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1.  Impact of Co-Infections and BCG Immunisation on Immune Responses among Household Contacts of Tuberculosis Patients in a Ugandan Cohort 
PLoS ONE  2014;9(11):e111517.
Tuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.
Adults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.
We enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.
We found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.
PMCID: PMC4221037  PMID: 25372043
2.  Improvement in Asthma Control and Inflammation in Children Undergoing Adenotonsillectomy 
Pediatric research  2013;75(3):403-408.
Observational studies suggest that asthma control improves after adenotonsillectomy, but longitudinal studies that correlate the effect of the procedure on the levels of biomarkers associated with airway inflammation are limited.
We conducted a longitudinal, observational study on pediatric patients, both with and without asthma, undergoing adenotonsillectomy. Asthma Control Test (ACT) scores and chitinase activity in the circulation were measured at time of surgery and at 6-month follow-up.
66 children with asthma and 64 control subjects were enrolled. Mean ACT scores improved by 3 points (p< 0.001) after 6 months. 85% of children with poorly-controlled asthma demonstrated an increase in ACT score of at least 3 points or a decrease in Emergency Department/Urgent Care visits, oral corticosteroid courses, or rescue short acting bronchodilator usage. Chitinase activity decreased significantly in asthmatics who improved (p< 0.01). Higher chitinase activity levels at baseline were associated with improved asthma control following surgery (p< 0.01).
In children with high pre-operative circulating chitinase activity levels, asthma control and healthcare utilization were significantly improved after adenotonsillecotmy. Chitinase activity decreased after surgery in children with improved control. This suggests that adenotonsillectomy modulates chitinase activity, affecting airway inflammation and improving airway disease.
PMCID: PMC3943680  PMID: 24452590
3.  Effect of Seasonal Variation on Adult Clinical Laboratory Parameters in Rwanda, Zambia, and Uganda: Implications for HIV Biomedical Prevention Trials 
PLoS ONE  2014;9(8):e105089.
To investigate the effect of seasonal variation on adult clinical laboratory parameters in Rwanda, Zambia, and Uganda and determine its implications for HIV prevention and other clinical trials.
Volunteers in a cross-sectional study to establish laboratory reference intervals were asked to return for a seasonal visit after the local season had changed from dry to rainy or vice versa. Volunteers had to be clinically healthy, not pregnant and negative for HIV, Hepatitis B and C, and syphilis infection at both visits. At each visit, blood was taken for measurement of hemoglobin, haematocrit, mean corpuscular volume, red blood cells, platelets, total white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, CD4/CD8 T cells, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, direct bilirubin, total bilirubin, total immunoglobulin gamma, total protein, creatinine, total amylase, creatine phosphokinase and lactate dehydrogenase (LDH). Consensus dry season reference intervals were applied to rainy season values (and vice versa) and the proportion of ‘out-of-range’ values determined. Percentage differences between dry and rainy season parameter mean values were estimated.
In this cohort of 903 volunteers, less than 10.0% of consensus parameter (except LDH) values in one season were “out-of-range” in the other. Twenty-two (22) percent of rainy season LDH values fell outside of the consensus dry season interval with the higher values observed in the rainy season. Variability between consensus seasonal means ranged from 0.0% (total WBC, neutrophils, monocytes, basophils, and direct bilirubin) to 40.0% (eosinophils). Within sites, the largest seasonal variations were observed for monocytes (Masaka, 11.5%), LDH (Lusaka, 21.7%), and basophils (Kigali, 22.2%).
Seasonality had minimal impact on adult clinical laboratory parameter values in Rwanda, Zambia, and Uganda. Seasonal variation may not be an important factor in the evaluation of adult clinical laboratory parameters in HIV prevention and other clinical trials in these countries.
PMCID: PMC4132051  PMID: 25118593
4.  Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53* 
Biochemical pharmacology  2013;85(8):1057-1065.
Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease.
PMCID: PMC3604153  PMID: 23353700
colorectal cancer; ceramide; C6-ceramide; tamoxifen; P-glycoprotein; p53
5.  Treatment Outcomes of New Tuberculosis Patients Hospitalized in Kampala, Uganda: A Prospective Cohort Study 
PLoS ONE  2014;9(3):e90614.
In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda
Methods and findings
Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 – 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 – 4.01, P = 0.045).
Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART.
PMCID: PMC3948371  PMID: 24608875
7.  Comparison of Methods for Correction of Mortality Estimates for Loss to Follow-Up after ART Initiation: A Case of the Infectious Diseases Institute, Uganda 
PLoS ONE  2013;8(12):e83524.
In sub-Saharan Africa, a large proportion of HIV positive patients on antiretroviral therapy (ART) are lost to follow-up, some of whom are dead. The objective of this study was to validate methods used to correct mortality estimates for loss-to-follow-up using a cohort with complete death ascertainment.
