of retention in care were 0.86 at both M12 and M24. At survey, 71 (83%, M12) and 32 (78%, M24) children remained on therapy, and 84% participated in the survey. At ART start, 39 (45%) were female; median age was 5 years. Median initial CD4 percent was 11% [IQR 9-15] in children < 5 years old (n = 12); CD4 count was 151 cells/mm3 [IQR 38-188] in those ≥ 5 years old (n = 26). At M12, median CD4 gains were 11% [IQR 10-14] in patients < 5 years old, and 206 cells/mm3 [IQR 98-348] in ≥ 5 years old. At M24, median CD4 gains were 11% [IQR 5-17] and 132 cells/mm3 [IQR 87-443], respectively. Viral suppression (< 400 copies/mL) was achieved in 59% (M12) and 33% (M24) of children. Antiretroviral resistance was found in 25% (M12) and 62% (M24) of children. Overall, 29% of patients had subtherapeutic NNRTI plasma concentrations. Conclusions After one year of therapy, satisfactory survival and immunological responses were observed, but nearly 1 in 4 children developed viral resistance and/or subtherapeutic plasma antiretroviral drug levels. Regular weight-adjustment dosing and strategies to reinforce and maintain ART adherence are essential to maximize duration of first-line therapy in children in resource-limited countries.

Abstract Background Little is known about immunovirological treatment outcomes and adherence in HIV/AIDS patients on antiretroviral therapy (ART) treated using a simplified management approach in rural areas of developing countries, or about the main factors influencing those outcomes in clinical practice. Methods Cross-sectional immunovirological, pharmacological, and adherence outcomes were evaluated in all patients alive and on fixed-dose ART combinations for 24 months, and in a random sample of those treated for 12 months. Risk factors for virological failure (>1,000 copies/ml) and subtherapeutic antiretroviral (ARV) concentrations were investigated with multiple logistic regression. Results At 12 and 24 months of ART, 72% (n = 701) and 70% (n = 369) of patients, respectively, were alive and in care. About 8% and 38% of patients, respectively, were diagnosed with immunological failure; and 75% and 72% of patients, respectively, had undetectable HIV RNA (1,000 copies/ml) were poor adherence, tuberculosis diagnosed after ART initiation, subtherapeutic NNRTI concentrations, general clinical symptoms, and lower weight than at baseline. About 14% of patients had low ARV plasma concentrations. Digestive symptoms and poor adherence to ART were risk factors for low ARV plasma concentrations. Conclusion Efforts to improve both access to care and patient management to achieve better immunological and virological outcomes on ART are necessary to maximize the duration of first-line therapy.

Abstract Background Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. Methods Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. Results Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518). Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to24.8], (ii) method 2a = 1.1% [0 to21.5], and (iii) method 2b = 0% [-38 to19.3]. The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. Conclusion The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

Objective: To determine whether a nurse-led model of care for patients with hepatitis C virus (HCV) infections can provide safe and effective diagnosis and treatment in a resource-poor setting in rural Cambodia., Methods: The nurse-led initiation pilot project was implemented by Médecins Sans Frontières in collaboration with the Cambodian health ministry in two operational districts in Battambang Province between 1 June and 30 September 2020. Nursing staff at 27 rural health centres were trained to identify signs of decompensated liver cirrhosis and to provide HCV treatment. Patients without decompensated cirrhosis or another comorbidity were initiated at health centres onto combined treatment with sofosbuvir, 400 mg/day, and daclatasvir, 60 mg/day, orally for 12 weeks. Treatment adherence and effectiveness were assessed during follow-up., Findings: Of 10 960 individuals screened, 547 had HCV viraemia (i.e. viral load ≥ 1000 IU/mL). Of the 547, 329 were eligible for treatment initiation at health centres through the pilot project. All 329 (100%) completed treatment and 310 (94%; 95% confidence interval: 91-96) achieved a sustained virological response 12 weeks post-treatment. Depending on patient subgroups, this response varied from 89% to 100%. Only two adverse events were recorded; both were determined as unrelated to treatment., Conclusion: The safety and effectiveness of direct-acting antiviral medication has previously been demonstrated. Models of HCV care now need to enable greater access for patients. The nurse-led initiation pilot project provides a model for use in other resource-poor settings to scale up national programmes., ((c) 2023 The authors; licensee World Health Organization.)

