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Find video protocols related to scientific articles indexed in Pubmed.
Low antigen-specific CD4 T-cell immune responses despite normal absolute CD4 counts after long-term antiretroviral therapy an African cohort.
Immunol. Lett.
PUBLISHED: 07-02-2014
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CD4 counts guide antiretroviral therapy (ART) initiation and prophylaxis for opportunistic infections. It is unclear whether normal CD4 counts translate to normalized immune responses among ART-treated adults. We compared antigen-specific CD4 T-cell immune responses among ART-treated adults with CD4?500cells/?l, optimal immune responders (O-IR), and their age-matched healthy HIV-negative counterparts.
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Short communication: circulating plasma HIV-1 viral protein R in dual HIV-1/tuberculosis infection.
AIDS Res. Hum. Retroviruses
PUBLISHED: 06-10-2014
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Circulating free HIV-1 viral protein R (Vpr) is found in up to one third of subjects with HIV-1 infection. Free Vpr presumably shares some of the immunopathogenic effects of cell-associated Vpr. Here we assessed Vpr in plasma and pleural fluid from HIV/tuberculosis (TB) dually infected subjects with pleural TB and from plasma of patients with pulmonary HIV/TB. Vpr was assessed by western blot analysis. In plasma from HIV/TB subjects with pulmonary TB free Vpr could be detected in 47%. Only one subject, among 26 tested, with HIV monoinfection showed plasma Vpr activity. The majority (87.5%) of patients with pleural HIV/TB demonstrated free Vpr reactivity in their plasma. However, no Vpr activity was found in autologous pleural fluid samples from pleural HIV/TB patients. Standard (s) Vpr reactivity was reduced markedly by the addition of sVpr to pleural fluid from HIV-uninfected subjects. A high incidence of plasma Vpr reactivity in HIV/TB patients implies heightened processing and release of this HIV-1 accessory protein during HIV/TB coinfection. The contribution of free Vpr to HIV-1 immunopathogenesis during HIV/TB needs to be studied.
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Two year mortality and associated factors in a cohort of children from rural Uganda.
BMC Public Health
PUBLISHED: 03-31-2014
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As part of site development for clinical trials in novel TB vaccines, a cohort of infants was enrolled in eastern Uganda to estimate the incidence of tuberculosis. The study introduced several mortality reduction strategies, and evaluated the mortality among study participants at two years. The specific of objective of this sub-study was to estimate 2 year mortality and associated factors in this community-based cohort.
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CD4 T-cell activation and reduced regulatory T-cell populations are associated with early development of cataracts among HIV-infected adults in Uganda.
Immunol. Lett.
PUBLISHED: 03-24-2014
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Cataracts contribute 12% of visual loss among HIV-infected adults in Uganda. Immuno-pathogenesis of cataracts may differ among HIV-infected individuals; thus the need for innovative therapeutic interventions among HIV-infected adults.
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What is the most reliable solid culture medium for tuberculosis treatment trials?
Tuberculosis (Edinb)
PUBLISHED: 02-25-2014
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We conducted a prospective study to determine which solid medium is the most reliable overall and after two months of therapy to detect Mycobacterium tuberculosis complex (MTB). MTB isolation and contamination rates on LJ and Middlebrook 7H10 and 7H11 agar with and without selective antibiotics were examined in a single laboratory and compared against a constructed reference standard and MGIT 960 results. Of 50 smear positive adults with pulmonary TB enrolled, 45 successfully completed standard treatment. Two spot sputum specimens were collected before treatment and at week 8 and one spot specimen each at weeks 2, 4, 6, and 12. The MTB recovery rate among all solid media for pre-treatment specimens was similar. After 8 weeks, selective (S) 7H11 had the highest positivity rate. Latent class analysis was used to construct the primary reference standard. The 98.7% sensitivity of 7H11S (95% Wilson confidence interval 96.4%-99.6%) was highest among the 5 solid media (P = 0.003 by bootstrap); the 82.6% specificity of 7H10S (95% CI 75.7%-87.8%) was highest (P = 0.098). Our results support 7H11S as the medium of choice. Further studies in different areas where recovery and contamination are likely to vary, are recommended.
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How we determined the most reliable solid medium for studying treatment of tuberculosis.
Tuberculosis (Edinb)
PUBLISHED: 02-20-2014
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Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein-Jensen (LJ) egg-base medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade. Specimens were collected every 2-4 weeks during the first 12 weeks of therapy. We compare the results for each culture to 2 composite reference standards--one that was deemed positive if any solid culture was positive for Mtb and another based on latent-class analysis. Both reference standards established that the 2 selective Middlebrook media most reliably determine the presence or absence of Mtb (P < 0.003), largely because of their lower contamination rates. We also showed that results on Middlebrook media were similar to each other, while LJ was most frequently discordant. Contaminated results appeared more likely to be truly negative than to harbor undetected Mtb.
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Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda.
BMC Infect. Dis.