Routinely collected data from HIV patients initiating first line antiretroviral therapy (ART) at the Infectious Diseases Institute (IDI) (Routine Cohort) was used. Three methods to estimate mortality after initiation were: 1) standard Kaplan-Meier estimation (uncorrected method) that uses passively observed data; 2) double-sampling methods by Frangakis and Rubin (F&R) where deaths obtained from patient tracing studies are given a higher weight than those passively ascertained; 3) Nomogram proposed by Egger et al. Corrected mortality estimates in the Routine Cohort, were compared with the estimates from the IDI research observational cohort (Research Cohort), which was used as the “gold-standard”.
We included 5,633 patients from the Routine Cohort and 559 from the Research Cohort. Uncorrected mortality estimates (95% confidence interval [1]) in the Routine Cohort at 1, 2 and 3 years were 5.5% (4.9%–6.3%), 6.6% (5.9%–7.5%) and 7.4% (6.5%–8.5%), respectively. The F&R corrected estimates at 1, 2 and 3 years were 11.2% (5.8%–21.2%), 15.8% (9.9%–24.8%) and 18.5% (12.3% –27.2%) respectively. The estimates obtained from the Research Cohort were 15.6% (12.8%–18.9%), 17.5% (14.6%–21.0%) and 19.0% (15.3%–21.9%) at 1, 2 and 3 years respectively. Using the nomogram method in the Routine Cohort, the corrected programme-level mortality estimate in year 1 was 11.9% (8.0%–15.7%).
Mortality adjustments provided by the F&R and nomogram methods are adequate and should be employed to correct mortality for loss-to-follow-up in large HIV care centres in Sub-Saharan Africa.
PMCID: PMC3877043  PMID: 24391780
8.  Ceramide-antiestrogen nanoliposomal combinations – novel impact of hormonal therapy in hormone-insensitive breast cancer 
Molecular cancer therapeutics  2012;11(11):2352-2361.
Although the sphingolipid ceramide exhibits potent tumor suppressor effects, efforts to harness this have been hampered by poor solubility, uptake, bioavailability, and metabolic conversion. Therefore, identification of avenues to improve efficacy is necessary for development of ceramide-based therapies. In this study we used mutant p53, triple negative breast cancer (TNBC) cells, a type of breast cancer highly refractory to treatment, and cell-permeable nanoliposomal C6-ceramide in conjunction with the antiestrogen tamoxifen, which has been shown to be an effective modulator of ceramide metabolism. We show for the first time that nanoliposomal tamoxifen enhances nanoliposomal C6-ceramide cytotoxicity in cultured TNBC cells, a response that was accompanied by induction of cell cycle arrest at G1 and G2, caspase-dependent induction of DNA fragmentation, and enhanced mitochondrial and lysosomal membrane permeability, at 18 and 2 hr, respectively. Tamoxifen metabolites were also effective. Only tamoxifen promoted lysosomal membrane permeability. In addition, we demonstrate for the first time that tamoxifen inhibits acid ceramidase, as measured in intact cell assays; this effect was irreversible. Together, our findings show that tamoxifen magnifies the antiproliferative effects of C6-ceramide via combined targeting of cell cycle traverse and lysosomal and mitochondrial integrity. We adduce that C6-ceramide-induced apoptosis is amplified by tamoxifen's impact on lysosomes and perhaps accompanying inhibition of acid ceramidase, which could result in decreased levels of sphingosine 1-phosphate. This drug regimen could serve as a promising therapy for chemoresistant and triple negative types of breast cancer, and thus represents an indication for tamoxifen, irrespective of estrogen receptor status.
PMCID: PMC3495995  PMID: 22962326
ceramide; liposomes; breast cancer; antiestrogen; ceramidase
9.  Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging 
PLoS ONE  2013;8(9):e75111.
Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43−/− mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43−/− mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43−/− mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.
PMCID: PMC3787095  PMID: 24098680
10.  Dynamic logistic regression model and population attributable fraction to investigate the association between adherence, missed visits and mortality: a study of HIV-infected adults surviving the first year of ART 
BMC Infectious Diseases  2013;13:395.
Adherence is one of the most important determinants of viral suppression and drug resistance in HIV-infected people receiving antiretroviral therapy (ART).
We examined the association between long-term mortality and poor adherence to ART in DART trial participants in Uganda and Zimbabwe randomly assigned to receive laboratory and clinical monitoring (LCM), or clinically driven monitoring (CDM). Since over 50% of all deaths in the DART trial occurred during the first year on ART, we focussed on participants continuing ART for 12 months to investigate the implications of longer-term adherence to treatment on mortality. Participants’ ART adherence was assessed by pill counts and structured questionnaires at 4-weekly clinic visits. We studied the effect of recent adherence history on the risk of death at the individual level (odds ratios from dynamic logistic regression model), and on mortality at the population level (population attributable fraction based on this model). Analyses were conducted separately for both randomization groups, adjusted for relevant confounding factors. Adherence behaviour was also confounded by a partial factorial randomization comparing structured treatment interruptions (STI) with continuous ART (CT).