Objective: We monitored a large-scale implementation of the Simple Amplification-Based Assay semi-quantitative viral load test for HIV-1 version I (SAMBA I Viral Load = SAMBA I VL) within Médecins Sans Frontières' HIV programmes in Malawi and Uganda, to assess its performance and operational feasibility., Methods: Descriptive analysis of routine programme data between August 2013 and December 2016. The dataset included samples collected for VL monitoring and tested using SAMBA I VL in five HIV clinics in Malawi (four peripheral health centres and one district hospital), and one HIV clinic in a regional referral hospital in Uganda. SAMBA I VL was used for VL testing in patients who had been receiving ART for between 6 months and ten years, to determine whether plasma VL was above or below 1000 copies/mL of HIV-1, reflecting ART failure or efficacy. Randomly selected samples were quantified with commercial VL assays. SAMBA I instruments and test performance, site throughput, and delays in communicating results to clinicians and patients were monitored., Results: Between August 2013 and December 2016 a total of 60 889 patient samples were analysed with SAMBA I VL. Overall, 0.23% of initial SAMBA I VL results were invalid; this was reduced to 0.04% after repeating the test once. Global test failure, including instrument failure, was 1.34%. Concordance with reference quantitative testing of VL was 2620/2727, 96.0% (1338/1382, 96.8% in Malawi; 1282/1345, 95.3% in Uganda). For Chiradzulu peripheral health centres and Arua Hospital HIV clinic, where testing was performed on-site, same-day results were communicated to clinicians for between 91% and 97% of samples. Same-day clinical review was obtained for 84.7% across the whole set of samples tested., Conclusions: SAMBA I VL testing is feasible for monitoring cohorts of 1000 to 5000 ART-experienced patients. Same-day results can be used to inform rapid clinical decision-making at rural and remote health facilities, potentially reducing time available for development of resistance and conceivably helping to reduce morbidity and mortality., (© 2020 John Wiley & Sons Ltd.)

We assessed effectiveness and safety of concomitant chronic hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) and multidrug-resistant tuberculosis (MDR-TB). Of 322 MDR-TB patients (19.4% HCV), 30 were treated concomitantly (23.3% human immunodeficiency virus-positive). Overall, 76.7% achieved HCV treatment success (95.8% among tested). One patient (3.3%) experienced a serious adverse event., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

: A multicentric, retrospective case-series analysis (facility-based) in five sites across Kenya, Malawi, Mozambique, and Uganda screened HIV-positive adults for hepatitis C virus (HCV) antibodies using Oraquick rapid testing and viral confirmation (in three sites). The results reveal a substantially lower prevalence than previously reported for these countries, suggesting that targeted integration of HCV screening in African HIV programs may be more impactful than routine screening.

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia., Methods and Findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria., Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Introduction: Early diagnosis of HIV-1 infection and the prompt initiation of antiretroviral therapy are critical to achieving a reduction in the morbidity and mortality of infected infants. The Simple AMplification-Based Assay (SAMBA) HIV-1 Qual Whole Blood Test was developed specifically for early infant diagnosis and prevention of mother-to-child transmission programs implemented at the point-of-care in resource-limited settings., Methods: We have evaluated the performance of this test run on the SAMBA I semiautomated platform with fresh whole blood specimens collected from 202 adults and 745 infants in Kenya, Uganda, and Zimbabwe. Results were compared with those obtained with the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 assay as performed with fresh whole blood or dried blood spots of the same subjects, and discrepancies were resolved with alternative assays., Results: The performance of the SAMBA and CAP/CTM assays evaluated at 5 laboratories in the 3 countries was similar for both adult and infant samples. The clinical sensitivity, specificity, positive predictive value, and negative predictive value for the SAMBA test were 100%, 99.2%, 98.7%, and 100%, respectively, with adult samples, and 98.5%, 99.8%, 99.7%, and 98.8%, respectively, with infant samples., Discussion: Our data suggest that the SAMBA HIV-1 Qual Whole Blood Test would be effective for early diagnosis of HIV-1 infection in infants at point-of-care settings in sub-Saharan Africa.