PUBLISHED: 02-18-2014
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Despite sustained exposure to a person with pulmonary tuberculosis (TB), some M. tuberculosis (Mtb) exposed individuals maintain a negative tuberculin skin test (TST). Our objective was to characterize these persistently negative TST (PTST-) individuals and compare them to TST converters (TSTC) and individuals who are TST positive at study enrollment.
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High CD56++CD16- natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort.
BMC Immunol.
PUBLISHED: 01-28-2014
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Up to 40% of HIV-infected individuals receiving Highly Active Antiretroviral Therapy (HAART) have poor CD4+ T-cell recovery. The role of natural killer (NK) cells in immune recovery during HAART is not well understood. We described the profiles of NK cell subsets and their expression of activating receptor, NKG2D and cytotoxicity receptor NKp46 among suboptimal immune responders to despite four years of suppressive HAART.
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Doctoral training in Uganda: evaluation of mentoring best practices at Makerere university college of health sciences.
BMC Med Educ
PUBLISHED: 01-08-2014
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Good mentoring is a key variable for determining success in completing a doctoral program. We identified prevailing mentoring practices among doctoral students and their mentors, identified common challenges facing doctoral training, and proposed some solutions to enhance the quality of the doctoral training experience for both candidates and mentors at Makerere University College of Health Sciences (MakCHS).
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Wasting among Uganda men with pulmonary tuberculosis is associated with linear regain in lean tissue mass during and after treatment in contrast to women with wasting who regain fat tissue mass: prospective cohort study.
BMC Infect. Dis.
PUBLISHED: 01-07-2014
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Nutritional changes during and after tuberculosis treatment have not been well described. We therefore determined the effect of wasting on rate of mean change in lean tissue and fat mass as measured by bioelectrical impedance analysis (BIA), and mean change in body mass index (BMI) during and after tuberculosis treatment.
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Evaluation of Cepheid's Xpert MTB/Rif test on pleural fluid in the diagnosis of pleural tuberculosis in a high prevalence HIV/TB setting.
PLoS ONE
PUBLISHED: 01-01-2014
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Diagnosis of pleural tuberculosis (TB) using routinely available diagnostic methods is challenging due to the paucibacillary nature of the disease. Histopathology and pleural tissue TB culture involves an invasive procedure which requires expertise and appropriate equipment, both often unavailable in many health units. Xpert MTB/Rif test has been widely evaluated in sputum specimens but data on its performance in pleural TB is scarce. We evaluated the accuracy of Cepheid's Xpert MTB/Rif test on pleural fluid in the diagnosis of pleural TB in Uganda.
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Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection.
PLoS ONE
PUBLISHED: 01-01-2014
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Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.
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Contact investigation for active tuberculosis among child contacts in Uganda.
Clin. Infect. Dis.
PUBLISHED: 09-27-2013
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Background.?Tuberculosis is a large source of morbidity and mortality among children. However, limited studies characterize childhood tuberculosis disease, and contact investigation is rarely implemented in high-burden settings. In one of the largest pediatric tuberculosis contact investigation studies in a resource-limited setting, we assessed the yield of contact tracing on childhood tuberculosis and indicators for disease progression in Uganda. Methods.?Child contacts aged <15 years in Kampala, Uganda, were enrolled from July 2002 to June 2009 and evaluated for tuberculosis disease via clinical, radiographic, and laboratory methods for up to 24 months. Results.?Seven hundred sixty-one child contacts were included in the analysis. Prevalence of tuberculosis in our child population was 10%, of which 71% were culture-confirmed positive. There were no cases of disseminated tuberculosis, and 483 of 490 children (99%) started on isoniazid preventative therapy did not develop disease. Multivariable testing suggested risk factors including human immunodeficiency virus (HIV) status (odds ratio [OR], 7.90; P < .001), and baseline positive tuberculin skin test (OR, 2.21; P = .03); BCG vaccination was particularly protective, especially among children aged ?5 years (OR, 0.23; P < .001). Adult index characteristics such as sex, HIV status, and extent or severity of disease were not associated with childhood disease. Conclusions.?Contact tracing for children in high-burden settings is able to identify a large percentage of culture-confirmed positive tuberculosis cases before dissemination of disease, while suggesting factors for disease progression to identify who may benefit from targeted screening.
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Mind the gaps: a qualitative study of perceptions of healthcare professionals on challenges and proposed remedies for cervical cancer help-seeking in post conflict northern Uganda.
BMC Fam Pract
PUBLISHED: 09-13-2013
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There are limited data on perceptions of health professionals on challenges faced by cervical cancer patients seeking healthcare in the developing countries. We explored the views of operational level health professionals on perceived barriers to cervical screening and early help-seeking for symptomatic cervical cancer and the proposed remedies to the challenges.
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Modulation of the complement system in monocytes contributes to tuberculosis-associated immune reconstitution inflammatory syndrome.
AIDS
PUBLISHED: 06-29-2013
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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). This study investigated a putative contribution of monocytes to the development of TB-IRIS.