In the CDM arm a significant association was found between poor adherence to ART in the previous 3-9 months with increased mortality risk. In the LCM arm the association was not significant. The odds ratios for mortality in participants with poor adherence against those with optimal adherence was 1.30 (95% CI 0.78,2.10) in the LCM arm and 2.18 (1.47,3.22) in the CDM arm. The estimated proportions of deaths that could have been avoided with optimal adherence (population attributable fraction) in the LCM and CDM groups during the 5 years follow-up period were 16.0% (95% CI 0.7%,31.6%) and 33.1% (20.5%,44.8%), correspondingly.
Recurrent poor adherence determined even through simple measures is associated with high mortality both at individual level as well as at the ART programme level. The number of lives saved through effective interventions to improve adherence could be considerable particularly for individuals monitored without using CD4 cell counts. The findings have important implications for clinical practice and for developing interventions to enhance adherence.
PMCID: PMC3847061  PMID: 24060199
Dynamic logistic regression model; Population attributable fraction; ART; Adherence; Mortality; HIV
11.  Prevalence, comorbidity and predictors of anxiety disorders in children and adolescents in rural north-eastern Uganda 
Child and adolescent anxiety disorders are the most prevalent form of childhood psychopathology. Research on child and adolescent anxiety disorders has predominantly been done in westernized societies. There is a paucity of data on the prevalence, comorbidity, and predictors of anxiety disorders in children and adolescents in non-western societies including those in sub-Saharan Africa. This paper investigates the prevalence, comorbidity, and predictors of anxiety disorders in children and adolescents in north-eastern Uganda.
To determine the prevalence of DSM-IV anxiety disorders, as well as comorbidity patterns and predictors in children and adolescents aged 3 to 19 years in north-eastern Uganda.
Four districts (Lira, Tororo, Kaberamaido and Gulu) in rural north-eastern Uganda participated in this study. Using a multi-stage sampling procedure, a sample of 420 households with children aged 3–19 years from each district was enrolled into the study. The MINI International Neuropsychiatric Interview for children and adolescents (MINI KID) was used to assess for psychiatric disorders in 1587 of 1680 respondents.
The prevalence of anxiety disorders was 26.6%, with rates higher in females (29.7%) than in males (23.1%). The most common disorders in both males and females were specific phobia (15.8%), posttraumatic stress disorder (PTSD) (6.6%) and separation anxiety disorder (5.8%). Children below 5 years of age were significantly more likely to have separation anxiety disorder and specific phobias, while those aged between 14–19 were significantly more likely to have PTSD. Anxiety disorders were more prevalent among respondents with other psychiatric disorders; in respondents with two or more co-morbid psychiatric disorders the prevalence of anxiety disorders was 62.1%. Predictors of anxiety disorders were experience of war trauma (OR = 1.93, p < 0.001) and a higher score on the emotional symptom scale of the SDQ (OR = 2.58, p < 0.001). Significant socio-demograghic associations of anxiety disorders were found for female gender, guardian unemployment, living in permanent housing, living without parents, and having parents without education.
The prevalence of anxiety disorders in children and adolescents in rural north-eastern Uganda is high, but consistent in terms of gender ratio and progression over time with a range of prior work in other contexts. Patterns of comorbidity and predictors of anxiety disorders in this setting are also broadly consistent with previous findings from western community studies. Both psychosocial stressors and exposure to war trauma are significant predictors of anxiety disorders.Prevention and treatment strategies need to be put in place to address the high prevalence rates of anxiety disorders in children and adolescents in Uganda.
PMCID: PMC3710504  PMID: 23841918
Children; Adolescents; Anxiety disorders; Comorbidity; Predictors; Uganda
12.  Prevalence and risk factors of depression in childhood and adolescence as seen in 4 districts of north-eastern Uganda 
Millions of African children are having to grow up under harsh and adverse psychosocial conditions but it’s not fully understood how this negative psychosocial environment is affecting their mental health. This paper examines the prevalence and risk factors of depression in childhood and adolescence as seen in a community sample derived from four disadvantaged districts in north-eastern Uganda.
1587 children were assessed using a structured instrument administered by trained psychiatric nurses to collect data on psychiatric disorders (DSM IV criteria), adverse psychosocial factors and socio-demographic factors.