Objective: To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010., Methods: Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in four sub-Saharan HIV programmes in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, programme attrition and first-line clinico-immunological failure were calculated by age group (<2, 2-4 and 5-14 years), 1 or 2 years after ART initiation, and risk factors were examined., Results: A total of 3949 children, 22.7% aged <2 years, 32.2% 2-4 years and 45.1% 5-14 years, were included. At ART initiation, 60.8% had clinical stage 3 or 4, and 46.5% severe immunosuppression. Overall mortality, attrition and 1-year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4, and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR = 0.57, 95% CI 0.42-0.77 than children aged 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR = 0.91, 95% CI 0.67-1.25 for <2 years; 1.01, 95% CI 0.83-1.23 for 2-4 years, vs. 5-14 years)., Conclusions: Good treatment outcomes were achieved during the first decade of HIV paediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child transmission programmes, and linkage to care services for early ART initiation, is needed to reduce mortality and delay treatment failure., (© 2016 John Wiley & Sons Ltd.)

Background: Understanding the factors associated with HIV drug resistance development and subsequent mortality is important to improve clinical patient management., Methods: Analysis of individual electronic health records from 4 HIV programs in Malawi, Kenya, Uganda, and Cambodia, linked to data from 5 cross-sectional virological studies conducted among patients receiving first-line antiretroviral therapy (ART) for ≥6 months. Adjusted logistic and Cox-regression models were used to identify risk factors for drug resistance and subsequent mortality., Results: A total of 2257 patients (62% women) were included. At ART initiation, median CD4 cell count was 100 cells per microliter (interquartile range, 40-165). A median of 25.1 months after therapy start, 18% of patients had ≥400 and 12.4% ≥1000 HIV RNA copies per milliliter. Of 180 patients with drug resistance data, 83.9% had major resistance(s) to nucleoside or nonnucleoside reverse transcriptase inhibitors, and 74.4% dual resistance. Resistance to nevirapine, lamivudine, and efavirenz was common, and 6% had etravirine cross-resistance. Risk factors for resistance were young age (<35 years), low CD4 cell count (<200 cells/μL), and poor treatment adherence. During 4978 person-years of follow-up after virological testing (median = 31.8 months), 57 deaths occurred [rate = 1.14/100 person-years; 95% confidence interval (CI): 0.88 to 1.48]. Mortality was higher in patients with resistance (hazard ratio = 2.08; 95% CI: 1.07 to 4.07 vs. <400 copies/mL), and older age (hazard ratio = 2.41; 95% CI: 1.24 to 4.71 for ≥43 vs. ≤34 years), and lower in those receiving ART for >30 months., Conclusions: Our findings underline the importance of optimal treatment adherence and adequate virological response monitoring and emphasize the need for resistance surveillance initiatives even in HIV programs achieving high virological suppression rates.

Objective: Little is known about the evolution of program outcomes associated with rapid expansion of antiretroviral therapy (ART) in resource-limited settings. We describe temporal trends and assess associations with mortality and loss to follow-up (LTFU) in HIV cohorts from 8 countries., Design: Multicohort study using electronic health records., Methods: Analysis included adults in 25 Médecins Sans Frontières-supported programs initiating ART between 2001 and 2011. Kaplan-Meier methods were used to describe time to death or LTFU and proportional hazards models to assess associations with individual and program factors., Results: ART programs (n = 132,334, median age 35 years, 61% female) expanded rapidly. Whereas 36-month mortality decreased from 22% to 9% over 5 years (≤2003-2008), LTFU increased from 11% to 21%. Hazard ratios (HR) of early (0-12 months) and late (12-72 months) LTFU increased over time, from 1.09 [95% confidence interval (CI): 0.83 to 1.43] and 1.04 (95% CI: 0.84 to 1.28) in 2004 to 3.29 (95% CI: 2.42 to 4.46) and 6.86 (95% CI: 4.94 to 9.53) in 2011, compared with 2001-2003. Rate of program expansion was strongly associated with increased early and late LTFU, adjusted HR (aHR) = 2.31 (95% CI: 1.78 to 3.01) and HR = 2.29 (95% CI: 1.76 to 2.99), respectively, for ≥125 vs. 0-24 patients per month. Larger program size was associated with decreased early mortality (aHR = 0.49, 95% CI: 0.31 to 0.77 for ≥20,000 vs. <500 patients) and increased early LTFU (aHR = 1.77, 95% CI: 1.04 to 3.04 for ≥20,000 vs. <500 patients)., Conclusions: As ART expands in resource-limited settings, challenges remain in improving access to ART and preventing program attrition. There is an urgent need for novel and sustainable models of care to increase long-term retention of patients.

