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1.
NPJ Genom Med ; 6(1): 24, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741997

RESUMO

Human immunodeficiency virus (HIV) infection remains a significant public health burden globally. The role of viral co-infection in the rate of progression of HIV infection has been suggested but not empirically tested, particularly among children. We extracted and classified 42 viral species from whole-exome sequencing (WES) data of 813 HIV-infected children in Botswana and Uganda categorised as either long-term non-progressors (LTNPs) or rapid progressors (RPs). The Ugandan participants had a higher viral community diversity index compared to Batswana (p = 4.6 × 10-13), and viral sequences were more frequently detected among LTNPs than RPs (24% vs 16%; p = 0.008; OR, 1.9; 95% CI, 1.6-2.3), with Anelloviridae showing strong association with LTNP status (p = 3 × 10-4; q = 0.004, OR, 3.99; 95% CI, 1.74-10.25). This trend was still evident when stratified by country, sex, and sequencing platform, and after a logistic regression analysis adjusting for age, sex, country, and the sequencing platform (p = 0.02; q = 0.03; OR, 7.3; 95% CI, 1.6-40.5). Torque teno virus (TTV), which made up 95% of the Anelloviridae reads, has been associated with reduced immune activation. We identify an association between viral co-infection and prolonged AIDs-free survival status that may have utility as a biomarker of LTNP and could provide mechanistic insights to HIV progression in children, demonstrating the added value of interrogating off-target WES reads in cohort studies.

2.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33625351

RESUMO

Introduction. Drug resistant tuberculosis remains a worldwide problem that requires prompt diagnosis.Hypothesis/Gap statement. The WHO recommended direct, rapid Xpert MTB/RIF is prohibitively costly, therefore, there is a need to validate a rapid, affordable DST for use in low- and middle-income settings.Aim. The technical performance and time to results of a simple, direct microscopy-based slide DST (SDST) assay for diagnosis of rifampicin-resistant TB was evaluated in Uganda.Methodology. Sputum samples from 122 smear-positive re-treatment TB patients presenting to the TB treatment centre at Uganda's National Referral Hospital, Mulago, Kampala, Uganda were examined. The sputum samples were tested by the direct SDST which was compared to the indirect Lowenstein Jensen Proportion Method (LJDST) method as the gold standard. The time to results was defined as the time from DST setting to results interpretation. The results were further analysed for sensitivity and specificity as well as agreement between LJDST and SDST for rifampicin resistance determination.Results. A total of 117 smear positive sputum samples with valid results for both tests were compared. The median time to results for SDST was 14 days with an interquartile range (IQR) of 10-14 days compared to 60 days with IQR of 60-75 days for LJDST. The number for rifampicin resistance by the gold standard LJDST was 26. The SDST had a sensitivity of 96 % (95 %; CI 81-99 %) and a specificity of 97.8 % (95 %; CI 93-100 %). The Positive Predictive and Negative Predictive values for SDST were 92.3 % (95 %; CI 76.8-99 %) and 98.9 % (95 %; CI 94-100 %), respectively. The kappa agreement between SDST and LJDST was 92.3 %.Conclusion. The SDST was found to be a rapid and accurate direct test for the detection of rifampicin resistance among retreatment TB cases in low-income settings.


Assuntos
Antibióticos Antituberculose/farmacologia , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Tuberculose/diagnóstico , Adulto , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/normas , Microscopia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Sensibilidade e Especificidade , Escarro/microbiologia , Fatores de Tempo , Uganda
3.
BMC Med Genomics ; 14(1): 15, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407441

RESUMO

BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years). RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months. CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.