The point prevalence of depressive disorder syndromes (DDS) in this study was 8.6% (95% CI 7.2%–10.1%) with a point prevalence for major depressive episode of 7.6% (95% CI 6.3%–9.0%) and dysthymia of 2.1% (95% CI 1.5%–3.0%). At multiple logistic regression, the factors that were independently significantly associated with DDS were: district (representing ecological factors), nature of living arrangements, domestic violence and psychiatric co-morbidities/psychiatric problems of emotional distress (assessed by the SDQ), suicidality and marginally, anxiety disorder syndromes, eating disorder syndromes, motor disorder syndromes and behavioral and developmental disorder syndromes (the later being protective against depression).
Disadvantaged north-eastern Uganda had a high prevalence of childhood depressive disorders. Ecological factors, markers of the quality of the child-principal caregiver relationship (nature of living arrangements and domestic violence) and the presence of psychiatric co-morbidities/psychiatric problems were the important independent determinants of childhood depression in this study.
PMCID: PMC3626891  PMID: 23561039
13.  Long-term consistent use of a vaginal microbicide gel among HIV-1 sero-discordant couples in a phase III clinical trial (MDP 301) in rural south-west Uganda 
Trials  2013;14:33.
A safe and effective vaginal microbicide could substantially reduce HIV acquisition for women. Consistent gel use is, however, of great importance to ensure continued protection against HIV infection, even with a safe and effective microbicide. We assessed the long-term correlates of consistent gel use in the MDP 301 clinical trial among HIV-negative women in sero-discordant couples in south-west Uganda.
HIV-negative women living with an HIV-infected partner were enrolled between 2005 and 2008, in a three-arm phase III microbicide trial and randomized to 2% PRO2000, 0.5% PRO2000 or placebo gel arms. Follow-up visits continued up to September 2009. The 2% arm was stopped early due to futility and the 229 women enrolled in this arm were excluded from this analysis. Data were analyzed on 544 women on the 0.5% and placebo arms who completed at least 52 weeks of follow-up, sero-converted or became pregnant before 52 weeks. Consistent gel use was defined as satisfying all of the following three conditions: (i) reported gel use at the last sex act for at least 92% of the 26 scheduled visits or at least 92% of the visits attended if fewer than 26; (ii) at least one used applicator returned for each visit for which gel use was reported at the last sex act; (iii) attended at least 13 visits (unless the woman sero-converted or became pregnant during follow-up). Logistic regression models were fitted to investigate factors associated with consistent gel use.
Of the 544 women, 473 (86.9%) were followed for at least 52 weeks, 29 (5.3%) sero-converted and 42 (7.7%) became pregnant before their week 52 visit. Consistent gel use was reported by 67.8%. Women aged 25 to 34 years and those aged 35 years or older were both more than twice as likely to have reported consistently using gel compared to women aged 17 to 24 years. Living in a household with three or more rooms used for sleeping compared to one room was associated with a twofold increase in consistent gel use.
In rural Uganda younger women and women in houses with less space are likely to require additional support to achieve consistent microbicide gel use.
Trial registration
Protocol Number ISRCTN64716212
PMCID: PMC3564905  PMID: 23374729
HIV; Vaginal microbicides; Consistent gel use; Adherence; Sero-discordant couples; Phase III trial; Microbicides Development Programme (MDP)
14.  In utero and intra-partum HIV-1 transmission and acute HIV-1 infection during pregnancy: using the BED capture enzyme-immunoassay as a surrogate marker for acute infection 
Objective The BED assay was developed to estimate the proportion of recent HIV infections in a population. We used the BED assay as a proxy for acute infection to quantify the associated risk of mother-to-child-transmission (MTCT) during pregnancy and delivery.
Design A total of 3773 HIV-1 sero-positive women were tested within 96 h of delivery using the BED assay, and CD4 cell count measurements were taken. Mothers were classified according to their likelihood of having recently seroconverted.
Methods The risk of MTCT in utero and intra-partum was assessed comparing different groups defined by BED and CD4 cell count, adjusting for background factors using multinomial logistic models.
Results Compared with women with BED ≥ 0.8/CD4 ≥ 350 (typical of HIV-1 chronic patients) there was insufficient evidence to conclude that women presenting with BED < 0.8/CD4 ≥ 350 (typical of recent infections) were more likely to transmit in utero [adjusted odds ratio (aOR) = 1.37, 96% confidence interval (CI) 0.90–2.08, P = 0.14], whereas women with BED < 0.8/CD4 200–349 (possibly recently infected patients) had a 2.57 (95% CI 1.39–4.77, P-value < 0.01) odds of transmitting in utero. Women who had BED < 0.8/CD4 < 200 were most likely to transmit in utero (aOR 3.73, 95% CI 1.27–10.96, P = 0.02). BED and CD4 cell count were not predictive of intra-partum infections.
Conclusions These data provide evidence that in utero transmission of HIV might be higher among women who seroconvert during pregnancy.