Background: Gaining understanding of the period before antiretroviral therapy (ART) is needed to improve treatment outcomes and to reduce HIV transmission. This study describes the cascade of enrollment in HIV care, pre-ART follow-up, and predictors of mortality and lost to follow-up (LTFU) before ART initiation., Methods: We conducted a cohort study among HIV-infected adult patients not yet started on ART in 4 HIV Sub-Saharan African programs. Patient follow-up began at enrollment and ended at the earliest of death, transfer-out, ART initiation, last visit date, or 60 months postenrollment. Risk factors for death and LTFU were investigated during the periods 0-6 and 6-60 months., Results: A total of 55,789 patients (65.4% women) were included as follows: 44.2% in clinical stage 3 or 4, with median CD4 of 261 cells per microliter [interquartile range (IQR): 125-447]. Patient care started with a median of 3 days (IQR: 0-11) after HIV diagnosis, and 31,104 of 55,789 (55.8%) patients had CD4 counts performed within 1 month of enrollment. Of 47,283 patients with known ART eligibility status at enrollment, 36,969 (78.2%) patients required ART and 27,798 of 36,969 (75.7%) patients initiated therapy. Median follow-up was 2.5 months (IQR: 0.9-13.1). Mortality and LTFU rates were 3.9 per 100 person-years [95% confidence interval (CI): 3.7 to 4.1] and 28.3 per 100 person-years (95% CI: 27.8 to 28.8), respectively. Regardless of period, increased mortality and LTFU were associated with male, lower body mass index, advanced clinical stage, and lower CD4 cell count., Conclusions: Short delays between HIV testing and care enrollment were observed in our HIV programs, but delays to determine ART eligibility were long. Interventions to initiate ART earlier, specifically targeted to men, are needed to improve patient retention in Africa.

Objectives: To examine age differences in mortality and programme attrition amongst paediatric patients treated in four African HIV programmes., Methods: Longitudinal analysis of data from patients enrolled in HIV care. Two-year mortality and programme attrition rates per 1000 person-years stratified by age group (<2, 2-4 and 5-15 years) were calculated. Associations between outcomes and age and other individual-level factors were studied using multiple Cox proportional hazards (mortality) and Poisson (attrition) regression models., Results: Six thousand two hundred and sixty-one patients contributed 9500 person-years; 27.1% were aged <2 years, 30.1% were 2-4, and 42.8% were 5-14 years old. At programme entry, 45.3% were underweight and 12.6% were in clinical stage 4. The highest mortality and attrition rates (98.85 and 244.00 per 1000 person-years), and relative ratios (adjusted hazard ratio [aHR] = 1.92, 95% CI 1.56-2.37; incidence ratio [aIR] = 2.10, 95% CI 1.86-2.37, respectively, compared with the 5- to 14-year group) were observed amongst the youngest children. Increased mortality and attrition were also associated with advanced clinical stage, underweight and diagnosis of tuberculosis at programme entry., Conclusions: These results highlight the need to increase access, diagnose and provide early HIV care and to accelerate antiretroviral treatment initiation for those eligible. Adapted education and support for children and their families would also be important., (© 2013 John Wiley & Sons Ltd.)