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Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort.
BMC Immunol.
PUBLISHED: 06-18-2013
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Most HIV-infected subjects exhibit a progressive rise in CD4 T-cell counts after initiation of highly active antiretroviral therapy (HAART). However, a subset of individuals exhibit very poor CD4 T-cell recovery despite effective control of HIV-RNA viraemia. We evaluated CD4 T-cell proliferation among suboptimal responders and its correlation with CD4 T-cell activation.
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Long-term dominance of Mycobacterium tuberculosis Uganda family in peri-urban Kampala-Uganda is not associated with cavitary disease.
BMC Infect. Dis.
PUBLISHED: 06-07-2013
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Previous studies have shown that Mycobacterium tuberculosis (MTB) Uganda family, a sub-lineage of the MTB Lineage 4, is the main cause of tuberculosis (TB) in Uganda. Using a well characterized patient population, this study sought to determine whether there are clinical and patient characteristics associated with the success of the MTB Uganda family in Kampala.
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Genetic and shared environmental influences on interferon-? production in response to Mycobacterium tuberculosis antigens in a Ugandan population.
Am. J. Trop. Med. Hyg.
PUBLISHED: 04-29-2013
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Interferon-? (IFN-?) is a key cytokine in the immune response to Mycobacterium tuberculosis (Mtb). Many studies established IFN-? responses are influenced by host genetics, however differed widely by the study design and heritability estimation method. We estimated heritability of IFN-? responses to Mtb culture filtrate (CF), ESAT-6, and Antigen 85B (Ag85B) in 1,104 Ugandans from a household contact study. Our method separately evaluates shared environmental and genetic variance, therefore heritability estimates were not upwardly biased, ranging from 11.6% for Ag85B to 22.9% for CF. Subset analyses of individuals with latent Mtb infection or without human immunodeficiency virus infection yielded higher heritability estimates, suggesting 10-30% of variation in IFN-? is caused by a shared environment. Immunosuppression does not negate the role of genetics on IFN-? response. These estimates are remarkably close to those reported for components of the innate immune response. These findings have implications for the interpretation of IFN-? response assays and vaccine studies.
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Vitamin D deficiency among adult patients with tuberculosis: a cross sectional study from a national referral hospital in Uganda.
BMC Res Notes
PUBLISHED: 03-21-2013
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Vitamin D deficiency has been reported among patients with tuberculosis in Africa despite abundant sunshine. Vitamin D plays a fundamental role in improving anti tuberculosis immunity, reducing progression and severity of TB in humans.
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Burden of tuberculosis disease among adolescents in a rural cohort in Eastern Uganda.
BMC Infect. Dis.
PUBLISHED: 03-14-2013
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The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12--18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents.
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Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.
J. Infect. Dis.
PUBLISHED: 03-11-2013
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Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis.
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Species and genotypic diversity of non-tuberculous mycobacteria isolated from children investigated for pulmonary tuberculosis in rural Uganda.
BMC Infect. Dis.
PUBLISHED: 02-14-2013
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Smear microscopy, a mainstay of tuberculosis (TB) diagnosis in developing countries, cannot differentiate M. tuberculosis complex from NTM infection, while pulmonary TB shares clinical signs with NTM disease, causing clinical and diagnostic dilemmas. This study used molecular assays to identify species and assess genotypic diversity of non-tuberculous mycobacteria (NTM) isolates from children investigated for pulmonary tuberculosis at a demographic surveillance site in rural eastern Uganda.
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Determinants of clinician knowledge on aging and HIV/AIDS: a survey of practitioners and policy makers in Kampala District, Uganda.
PLoS ONE
PUBLISHED: 01-17-2013
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The HIV/AIDS epidemic has evolved with an increasing burden in older adults. We assessed for knowledge about aging and HIV/AIDS, among clinicians in Kampala district, Uganda.
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Mycobacterium tuberculosis Specific CD8(+) T Cells Rapidly Decline with Antituberculosis Treatment.
PLoS ONE
PUBLISHED: 01-01-2013
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Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.
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LPS-Binding Protein and IL-6 Mark Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome in HIV Patients.
PLoS ONE
PUBLISHED: 01-01-2013
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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers.
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Clinical differences between younger and older adults with HIV/AIDS starting antiretroviral therapy in Uganda and Zimbabwe: a secondary analysis of the DART trial.
PLoS ONE
PUBLISHED: 01-01-2013
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Clinical and immunological data about HIV in older adults from low and middle income countries is scarce. We aimed to describe differences between younger and older adults with HIV starting antiretroviral therapy in two low-income African countries.
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Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.
PLoS ONE
PUBLISHED: 01-01-2013
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Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.
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Mycobacterium tuberculosis bacteremia in a cohort of HIV-infected patients hospitalized with severe sepsis in Uganda-high frequency, low clinical sand derivation of a clinical prediction score.