4.
BMC Infect Dis ; 21(1): 63, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33435896

RESUMO

BACKGROUND: Chest X-ray (CXR) interpretation remains a central component of the current World Health Organization recommendations as an adjuvant test in diagnosis of smear-negative tuberculosis (TB). With its low specificity, high maintenance and operational costs, utility of CXR in diagnosis of smear-negative TB in high HIV/TB burden settings in the Xpert MTB/RIF era remains unpredictable. We evaluated accuracy and additive value of CXR to Xpert MTB/RIF in the diagnosis of TB among HIV-positive smear-negative presumptive TB patients. METHODS: HIV co-infected presumptive TB patients were recruited from the Infectious Diseases Institute outpatient clinic and in-patient medical wards of Mulago Hospital, Uganda. CXR films were reviewed by two independent radiologists using a standardized evaluation form. CXR interpretation with regard to TB was either positive (consistent with TB) or negative (normal or unlikely TB). Sensitivity, specificity and predictive values of CXR and CXR combined with Xpert MTB/RIF for diagnosis of smear-negative TB in HIV-positive patients were calculated using sputum and/or blood mycobacterial culture as reference standard. RESULTS: Three hundred sixty-six HIV co-infected smear-negative participants (female, 63.4%; hospitalized, 68.3%) had technically interpretable CXR. Median (IQR) age was 32 (28-39) years and CD4 count 112 (23-308) cells/mm3. Overall, 22% (81/366) were positive for Mycobacterium tuberculosis (Mtb) on culture; 187/366 (51.1%) had CXR interpreted as consistent with TB, of which 55 (29.4%) had culture-confirmed TB. Sensitivity and specificity of CXR interpretation in diagnosis of culture-positive TB were 67.9% (95%CI 56.6-77.8) and 53.7% (95%CI 47.7-59.6) respectively, while Xpert MTB/RIF sensitivity and specificity were 65.4% (95%CI 54.0-75.7) and 95.8% (95%CI 92.8-97.8) respectively. Addition of CXR to Xpert MTB/RIF had overall sensitivity and specificity of 87.7% (95%CI 78.5-93.9) and 51.6% (95%CI 45.6-57.5) respectively; 86.2% (95%CI 75.3-93.5) and 48.1% (95%CI 40.7-55.6) among inpatients and 93.8% (95%CI 69.8-99.8) and 58.0% (95%CI 47.7-67.8) among outpatients respectively. CONCLUSION: In this high prevalence TB/HIV setting, CXR interpretation added sensitivity to Xpert MTB/RIF test at the expense of specificity in the diagnosis of culture-positive TB in HIV-positive individuals presenting with TB symptoms and negative smear. CXR interpretation may not add diagnostic value in settings where Xpert MTB/RIF is available as a TB diagnostic tool.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , Coinfecção/diagnóstico , HIV/isolamento & purificação , Radiografia Pulmonar de Massa/métodos , Mycobacterium tuberculosis/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Contagem de Linfócito CD4 , Coinfecção/epidemiologia , Coinfecção/virologia , Confiabilidade dos Dados , Feminino , Recursos em Saúde , Humanos , Masculino , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Uganda/epidemiologia
5.
BMC Public Health ; 20(1): 1561, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066745

RESUMO

BACKGROUND: With many medical equipment in hospitals coming in direct contact with healthcare workers, patients, technicians, cleaners and sometimes care givers, it is important to pay close attention to their capacity in harboring potentially harmful pathogens. The goal of this study was to assess the role that medical equipment may potentially play in hospital acquired infections in four public health facilities in Uganda. METHODS: A cross-sectional study was conducted from December 2017 to January 2018 in four public health facilities in Uganda. Each piece of equipment from the neonatal department, imaging department or operating theatre were swabbed at three distinct points: a location in contact with the patient, a location in contact with the user, and a remote location unlikely to be contacted by either the patient or the user. The swabs were analyzed for bacterial growth using standard microbiological methods. Seventeen bacterial isolates were randomly selected and tested for susceptibility/resistance to common antibiotics. The data collected analyzed in STATA version 14. RESULTS: A total of 192 locations on 65 equipment were swabbed, with 60.4% of these locations testing positive (116/192). Nearly nine of ten equipment (57/65) tested positive for contamination in at least one location, and two out of three equipment (67.7%) tested positive in two or more locations. Of the 116 contaminated locations 52.6% were positive for Bacillus Species, 14.7% were positive for coagulase negative staphylococcus, 12.9% (15/116) were positive for E. coli, while all other bacterial species had a pooled prevalence of 19.8%. Interestingly, 55% of the remote locations were contaminated compared to 66% of the user contacted locations and 60% of the patient contacted locations. Further, 5/17 samples were resistant to at least three of the classes of antibiotics tested including penicillin, glycylcycline, tetracycline, trimethoprim sulfamethoxazole and urinary anti-infectives. CONCLUSION: These results provides strong support for strengthening overall disinfection/sterilization practices around medical equipment use in public health facilities in Uganda. There's also need for further research to make a direct link to the bacterial isolates identified and cases of infections recorded among patients in similar settings.


Assuntos
Infecção Hospitalar/epidemiologia , Contaminação de Equipamentos/estatística & dados numéricos , Equipamentos e Provisões/microbiologia , Hospitais Públicos , Centros de Atenção Terciária , Estudos Transversais , Humanos , Uganda/epidemiologia
6.
Crit Care Med ; 48(9): e734-e743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32618701

RESUMO

OBJECTIVES: Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors. DESIGN: Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. SETTING: Mulago National Referral Hospital in Kampala, Uganda. SUBJECTS: Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, ß -0.42, 95% CI, -0.69 to -0.15, p = 0.002; children ≥ 5, ß -0.39, 95% CI, -0.67 to -0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau). CONCLUSIONS: These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.