Objectives: To identify factors influencing mortality in an HIV programme providing care to large numbers of injecting drug users (IDUs) and patients co-infected with hepatitis C (HCV)., Methods: A longitudinal analysis of monitoring data from HIV-infected adults who started antiretroviral therapy (ART) between 2003 and 2009 was performed. Mortality and programme attrition rates within 2 years of ART initiation were estimated. Associations with individual-level factors were assessed with multivariable Cox and piece-wise Cox regression., Results: A total of 1671 person-years of follow-up from 1014 individuals was analysed. Thirty-four percent of patients were women and 33% were current or ex-IDUs. 36.2% of patients (90.8% of IDUs) were co-infected with HCV. Two-year all-cause mortality rate was 5.4 per 100 person-years (95% CI, 4.4-6.7). Most HIV-related deaths occurred within 6 months of ART start (36, 67.9%), but only 5 (25.0%) non-HIV-related deaths were recorded during this period. Mortality was higher in older patients (HR = 2.50; 95% CI, 1.42-4.40 for ≥40 compared to 15-29 years), and in those with initial BMI < 18.5 kg/m(2) (HR = 3.38; 95% CI, 1.82-5.32), poor adherence to treatment (HR = 5.13; 95% CI, 2.47-10.65 during the second year of therapy), or low initial CD4 cell count (HR = 4.55; 95% CI, 1.54-13.41 for <100 compared to ≥100 cells/μl). Risk of death was not associated with IDU status (P = 0.38)., Conclusion: Increased mortality was associated with late presentation of patients. In this programme, death rates were similar regardless of injection drug exposure, supporting the notion that satisfactory treatment outcomes can be achieved when comprehensive care is provided to these patients., (© 2012 Blackwell Publishing Ltd.)

Docosahexaenoic acid (DHA), a major polyunsaturated fatty acid (PUFA) in the phospholipid fraction of the brain, is essential for normal cellular function. Neurodegenerative disorders such as Parkinson's disease (PD) often exhibit significant declines in PUFAs. The aim of this study was to observe the effects of DHA supplementation in an experimental rat model of PD created with '1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine' (MPTP). Adult male Wistar rats were divided into four groups: (1) Control; (2) DHA-treated; (3) MPTP-induced; and (4) MPTP-induced + DHA-treated. Motor activity was investigated using the 'vertical pole' and 'vertical wire' tests. The dopaminergic lesion was determined by immunohistochemical analysis for tyrosine hydroxylase (TH)-immunopositive cells in substantia nigra (SN). Immunoreactivities of Bcl-2, Akt and phosphorylated-Akt (p-Akt) in SN were evaluated by immunohistochemistry. MPTP-induced animals exhibited decreased locomotor activity, motor coordination and loss of equilibrium. Diminished Parkinsonism symptoms and decreased dopaminergic neuron death were detected in the MPTP-induced + DHA-treated group compared to the MPTP-induced group. Moderate decreases in Akt staining were found in the MPTP-induced and MPTP-induced + DHA-treated groups compared to controls. p-Akt immunoreactivity decreased dramatically in the MPTP-induced group compared to the control; however, it was increased in the MPTP-induced + DHA-treated group compared to the MPTP-induced group. The staining intensity for Bcl-2 decreased prominently in the MPTP-induced group compared to the control, while it was stronger in the MPTP-induced + DHA-treated group compared to the MPTP-induced group. In conclusion, DHA significantly protects dopaminergic neurons against cell death in an experimental PD model. Akt/p-Akt and Bcl-2 pathways are related to this protective effect of DHA in experimental PD.

Background: Ensuring long-term adherence to therapy is essential for the success of HIV treatment. As access to viral load monitoring and genotyping is poor in resource-limited settings, a simple tool to monitor adherence is needed. We assessed the relationship between an indicator based on timeliness of clinic attendance and virological response and HIV drug resistance., Methods: Data from 7 virological cross-sectional studies were pooled. An adherence indicator was calculated as the number of appointments attended with delay divided by the number of months between antiretroviral treatment (ART) initiation and date of virological testing and multiplying this by 100. Delays of 1 or more to 5 or more days were considered in turn. Multivariate random-intercept logistic regression was fitted to examine the effect on outcomes, separately for adults and children., Results: A total of 3580 adults and 253 children were included. Adults were followed for a median of 26.0 months (IQR 12.8-45.0) and attended a median of 24 visits (IQR 13-34). The 1-day delay adherence indicator was strongly associated with viral load suppression (OR 0.96, 95% CI 0.95-0.97 per unit increase), virological failure (OR 1.05, 95% CI 1.03-1.06) and HIV drug resistance (OR 1.03, 95% CI 1.01-1.05) after adjusting for initial age and CD4 count, previous ART experience, type of regimen and Tuberculosis diagnosis at start of therapy. Similar results were observed in children., Conclusion: An adherence indicator based on timeliness of clinic attendance predicts strongly both virological response and drug resistance, and could help to timely identify non-adherent patients in settings where viral load monitoring is not available.