PMCID: PMC3156369  PMID: 21471020
BED; CD4; in utero; intra-partum; seroconversion; HIV
15.  Mortality in an antiretroviral therapy programme in Jinja, south-east Uganda: a prospective cohort study 
There have been few reports of long-term survival of HIV-infected patients on antiretroviral therapy (ART) in Africa managed under near normal health service conditions.
Participants starting ART between February 2005 and December 2006 in The AIDS Support (TASO) clinic in Jinja, Uganda, were enrolled into a cluster-randomised trial of home versus facility-based care and followed up to January 2009. The trial was integrated into normal service delivery with patients managed by TASO staff according to national guidelines. Rates of survival, virological failure, hospital admissions and CD4 count over time were similar between the two arms. Data for the present analysis were analysed using Cox regression analyses.
1453 subjects were enrolled with baseline median count of 108 cells/μl. Over time, 119 (8%) withdrew and 34 (2%) were lost to follow-up. 197/1453 (14%) died. Mortality rates (95% CI) per 100 person-years were 11.8 (10.1, 13.8) deaths in the first year and 2.4 (1.8, 3.2) deaths thereafter. The one, two and three year survival probabilities (95% CI) were 0.89 (0.87 - 0.91), 0.86 (0.84 - 0.88) and 0.85 (0.83 - 0.87) respectively. Low baseline CD4 count, low body weight, advanced clinical condition (WHO stages III and IV), not being on cotrimoxazole prophylaxis and male gender were associated independently with increased mortality. Tuberculosis, cryptococcal meningitis and diarrhoeal disease were estimated to be major causes of death.
Practical and affordable interventions are needed to enable earlier initiation of ART and to reduce mortality risk among those who present late for treatment with advanced disease.
PMCID: PMC3210087  PMID: 22018282
Antiretroviral therapy; HIV; Africa; survival; cause of death; adult; Uganda; health care delivery
16.  Prevalence and Incidence of HIV in a Rural Community-Based HIV Vaccine Preparedness Cohort in Masaka, Uganda 
PLoS ONE  2011;6(6):e20684.
Local HIV epidemiology data are critical in determining the suitability of a population for HIV vaccine efficacy trials. The objective of this study was to estimate the prevalence and incidence of, and determine risk factors for HIV transmission in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda.
Between February and July 2004, we conducted a house-to-house HIV sero-prevalence survey among consenting individuals aged 18–60 years. Participants were interviewed, counseled and asked to provide blood for HIV testing. We then enrolled the HIV uninfected participants in a 2-year HIV sero-incidence study. Medical evaluations, HIV counseling and testing, and sample collection for laboratory analysis were done quarterly. Sexual risk behaviour data was collected every 6 months.
The HIV point prevalence was 11.2%, and was higher among women than men (12.9% vs. 8.6%, P = 0.007). Risk factors associated with prevalent HIV infection for men were age <25 years (aOR = 0.05, 95% CI 0.01–0.35) and reported genital ulcer disease in the past year (aOR = 2.17, 95% CI 1.23–3.83). Among women, being unmarried (aOR = 2.59, 95% CI 1.75–3.83) and reported genital ulcer disease in the past year (aOR = 2.40, 95% CI 1.64–3.51) were associated with prevalent HIV infection. Twenty-one seroconversions were recorded over 2025.8 person-years, an annual HIV incidence of 1.04% (95% CI: 0.68–1.59). The only significant risk factor for incident HIV infection was being unmarried (aRR = 3.44, 95% CI 1.43–8.28). Cohort retention after 2 years was 87%.
We found a high prevalence but low incidence of HIV in this cohort. HIV vaccine efficacy trials in this population may not be feasible due to the large sample sizes that would be required. HIV vaccine preparatory efforts in this setting should include identification of higher risk populations.
PMCID: PMC3108994  PMID: 21677779
17.  Beyond Testing: Empirical Models of Insurance Markets 
Annual review of economics  2010;2:311-336.
We describe recent advances in the empirical analysis of insurance markets. This new research proposes ways to estimate individual demand for insurance and the relationship between prices and insurer costs in the presence of adverse and advantageous selection. We discuss how these models permit the measurement of welfare distortions arising from asymmetric information and the welfare consequences of potential government policy responses. We also discuss some challenges in modeling imperfect competition between insurers and outline a series of open research questions.
PMCID: PMC3092551  PMID: 21572939
asymmetric information; adverse selection
18.  Effectiveness of the Standard WHO Recommended Retreatment Regimen (Category II) for Tuberculosis in Kampala, Uganda: A Prospective Cohort Study 
PLoS Medicine  2011;8(3):e1000427.
Prospective evaluation of the effectiveness of the WHO-recommended standardized retreatment regimen for tuberculosis by Edward Jones-López and colleagues reveals an unacceptable proportion of unsuccessful outcomes.
Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated.
Methods and Findings
From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrolment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0–53.4) and HIV-uninfected (14.7; 4.1–52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0–18.8) and Karnofsky score <70 (2.1; 1.1–4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1–10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0–3.5).
The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
One-third of the world's population is currently infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), and 5%–10% of HIV-uninfected individuals will go on to develop disease and become infectious. The risk of progression from infection to disease in HIV infected is much higher. If left untreated, each person with active TB may infect 10 to 15 people every year, reinforcing the public health priority of controlling TB through adequate treatment. Patients with a previous history of TB treatment are a major concern for TB programs throughout the world because these patients are at a much higher risk of harboring a form of TB that is resistant to the drugs most frequently used, resulting in poorer treatment outcomes and significantly complicating current management strategies. More then 1 million people in over 90 countries need to be “re-treated” after failing, interrupting, or relapsing from previous TB treatment.
Every year, 10%–20% of people with TB in low- and middle-income countries are started on a standardized five-drug retreatment regimen as recommended by the World Health Organization (WHO). Yet, unlike treatment regimens for newly diagnosed TB patients, the recommended retreatment regimen (also known as the category II regimen) has never been properly evaluated in randomized clinical trials or prospective cohort studies. Rather, this regimen was recommended by experts before the current situation of widespread drug-resistant TB and HIV infection.
Why Was This Study Done?
WHO surveillance data suggest that the retreatment regimen is successful in about 70% of patients, but retrospective studies that have evaluated the regimen's efficacy showed variable treatment responses with success rates ranging from 26% to 92%. However, these studies have generally only assessed outcomes at the completion of the retreatment regimen, and few have examined the risk of TB recurrence, especially in people who are also infected with HIV and so are more likely to experience TB recurrence—an issue of particular concern in sub-Saharan Africa. Therefore, in this study based in Kampala, Uganda, the researchers conducted a prospective cohort study to assess treatment and survival outcomes in patients previously treated for TB and to identify factors associated with poor outcomes. Given the overwhelming contribution of HIV infection to death, the researchers categorized their survival analysis by HIV status.
What Did the Researchers Do and Find?
The researchers recruited consecutive smear-positive TB patients who were admitted to Mulago Hospital, Kampala, Uganda, for the retreatment of TB with the standard retreatment regimen between July 2003 and January 2007. Eligible patients received daily directly observed therapy and after hospital discharge, were seen every month during their 8-month TB-retreatment course. Home health visitors assessed treatment adherence through treatment card review, monthly pill counts, and patient self-report. After the completion of the retreatment regimen, patients were evaluated for TB recurrence every 3 months for a median of 21 months. The researchers then used a statistical model to identify treatment outcomes and mortality HIV-uninfected and HIV-infected patients.
The researchers found that 29/148 (20%) of HIV-uninfected and 37/140 (26%) of HIV-infected patients had an unsuccessful treatment outcome. Factors associated with an unsuccessful treatment outcome were poor adherence, HIV infection, increasing age, and duration of TB symptoms. All patients with multidrug resistant TB, a form of TB that is resistant to the two most important drugs used to treat TB, had an unsuccessful treatment outcome. In addition, HIV-infected subjects were more likely to die than HIV-uninfected subjects (p<0.0001), and having multidrug resistant TB at enrollment was the only common risk factor for death during follow-up for both HIV-infected and HIV uninfected patients. Other risk factors for death among HIV-infected patients were CD4<50 cells/ml and no antiretroviral therapy treatment and among HIV-uninfected patients were poor adherence and duration of TB symptoms.
What Do These Findings Mean?
The researchers found that although 70%–80% of patients had a successful treatment outcome on completion of antituberculous therapy (a result that compares well with retrospective studies), the standard retreatment regimen had low treatment response rates and was associated with poor long-term outcomes in certain subgroups of patients, particularly those with multidrug resistant TB and HIV.
These findings indicate that the standard retreatment approach to TB as implemented in low- and middle-income settings is inadequate and stress the importance of a new, more effective, strategies. Improved access to rapid diagnostics for TB drug-resistance, second-line TB treatment, and antiretroviral therapy is urgently needed, along with a strong evidence base to guide clinicians and policy makers on how best to use these tools.