PLoS ONE
PUBLISHED: 01-01-2013
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When manifested as Mycobacterium tuberculosis (MTB) bacteremia, disseminated MTB infection clinically mimics other serious blood stream infections often hindering early diagnosis and initiation of potentially life-saving anti-tuberculosis therapy. In a cohort of hospitalized HIV-infected Ugandan patients with severe sepsis, we report the frequency, management and outcomes of patients with MTB bacteremia and propose a risk score based on clinical predictors of MTB bacteremia.
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CD8+ T cells provide an immunologic signature of tuberculosis in young children.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 10-27-2011
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The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis-specific CD8(+) T cells are generated in response to high bacillary loads occurring during tuberculosis.
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Urinary lipoarabinomannan as predictor for the tuberculosis immune reconstitution inflammatory syndrome.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 10-04-2011
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Upon initiation of antiretroviral therapy (ART), 15.7% [95% confidence interval (CI): 9.7% to 24.5%] of tuberculosis (TB)-HIV-coinfected individuals experience paradoxical worsening of their clinical status with exuberant inflammation consistent with immune reconstitution inflammatory syndrome (IRIS). We investigated whether a positive urinary TB lipoarabinomannan (LAM) antigen enzyme-linked immunosorbent assay test before ART initiation was associated with development of paradoxical TB-IRIS.
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Mentorship needs at academic institutions in resource-limited settings: a survey at Makerere University College of Health Sciences.
BMC Med Educ
PUBLISHED: 07-29-2011
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Mentoring is a core component of medical education and career success. There is increasing global emphasis on mentorship of young scientists in order to train and develop the next leaders in global health. However, mentoring efforts are challenged by the high clinical, research and administrative demands. We evaluated the status and nature of mentoring practices at Makerere University College of Health Sciences (MAKCHS).
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Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis.
Crit. Care Med.
PUBLISHED: 06-14-2011
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Dysglycemia during sepsis is associated with poor outcomes in resource-rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda.
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Missed opportunities for HIV testing and late-stage diagnosis among HIV-infected patients in Uganda.
PLoS ONE
PUBLISHED: 06-11-2011
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Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis.
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Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 06-10-2011
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Tuberculosis-HIV (TB-HIV) coinfection remains an important cause of mortality in antiretroviral therapy (ART) programs. In a cohort of TB-HIV-coinfected patients starting ART, we examined the incidence and predictors of early mortality.
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Autopsy acceptance rate and reasons for decline in Mulago Hospital, Kampala, Uganda.
Trop. Med. Int. Health
PUBLISHED: 05-12-2011
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To determine the autopsy acceptance rate and reasons for decline at Mulago Hospital, Kampala, Uganda.
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Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcriptional activation by the inhibitor of CDK9, Indirubin-3-monoxime.
AIDS Res. Hum. Retroviruses
PUBLISHED: 05-06-2011
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At sites of Mycobacterium tuberculosis (MTB) infection, HIV-1 replication is increased during tuberculosis (TB). Here we investigated the role of positive transcription elongation factor (P-TEFb), comprised of CycT1 and CDK9, as the cellular cofactor of HIV-1 Tat protein in transcriptional activation of HIV-1 in mononuclear cells from HIV-1-infected patients with pleural TB. Expression of CycT1 in response to MTB was assessed in mononuclear cells from pleural fluid (PFMC) and blood (PBMC) from HIV/TB patients with pleural TB, and in blood monocytes (MN) from singly infected HIV-1-seropositive subjects. We then examined whether the CDK9 inhibitor, Indirubin 3-monoxime (IM), was effective in inhibition of MTB-induced HIV-1 mRNA expression. We found higher expression of CycT1 mRNA in PFMCs as compared to PBMCs from HIV/TB-coinfected subjects. MTB induced the expression of CycT1 and HIV-1 gag/pol mRNA in both PFMCs from HIV/TB subjects and MN from HIV-1-infected subjects. CycT1 protein was also induced by MTB stimulation in PFMCs from HIV/TB patients, and both MN and in vitro-derived macrophages. Inhibition of CDK9 by IM in both PFMCs from HIV/TB and MN from HIV-1-infected subjects in response to MTB led to inhibition of HIV-1 mRNA expression. These data imply that IM may be useful as an adjunctive therapy in control of HIV-1 replication in HIV/TB dually infected subjects.
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Effects of antiretroviral therapy on immune function of HIV-infected adults with pulmonary tuberculosis and CD4+ >350 cells/mm3.
J. Infect. Dis.
PUBLISHED: 03-16-2011
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Human immunodeficiency virus (HIV)-tuberculosis coinfection is associated with heightened immune activation, viral replication, and T cell dysfunction. We compared changes in T cell activation and function between patients receiving concurrent treatment for HIV-tuberculosis coinfection and those receiving treatment for tuberculosis alone.
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Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals.
Malar Res Treat
PUBLISHED: 02-14-2011
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Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemether-lumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used for HIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed.
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Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults.
Chemother Res Pract
PUBLISHED: 02-14-2011
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Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400?mg) alone or with LPV/r (400/100?mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.
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High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort.