Background: Children living with HIV continue to be in urgent need of combined antiretroviral therapy (ART). Strategies to scale up and improve pediatric HIV care in resource-poor regions, especially in sub-Saharan Africa, require further research from these settings. We describe treatment outcomes in children treated in rural Uganda after 1 and 2 years of ART start., Methods: Cross-sectional assessment of all children treated with ART for 12 (M12) and 24 (M24) months was performed. CD4 counts, HIV RNA levels, antiretroviral resistance patterns, and non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations were determined. Patient adherence and antiretroviral-related toxicity were assessed., Results: Cohort probabilities of retention in care were 0.86 at both M12 and M24. At survey, 71 (83%, M12) and 32 (78%, M24) children remained on therapy, and 84% participated in the survey. At ART start, 39 (45%) were female; median age was 5 years. Median initial CD4 percent was 11% [IQR 9-15] in children < 5 years old (n = 12); CD4 count was 151 cells/mm(3) [IQR 38-188] in those ≥ 5 years old (n = 26). At M12, median CD4 gains were 11% [IQR 10-14] in patients < 5 years old, and 206 cells/mm(3) [IQR 98-348] in ≥ 5 years old. At M24, median CD4 gains were 11% [IQR 5-17] and 132 cells/mm(3) [IQR 87-443], respectively. Viral suppression (< 400 copies/mL) was achieved in 59% (M12) and 33% (M24) of children. Antiretroviral resistance was found in 25% (M12) and 62% (M24) of children. Overall, 29% of patients had subtherapeutic NNRTI plasma concentrations., Conclusions: After one year of therapy, satisfactory survival and immunological responses were observed, but nearly 1 in 4 children developed viral resistance and/or subtherapeutic plasma antiretroviral drug levels. Regular weight-adjustment dosing and strategies to reinforce and maintain ART adherence are essential to maximize duration of first-line therapy in children in resource-limited countries.

Objectives: To report immunovirological outcomes and resistance patterns in adults treated with triple combination antiretroviral therapy (cART) for 4 years in an HIV programme of Phnom Penh, Cambodia., Methods: It is a longitudinal study and cross-sectional evaluation of adults receiving cART for 4 years. CD4 cell counts and HIV-1 RNA were quantified, and resistance patterns were determined. Drug-related toxicity was assessed by clinicians and through laboratory testing., Results: After 4 years of cART start, the cumulative probability of retention in care was 0.80 and survival among patients not lost to follow-up was 0.85. A total of 349 patients (98% of eligible) participated in the cross-sectional evaluation. Ninety per cent were receiving first-line therapy, 29% stavudine- and 58% zidovudine-containing regimens (compared with 94% and 3% at cART initiation). Ninety-three per cent of patients were clinically asymptomatic, and severe lipodystrophy and dyslipidemia were diagnosed in 7.2% and 4.0%, respectively. Good treatment adherence was reported by 83% of patients. Median CD4 T-cell count was 410 cells/μl [IQR 290-511], and 90% of patients had >200 cells/μl. Only 15 (4%) patients had detectable HIV viral load (eight had <200 CD4 cells/μl), five had thymidine analogue mutations, and nine were resistant to two drug classes. In an intention-to-treat analysis, 26.1% (95% CI 22.0-30.5) of patients had failed first-line therapy., Conclusions: In this Cambodian cohort of adults who started cART at an advanced stage of HIV disease, we observed good clinical and immunovirological outcomes and self-reported treatment adherence at 4 years of therapy., (© 2010 Blackwell Publishing Ltd.)