Additional Information
Please access these Web sites via the online version of this summary at
The World Health Organization has information on TB, TB retreatment, and multidrug-resistant TB
WHO also provides information on TB/HIV coinfection
The Stop TB Partnership provides information on the global plan to stop TB
PMCID: PMC3058098  PMID: 21423586
19.  Clustering based on adherence data 
Adherence to a medical treatment means the extent to which a patient follows the instructions or recommendations by health professionals. There are direct and indirect ways to measure adherence which have been used for clinical management and research. Typically adherence measures are monitored over a long follow-up or treatment period, and some measurements may be missing due to death or other reasons. A natural question then is how to describe adherence behavior over the whole period in a simple way. In the literature, measurements over a period are usually combined just by using averages like percentages of compliant days or percentages of doses taken. In the paper we adapt an approach where patient adherence measures are seen as a stochastic process. Repeated measures are then analyzed as a Markov chain with finite number of states rather than as independent and identically distributed observations, and the transition probabilities between the states are assumed to fully describe the behavior of a patient. The patients can then be clustered or classified using their estimated transition probabilities. These natural clusters can be used to describe the adherence of the patients, to find predictors for adherence, and to predict the future events. The new approach is illustrated and shown to be useful with a simple analysis of a data set from the DART (Development of AntiRetroviral Therapy in Africa) trial in Uganda and Zimbabwe.
PMCID: PMC3068077  PMID: 21385451
20.  War related sexual violence and it's medical and psychological consequences as seen in Kitgum, Northern Uganda: A cross-sectional study 
Despite the recent adoption of the UN resolution 1820 (2008) which calls for the cessation of war related sexual violence against civilians in conflict zones, Africa continues to see some of the worst cases of war related sexual violence including the mass sexual abuse of entire rural communities particularly in the Great Lakes region. In addition to calling for a complete halt to this abuse, there is a need for the systematic study of the reproductive, surgical and psychological effects of war related sexual violence in the African socio-cultural setting.
This paper examines the specific long term health consequences of war related sexual violence among rural women living in two internally displaced person's camps in Kitgum district in war affected Northern Uganda who accessed the services of an Isis-Women's International Cross Cultural Exchange (Isis-WICCE) medical intervention.
The study employed a purposive cross-sectional study design where 813 respondents were subjected to a structured interview as part of a screening procedure for an emergency medical intervention to identify respondents who required psychological, gynaecological and surgical treatment.
Over a quarter (28.6%) of the women (n = 573) reported having suffered at least one form of war related sexual violence. About three quarters of the respondents had 'at least one gynaecological complaint' (72.4%) and 'at least one surgical complaint' (75.6%), while 69.4% had significant psychological distress scores (scores greater than or equal to 6 on the WHO SRQ-20). The factors that were significantly associated with war related sexual violence were the age group of less than or equal to 44 years, being Catholic, having suffered other war related physical trauma, and having 'at least one gynaecological complaint'. The specific gynaecological complaints significantly associated with war related sexual violence were infertility, chronic lower abdominal pain, abnormal vaginal bleeding, and sexual dysfunction. In a multivariable analysis the age group of less than or equal to 44 years, being Catholic and having 'at least one gynaecological complaint' remained significantly associated with war related sexual violence.
The results from this study demonstrate that war related sexual violence is independently associated with the later development of specific gynaecological complaints.
PMCID: PMC2996351  PMID: 21067571
21.  Rate and Amplification of Drug Resistance among Previously-Treated Patients with Tuberculosis in Kampala, Uganda 
Drug-resistant Mycobacterium tuberculosis has emerged as a global threat. In resource-constrained settings, patients with a history of tuberculosis (TB) treatment may have drug-resistant disease and may experience poor outcomes. There is a need to measure the extent of and risk factors for drug resistance in such patients.
From July 2003 through November 2006, we enrolled 410 previously treated patients with TB in Kampala, Uganda. We measured the prevalence of resistance to first- and second-line drugs and analyzed risk factors associated with baseline and acquired drug resistance.
The prevalence of multidrug-resistant TB was 12.7% (95% confidence interval [95% CI], 9.6%–16.3%). Resistance to second-line drugs was low. Factors associated with multidrug-resistant TB at enrollment included a history of treatment failure (odds ratio, 23.6; 95% CI, 7.7–72.4), multiple previous TB episodes (odds ratio, 15.6; 95% CI, 5.0–49.1), and cavities present on chest radiograph (odds ratio, 5.9; 95% CI, 1.2–29.5). Among a cohort of 250 patients, 5.2% (95% CI, 2.8%–8.7%) were infected with M. tuberculosis that developed additional drug resistance. Amplification of drug resistance was associated with existing drug resistance at baseline (P<.01) and delayed sputum culture conversion (P<.01).
The burden of drug resistance in previously treated patients with TB in Uganda is sizeable, and the risk of generating additional drug resistance is significant. There is an urgent need to improve the treatment for such patients in low-income countries.