BMC Infect. Dis.
PUBLISHED: 02-08-2011
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Antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated.
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Genetic susceptibility to tuberculosis associated with cathepsin Z haplotype in a Ugandan household contact study.
Hum. Immunol.
PUBLISHED: 01-14-2011
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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), causes 9 million new cases worldwide and 2 million deaths annually. Genetic linkage and association analyses have suggested several chromosomal regions and candidate genes involved in TB susceptibility. This study examines the association of TB disease susceptibility with a selection of biologically relevant genes on regions on chromosomes 7 (IL6 and CARD11) and 20 (CTSZ and MC3R) and fine mapping of the chromosome 7p22-p21 region identified through our genome scan. We analyzed 565 individuals from Kampala, Uganda, who were previously included in our genome-wide linkage scan. Association analyses were conducted for 1,417 single-nucleotide polymorphisms (SNP) that passed quality control. None of the candidate gene or fine mapping SNPs was significantly associated with TB susceptibility (p > 0.10). When we restricted the analysis to HIV-negative individuals, 2 SNPs on chromosome 7 were significantly associated with TB susceptibility (p < 0.05). Haplotype analyses identified a significant risk haplotype in cathepsin X (CTSZ; p = 0.0281, odds ratio = 1.5493, 95% confidence interval [1.039, 2.320]).
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Antiretroviral treatment-associated tuberculosis in a prospective cohort of HIV-infected patients starting ART.
Clin. Dev. Immunol.
PUBLISHED: 07-07-2010
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Commencement of antiretroviral treatment (ART) in severely immunosuppressed HIV-infected persons is associated with unmasking of subclinical disease. The subset of patients that are diagnosed with tuberculosis (TB) disease while on ART have been classified as ART-associated TB. Few studies have reported the incidence of ART-associated TB and unmasking TB-IRIS according to the International Network for the Study of HIV-Associated IRIS (INSHI) consensus definition. To determine the incidence and predictors of ART-associated TB, we screened 219 patients commencing ART at the Infectious Diseases Clinic in Kampala, Uganda for TB by symptoms, sputum microscopy, and chest X-rays and followed them for one year. Fourteen (6.4%) patients were diagnosed with TB during followup. Eight (3.8%) patients had ART-associated TB (incidence rate of 4.3 per 100 person years); of these, three patients fulfilled INSHI criteria for unmasking TB-associated IRIS (incidence rate of 1.6 per 100 person years). A body mass index of less than 18.5?kg/m(2) BMI (HR 5.85 95% CI 1.24-27.46, P = .025) and a C-reactive protein greater than 5?mg/L (HR 8.23 95% CI 1.36-38.33, P = .020) were risk factors for ART-associated TB at multivariate analysis. In conclusion, with systematic TB screening (including culture and chest X-ray), the incidence of ART-associated TB is relatively low in settings with high HIV and TB prevalence.
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Sero-prevalence and risk factors for hepatitis B virus infection among health care workers in a tertiary hospital in Uganda.
BMC Infect. Dis.
PUBLISHED: 06-29-2010
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Hepatitis B virus (HBV) infection is a global public health challenge. Prevalence of current hepatitis B virus infection in the general population in Uganda is about 10%. Health care workers (HCW) have an extra risk of getting infected from their workplace and yet they are not routinely vaccinated against HBV infection. This study aimed at estimating prevalence of hepatitis B virus infection and associated risk factors among health care workers in a tertiary hospital in Uganda.
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Mycobacterium tuberculosis microbiologic and clinical treatment outcomes in a randomized trial of immediate versus CD4(+)-initiated antiretroviral therapy in HIV-infected adults with a high CD4(+) cell count.
Clin. Infect. Dis.
PUBLISHED: 06-24-2010
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In a prospective randomized, controlled trial in Uganda comparing the efficacy of antiretroviral therapy during tuberculosis therapy with the efficacy of tuberculosis therapy alone in HIV-infected patients with tuberculosis who have a CD4(+) cell count >350 cells/microL, it was found that antiretroviral therapy did not accelerate microbiologic, radiographic, or clinical responses to tuberculosis therapy: 18% of participants had sputum smears positive for Mycobacterium tuberculosis after 5 months of tuberculosis therapy, despite having had negative culture results. Trial registration. ClinicalTrials.gov identifier: NCT00078247 .
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Detection of multiple strains of Mycobacterium tuberculosis using MIRU-VNTR in patients with pulmonary tuberculosis in Kampala, Uganda.
BMC Infect. Dis.
PUBLISHED: 05-12-2010
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Many studies using DNA fingerprinting to differentiate Mycobacterium tuberculosis (MTB) strains reveal single strains in cultures, suggesting that most disease is caused by infection with a single strain. However, recent studies using molecular epidemiological tools that amplify multiple targets have demonstrated simultaneous infection with multiple strains of MTB. We aimed to determine the prevalence of MTB multiple strain infections in Kampala, and the impact of these infections on clinical presentation of tuberculosis (TB) and response to treatment.