Background: Among people living with HIV/AIDS, nutritional support is increasingly recognized as a critical part of the essential package of care, especially for patients in sub-Saharan Africa. The objectives of the study were to evaluate the outcomes of HIV-positive malnourished adults treated with ready-to-use therapeutic food and to identify factors associated with nutrition programme failure., Methods: We present results from a retrospective cohort analysis of patients aged 15 years or older with a body mass index of less than 17 kg/m² enrolled in three HIV/AIDS care programmes in Africa between March 2006 and August 2008. Factors associated with nutrition programme failure (patients discharged uncured after six or more months of nutritional care, defaulting from nutritional care, remaining in nutritional care for six or more months, or dead) were investigated using multiple logistic regression., Results: Overall, 1340 of 8685 (15.4%) HIV-positive adults were enrolled in the nutrition programme. At admission, median body mass index was 15.8 kg/m² (IQR 14.9-16.4) and 12% received combination antiretroviral therapy (ART). After a median of four months of follow up (IQR 2.2-6.1), 524 of 1106 (47.4%) patients were considered cured. An overall total of 531 of 1106 (48.0%) patients failed nutrition therapy, 132 (11.9%) of whom died and 250 (22.6%) defaulted from care. Men (OR = 1.5, 95% CI 1.2-2.0), patients with severe malnutrition at nutrition programme enrolment (OR = 2.2, 95% CI 1.7-2.8), and those never started on ART (OR = 4.5, 95% CI 2.7-7.7 for those eligible; OR = 1.6, 95% CI 1.0-2.5 for those ineligible for ART at enrolment) were at increased risk of nutrition programme failure. Diagnosed tuberculosis at nutrition programme admission or during follow up, and presence of diarrhoeal disease or extensive candidiasis at admission, were unrelated to nutrition programme failure., Conclusions: Concomitant administration of ART and ready-to-use therapeutic food increases the chances of nutritional recovery in these high-risk patients. While adequate nutrition is necessary to treat malnourished HIV patients, development of improved strategies for the management of severely malnourished patients with HIV/AIDS are urgently needed.

Background: Cryptococcal infection is a frequent cause of mortality in Cambodian HIV-infected patients with CD4+ count ≤100 cells/µl. This study assessed the cost-effectiveness of three strategies for cryptococcosis prevention in HIV-infected patients., Methods: A MARKOV DECISION TREE WAS USED TO COMPARE THE FOLLOWING STRATEGIES AT THE TIME OF HIV DIAGNOSIS: no intervention, one time systematic serum cryptococcal antigen (CRAG) screening and treatment of positive patients, and systematic primary prophylaxis with fluconazole. The trajectory of a hypothetical cohort of HIV-infected patients with CD4+ count ≤100 cells/µl initiating care was simulated over a 1-year period (cotrimoxazole initiation at enrollment; antiretroviral therapy within 3 months). Natural history and cost data (US$ 2009) were from Cambodia. Efficacy data were from international literature., Results: In a population in which 81% of patients had a CD4+ count ≤50 cells/ µl and 19% a CD4+ count between 51-100 cells/µl, the proportion alive 1 year after enrollment was 61% (cost $ 472) with no intervention, 70% (cost $ 483) with screening, and 72% (cost $ 492) with prophylaxis. After one year of follow-up, the cost-effectiveness of screening vs. no intervention was US$ 180/life year gained (LYG). The cost-effectiveness of prophylaxis vs. screening was $ 511/LYG. The cost-effectiveness of prophylaxis vs. screening was estimated at $1538/LYG if the proportion of patients with CD4+ count ≤50 cells/µl decreased by 75%., Conclusion: In a high endemic area of cryptococcosis and HIV infection, serum CRAG screening and prophylaxis are two cost effective strategies to prevent AIDS associated cryptococcosis in patients with CD4+ count ≤100 cells/µl, at a short-term horizon, screening being more cost-effective but less effective than prophylaxis. Systematic primary prophylaxis may be preferred in patients with CD4+ below 50 cells/µl while systematic serum CRAG screening for early targeted treatment may be preferred in patients with CD4+ between 51-100 cells/µl.