PMCID: PMC2883442  PMID: 18808360
22.  Differential effects of acute cocaine and placebo administration on visual cortical activation in healthy subjects measured using BOLD fMRI 
Many blood oxygenation level dependent (BOLD) functional magnetic resonance imaging studies have shown a strong response due to cocaine in brain regions with high concentrations of dopamine receptors. However, cocaine also has non-specific effects, including cardiovascular changes that may cause changes in BOLD signals, raising the possibility that measured changes could be due to these non-specific effects. The following experiment was conducted to address this concern. Subjects were given either cocaine or saline infusions during a long BOLD functional magnetic resonance imaging study. A flashing uniform-field stimulus, periodically alternating between on and off, provided a strong activation of primary visual cortex. There was a significant main effect of drug between cocaine and placebo. Although we did not demonstrate a significant drug × time interaction, BOLD signal changes associated with visual stimulation appeared unchanged after cocaine administration, whereas the signal differences appeared to decrease during placebo. Explanation of the differential response between the two groups may reflect cocaine expectancy instead of a direct effect of cocaine on BOLD signal changes but will require further investigation to fully eludicate.
PMCID: PMC2701656  PMID: 19138702
BOLD fMRI; Cocaine; Drug expectancy; Non-specific effects; Placebo; Visual stimulation
23.  Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial 
Lancet  2009;374(9707):2080-2089.
Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care.
We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per μL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0·69–1·45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at, number ISRCTN 17184129.
859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8·19 (95% CI 6·84–9·82) for home and 8·67 (6·96–10·79) for facility care (rate ratio [RR] 1·04, 0·78–1·40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0·95 [0·71–1·28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0·91, 0·64–1·28).
This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.
US Centers for Disease Control and Prevention and UK Medical Research Council.
PMCID: PMC2806484  PMID: 19939445
24.  Mortality and loss-to-follow-up during the pre-treatment period in an antiretroviral therapy programme under normal health service conditions in Uganda 
BMC Public Health  2009;9:290.
In many HIV programmes in Africa, patients are assessed clinically and prepared for antiretroviral treatment over a period of 4–12 weeks. Mortality rates following initiation of ART are very high largely because patients present late with advanced disease. The rates of mortality and retention during the pre-treatment period are not well understood. We conducted an observational study to determine these rates.
HIV-infected subjects presenting at The AIDS Support Clinic in Jinja, SE Uganda, were assessed for antiretroviral therapy (ART). Eligible subjects were given information and counselling in 3 visits done over 4–6 weeks in preparation for treatment. Those who did not complete screening were followed-up at home. Survival analysis was done using poisson regression.
4321 HIV-infected subjects were screened of whom 2483 were eligible for ART on clinical or immunological grounds. Of these, 637 (26%) did not complete screening and did not start ART. Male sex and low CD4 count were associated independently with not completing screening. At follow-up at a median 351 days, 181 (28%) had died, 189 (30%) reported that they were on ART with a different provider, 158 (25%) were alive but said they were not on ART and 109 (17%) were lost to follow-up. Death rates (95% CI) per 100 person-years were 34 (22, 55) (n.18) within one month and 37 (29, 48) (n.33) within 3 months. 70/158 (44%) subjects seen at follow-up said they had not started ART because they could not afford transport.
About a quarter of subjects eligible for ART did not complete screening and pre-treatment mortality was very high even though patients in this setting were well informed. For many families, the high cost of transport is a major barrier preventing access to ART.
PMCID: PMC2734853  PMID: 19671185
25.  Transactional sex and economic exchange with partners among young South African men in the rural Eastern Cape: prevalence, predictors, and associations with gender-based violence 
Social science & medicine (1982)  2007;65(6):1235-1248.
We explored the prevalence and predictors of transactional sex with casual partners and main girlfriends among 1,288 men aged 15-26 from 70 villages in the rural Eastern Cape province of South Africa. Data were collected through face-to-face interviews with young men enrolling in the Stepping Stones HIV prevention trial. A total of 17.7% of participants reported giving material resources or money to casual sex partners and 6.6% received resources from a casual partner. Transactionally motivated relationships with main girlfriends were more balanced between giving (14.9%) and getting (14.3%). We constructed multivariable models to identify the predictors for giving and for getting material resources in casual and in main relationships. Each model resulted in remarkably similar predictors. All four types of exchange were associated with higher socio-economic status, more adverse childhood experiences, more lifetime sexual partners, and alcohol use. Men who were more resistant to peer pressure to have sex were less likely to report transactional sex with casual partners, and men who reported more equitable gender attitudes were less likely to report main partnerships underpinned by exchange. The most consistent predictor of all four types of transaction was the perpetration of intimate partner violence and rape against women other than a main partner. The strong and consistent association between perpetration of gender-based violence and both giving and getting material goods from female partners suggests that transactional sex in both main and casual relationships can be viewed within a broader continuum of men's exercise of gendered power and control. HIV prevention interventions need to explicitly address transactional sex in the context of ideas about masculinity which place a high emphasis on heterosexual success with, and control of, women.
PMCID: PMC2709788  PMID: 17560702
South Africa; transactional sex; HIV; gender-based violence; men

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