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Update on the efficacy, effectiveness and safety of artemether-lumefantrine combination therapy for treatment of uncomplicated malaria.
Ther Clin Risk Manag
PUBLISHED: 02-02-2010
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Artemether-lumefantrine is one of the artemisisnin-based combination therapies recommended for treatment of uncomplicated falciparum malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain. There are still concerns about safety and pharmacokinetics of the drug combination in children, especially infants, pregnant mothers and drug interactions with mainly non-nucleoside reverse transcriptase inhibitors and protease inhibitors used for HIV therapy.
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Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.
PLoS ONE
PUBLISHED: 01-21-2010
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Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone.
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Immunogenicity of novel DosR regulon-encoded candidate antigens of Mycobacterium tuberculosis in three high-burden populations in Africa.
Clin. Vaccine Immunol.
PUBLISHED: 06-24-2009
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Increasing knowledge about DosR regulon-encoded proteins has led us to produce novel Mycobacterium tuberculosis antigens for immunogenicity testing in human populations in three countries in Africa to which tuberculosis (TB) is endemic. A total of 131 tuberculin skin test-positive and/or ESAT-6/CFP10-positive, human immunodeficiency virus-negative adult household contacts of active pulmonary TB cases from South Africa (n = 56), The Gambia (n = 26), and Uganda (n = 49) were tested for gamma interferon responses to 7 classical and 51 DosR regulon-encoded M. tuberculosis recombinant protein antigens. ESAT-6/CFP10 fusion protein evoked responses in >75% of study participants in all three countries. Of the DosR regulon-encoded antigens tested, Rv1733c was the most commonly recognized by participants from both South Africa and Uganda and the third most commonly recognized antigen in The Gambia. The four most frequently recognized DosR regulon-encoded antigens in Uganda (Rv1733c, Rv0081, Rv1735c, and Rv1737c) included the three most immunogenic antigens in South Africa. In contrast, Rv3131 induced the highest percentage of responders in Gambian contacts (38%), compared to only 3.4% of Ugandan contacts and no South African contacts. Appreciable percentages of TB contacts with a high likelihood of latent M. tuberculosis infection responded to several novel DosR regulon-encoded M. tuberculosis proteins. In addition to significant similarities in antigen recognition profiles between the three African population groups, there were also disparities, which may stem from genetic differences between both pathogen and host populations. Our findings have implications for the selection of potential TB vaccine candidates and for determining biosignatures of latent M. tuberculosis infection, active TB disease, and protective immunity.
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Severe sepsis in two Ugandan hospitals: a prospective observational study of management and outcomes in a predominantly HIV-1 infected population.
PLoS ONE
PUBLISHED: 05-05-2009
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Sepsis likely contributes to the high burden of infectious disease morbidity and mortality in low income countries. Data regarding sepsis management in sub-Saharan Africa are limited. We conducted a prospective observational study reporting the management and outcomes of severely septic patients in two Ugandan hospitals. We describe their epidemiology, management, and clinical correlates for mortality.
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Treatment of severe sepsis with artemether-lumefantrine is associated with decreased mortality in Ugandan patients without malaria.
Am. J. Trop. Med. Hyg.
PUBLISHED: 05-02-2009
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We enrolled 382 patients at two hospitals in Uganda in a prospective observational study of severe sepsis. Because artemisinins improve survival in murine sepsis models, we performed a post hoc analysis of the association between the use of artemether-lumefantrine (A-L) and mortality in patients with or without malaria. In patients with negative malaria smears (N = 328 of 379), Kaplan-Meier curves revealed decreased combined inpatient and 30-day mortality among patients receiving A-L versus those who did not (20.6%, SE = 10.6 versus 48.8%, SE = 3.2; Log rank chi(2) = 3.93, P = 0.048). The decrease in mortality associated with A-L was maintained in the most clinically ill patients determined by Karnofsky Performance Scores
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Resurrecting the triple threat: academic social responsibility in the context of global health research.
Clin. Infect. Dis.
PUBLISHED: 04-17-2009
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As a result of the pandemic of human immunodeficiency virus infection, more academic physicians involved in research are working in resource-limited settings, especially in the field of infectious diseases. These researchers are often located in close proximity to health care facilities with serious workforce shortages. Because institutions and funders support global health research, they have the opportunity to make a lasting impact on the health system by training local health workers where the research is being conducted. Academic researchers who spend clinical time in local health care centers and who teach and mentor students as part of academic social responsibility will build capacity, an investment that will yield dividends for future generations.
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Therapeutic evaluation of polyamine analogue drug candidates against Enterocytozoon bieneusi in a SCID mouse model.
Antimicrob. Agents Chemother.
PUBLISHED: 03-16-2009
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Enterocytozoon bieneusi is the most common cause of chronic diarrhea in individuals with human immunodeficiency virus infection or AIDS, and there is no effective therapy. The inhibitory activities of polyamine analogues (PG-11157, PG-11158, and PG-11302) against E. bieneusi infection were evaluated in SCID mice preconditioned with anti-gamma interferon monoclonal antibody intraperitoneally (i.p.). Mice were challenged orally with 10(4) E. bieneusi spores, and groups of mice were treated orally or i.p. 14 days later for 7 days. The inhibitory activities of the drugs against infection were determined by enumerating the E. bieneusi spores in feces three times a week by an immunofluorescence assay. Immunohistochemistry staining confirmed the infection within enterocytes. Oral administration of the analogues PG-11157 (at 150 or 75 mg/kg of body weight/day) and PG-11302 (at 250 mg/kg/day) had significant inhibitory activity (96.2 to 99.6%) that was slightly better than that of fumagillin (1 mg/kg/day; 93.7%). The inhibitory activity with i.p. injection was significant only with PG-11302 at 20 mg/kg/day. While the treatments considerably reduced the levels of spore excretion, neither polyamine analogues nor fumagillin was able to completely eliminate E. bieneusi, as excretion reappeared within 7 days after the end of treatment. Drug toxicity was apparent during treatment, but it disappeared at the end of treatment. These results warrant further examination of the analogues PG-11157 and PG-11302.
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Induction of HIV type 1 expression correlates with T cell responsiveness to mycobacteria in patients coinfected with HIV type 1 and Mycobacterium tuberculosis.
AIDS Res. Hum. Retroviruses
PUBLISHED: 02-26-2009
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An in vitro mononuclear cell system to model the microenvironment of coinfection with HIV-1 and Mycobacterium tuberculosis (MTB) was developed. This cellular system was used to assess the interaction of MTB-infected monocytes and T cells from dually infected HIV-1/TB patients with pulmonary tuberculosis (TB). Subjects with higher induction of HIV-1 gag/pol mRNA expression after MTB stimulation had increased MTB-specific T cell IFN-gamma and TNF-alpha production. Lack of HIV-1 mRNA induction did not correlate with increased induction of regulatory T cells (T-reg) as measured by MTB-induced Foxp3 mRNA. HIV-1 induction did not significantly correlate with clinical parameters including plasma HIV-1 viral load or CD4(+) T cell count. These data model MTB-induced HIV-1 replication at the microenvironment of MTB reactivation/infection. The data suggest that the magnitude of MTB-specific T cell responses drives local viral pathogenesis regardless of the stage of HIV-1 disease as reflected by plasma viral load or CD4(+) T cell count.
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Genomic survey of the non-cultivatable opportunistic human pathogen, Enterocytozoon bieneusi.
PLoS Pathog.
PUBLISHED: 01-09-2009
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Enterocytozoon bieneusi is the most common microsporidian associated with human disease, particularly in the immunocompromised population. In the setting of HIV infection, it is associated with diarrhea and wasting syndrome. Like all microsporidia, E. bieneusi is an obligate, intracellular parasite, but unlike others, it is in direct contact with the host cell cytoplasm. Studies of E. bieneusi have been greatly limited due to the absence of genomic data and lack of a robust cultivation system. Here, we present the first large-scale genomic dataset for E. bieneusi. Approximately 3.86 Mb of unique sequence was generated by paired end Sanger sequencing, representing about 64% of the estimated 6 Mb genome. A total of 3,804 genes were identified in E. bieneusi, of which 1,702 encode proteins with assigned functions. Of these, 653 are homologs of Encephalitozoon cuniculi proteins. Only one E. bieneusi protein with assigned function had no E. cuniculi homolog. The shared proteins were, in general, evenly distributed among the functional categories, with the exception of a dearth of genes encoding proteins associated with pathways for fatty acid and core carbon metabolism. Short intergenic regions, high gene density, and shortened protein-coding sequences were observed in the E. bieneusi genome, all traits consistent with genomic compaction. Our findings suggest that E. bieneusi is a likely model for extreme genome reduction and host dependence.
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An Early Morning Sputum Sample Is Necessary for the Diagnosis of Pulmonary Tuberculosis, Even with More Sensitive Techniques: A Prospective Cohort Study among Adolescent TB-Suspects in Uganda.
Tuberc Res Treat
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The World Health Organization (WHO) recommends collection of two sputum samples for tuberculosis (TB) diagnosis, with at least one being an early morning (EM) using smear microscopy. It remains unclear whether this is necessary even when sputum culture is employed. Here, we determined the diagnostic yield from spot and the incremental yield from the EM sputum sample cultures among TB-suspected adolescents from rural Uganda. Sputum samples (both spot and early-morning) from 1862 adolescents were cultured by the Lowenstein-Jensen (LJ) and Mycobacterium Growth Indicator Tube (MGIT) methods. For spot samples, the diagnostic yields for TB were 19.0% and 57.1% with LJ and MGIT, respectively, whereas the incremental yields (not totals) of the early-morning sample were 9.5% and 42.9% (P < 0.001) with LJ and MGIT, respectively. Among TB-suspected adolescents in rural Uganda, the EM sputum culture has a high incremental diagnostic yield. Therefore, EM sputum in addition to spot sample culture is necessary for improved TB case detection.
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Low nutrient intake among adult women and patients with severe tuberculosis disease in Uganda: a cross-sectional study.
BMC Public Health
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Information regarding dietary nutrient intake during tuberculosis disease is lacking. We established the relationship between disease severity or wasting during pulmonary tuberculosis and nutrient intake.
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Enrichment of HIV-1 subtype AD recombinants in a Ugandan cohort of severely septic patients.
PLoS ONE
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Several population-wide HIV-1 subtype distribution studies in Uganda have evaluated relatively healthy clinic patients. Given the differences in HIV-1 disease progression based on subtype, we examined HIV-1 subtype distribution and disease outcomes among hospitalized patients with severe sepsis.
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Genetic variation in TLR genes in Ugandan and South African populations and comparison with HapMap data.
PLoS ONE
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Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts.
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Evaluation of in-house PCR for diagnosis of smear-negative pulmonary tuberculosis in Kampala, Uganda.
BMC Res Notes
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Nucleic acid amplification tests (NAATs) have offered hope for rapid diagnosis of tuberculosis (TB). However, their efficiency with smear-negative samples has not been widely studied in low income settings. Here, we evaluated in-house PCR assay for diagnosis of smear-negative TB using Lowenstein-Jensen (LJ) culture as the baseline test. Two hundred and five pulmonary TB (PTB) suspects with smear-negative sputum samples, admitted on a short stay emergency ward at Mulago Hospital in Kampala, Uganda, were enrolled. Two smear-negative sputum samples were obtained from each PTB suspect and processed simultaneously for identification of MTBC using in-house PCR and LJ culture.
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Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults.
J. Antimicrob. Chemother.
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Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drug-drug interactions between artemether/lumefantrine and efavirenz or nevirapine.
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Lean tissue mass wasting is associated with increased risk of mortality among women with pulmonary tuberculosis in urban Uganda.
Ann Epidemiol
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We assessed the impact of wasting on survival in patients with tuberculosis by using a precise height-normalized lean tissue mass index (LMI) estimated by bioelectrical impedance analysis and body mass index (BMI).
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The impact of early monitored management on survival in hospitalized adult Ugandan patients with severe sepsis: a prospective intervention study*.
Crit. Care Med.
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In sub-Saharan Africa, sepsis is an important cause of mortality. Optimal sepsis management including fluid resuscitation, early antibiotic administration, and patient monitoring is limited by lack of supplies and skilled health workers.
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Clinical spectrum, risk factors and outcome of immune reconstitution inflammatory syndrome in patients with tuberculosis-HIV coinfection.
Antivir. Ther. (Lond.)
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Here, we aimed to determine the clinical spectrum, predictors and outcomes of paradoxical tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in a resource-limited setting.
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Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.
Malar. J.
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Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.
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Innate and adaptive immune responses during acute M. tuberculosis infection in adult household contacts in Kampala, Uganda.
Am. J. Trop. Med. Hyg.
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Contacts of active pulmonary tuberculosis (TB) patients are at risk for Mycobacterium tuberculosis (MTB) infection. Because most infections are controlled, studies during MTB infection provide insight into protective immunity. We compared immune responses of adult household contacts that did and did not convert the tuberculin skin test (TST). Innate and adaptive immune responses were measured by whole blood assay. Responses of TST converters (TSTC) were compared with persistently TST negative contacts (PTST-) and contacts who were TST+ at baseline (TST+). TLR-2, TLR-4, and IFN-?R responses to IFN-? did not differ between the groups, nor did ?? T cell responses. T cell responses to MTB antigens differed markedly among TSTC, PTST-, and TST+ contacts. Thus, no differences in innate responses were found among the three household contact groups. However, adaptive T cell responses to MTB antigens did differ before and during MTB infection among PTST-, TSTC, and TST+ contacts.
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An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda.
PLoS ONE
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Information on causes of death in HIV-infected patients in Sub-Saharan Africa is mainly derived from observational cohort and verbal autopsy studies. Autopsy is the gold standard to ascertain cause of death. We conducted an autopsy study to describe and compare the clinical and autopsy causes of death and contributory findings in hospitalized HIV-infected and HIV-uninfected patients in Uganda.
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Potential for false positive HIV test results with the serial rapid HIV testing algorithm.
BMC Res Notes
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Rapid HIV tests provide same-day results and are widely used in HIV testing programs in areas with limited personnel and laboratory infrastructure. The Uganda Ministry of Health currently recommends the serial rapid testing algorithm with Determine, STAT-PAK, and Uni-Gold for diagnosis of HIV infection. Using this algorithm, individuals who test positive on Determine, negative to STAT-PAK and positive to Uni-Gold are reported as HIV positive. We conducted further testing on this subgroup of samples using qualitative DNA PCR to assess the potential for false positive tests in this situation.
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Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults.
J. Antimicrob. Chemother.
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Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir.
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