7.
BMC Infect Dis ; 19(1): 853, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619192

RESUMO

BACKGROUND: Between January 2015 and July 2017, we investigated the frequency of carbapenem resistant Acinetobacter baumannii (CRAB) and carbapenem resistant Pseudomonas aeruginosa (CRPA) at the Mulago Hospital intensive care unit (ICU) in Kampala, Uganda. Carbapenemase production and carbapenemase gene carriage among CRAB and CRPA were determined; mobility potential of carbapenemase genes via horizontal gene transfer processes was also studied. METHODS: Clinical specimens from 9269 patients were processed for isolation of CRAB and CRPA. Drug susceptibility testing was performed with the disk diffusion method. Carriage of carbapenemase genes and class 1 integrons was determined by PCR. Conjugation experiments that involved blaVIM positive CRAB/CRPA (donors) and sodium azide resistant Escherichia coli J53 (recipient) were performed. RESULTS: The 9269 specimens processed yielded 1077 and 488 isolates of Acinetobacter baumannii and Pseudomonas aeruginosa, respectively. Of these, 2.7% (29/1077) and 7.4% (36/488) were confirmed to be CRAB and CRPA respectively, but 46 were available for analysis (21 CRAB and 25 CRPA). Majority of specimens yielding CRAB and CRPA were from the ICU (78%) while 20 and 2% were from the ENT (Ear Nose & Throat) Department and the Burns Unit, respectively. Carbapenemase assays performed with the MHT assay showed that 40 and 33% of CRPA and CRAB isolates respectively, were carbapenemase producers. Also, 72 and 48% of CRPA and CRAB isolates respectively, were metallo-beta-lactamase producers. All the carbapenemase producing isolates were multidrug resistant but susceptible to colistin. blaVIM was the most prevalent carbapenemase gene, and it was detected in all CRAB and CRPA isolates while blaOXA-23 and blaOXA-24 were detected in 29 and 24% of CRAB isolates, respectively. Co-carriage of blaOXA-23 and blaOXA-24 occurred in 14% of CRAB isolates. Moreover, 63% of the study isolates carried class 1 integrons; of these 31% successfully transferred blaVIM to E. coli J53. CONCLUSIONS: CRAB and CRPA prevalence at the Mulago Hospital ICU is relatively low but carbapenemase genes especially blaVIM and blaOXA-23 are prevalent among them. This requires strengthening of infection control practices to curb selection and transmission of these strains in the hospital.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii , Infecção Hospitalar/microbiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Resistência beta-Lactâmica , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Humanos , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Uganda , beta-Lactamases
8.
PLoS One ; 14(9): e0221644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31498808

RESUMO

BACKGROUND: Limited data existed exclusively describing Mycobacterium tuberculosis lineage 3 (MTB-L3), sub-lineages, and clinical manifestations in Kampala, Uganda. This study sought to elucidate the circulating MTB-L3 sub-lineages and their corresponding clinical phenotypes. METHOD: A total of 141 M. tuberculosis isolates were identified as M. tuberculosis lineage 3 using Single nucleotide polymorphism (SNP) marker analysis method. To ascertain the sub-lineages/sub-strains within the M. tuberculosis lineage 3, the direct repeat (DR) loci for all the isolates was examined for sub-lineage specific signatures as described in the SITVIT2 database. The infecting sub-strains were matched with patients' clinical and demographic characteristics to identify any possible association. RESULT: The data showed 3 sub-lineages circulating with CAS 1 Delhi accounting for 55% (77/141), followed by CAS 1-Kili 16% (22/141) and CAS 2/CAS 8% (12/141). Remaining isolates 21% (30/141) were unclassifiable. To explore whether the sub-lineages differ in their ability to cause increased severe disease, we used extent of lung involvement as a proxy for severe disease. Multivariable analysis showed no association between M. tuberculosis lineage 3 sub-lineages with severe disease. The risk factors associated with severe disease include having a positive smear (OR = 9.384; CI 95% = 2.603-33.835), HIV (OR = 0.316; CI 95% = 0.114-0.876), lymphadenitis (OR = 0. 171; CI 95% = 0.034-0.856) and a BCG scar (OR = 0.295; CI 95% = 0.102-0.854). CONCLUSION: In Kampala, Uganda, there are three sub-lineages of M. tuberculosis lineage 3 that cause disease of comparable severity with CAS-Dehli as the most prevalent. Having HIV, lymphadenitis, a BCG scar and a smear negative status is associated with reduced severe disease.


Assuntos
Variação Genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/fisiologia , Adulto , Genótipo , Humanos , Análise Multivariada , Fenótipo , Fatores de Risco , Tuberculose Pulmonar/microbiologia , Uganda
10.
Front Genet ; 10: 705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428136

RESUMO

Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.

11.
BMC Pulm Med ; 19(1): 124, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291943

RESUMO

BACKGROUND: Pulmonary tuberculosis is a leading cause of morbidity and mortality in developing countries. Drug resistance, a huge problem in this contagious disease, is driven by point mutations in the Mycobacterium tuberculosis genome however, their frequencies vary geographically and this affects applicability of molecular diagnostics for rapid detection of resistance. Here, we report the frequency and patterns of mutations associated with resistance to second-line anti-TB drugs in multidrug-resistant (MDR) M. tuberculosis isolates from eSwatini, Somalia and Uganda that were resistant to a second-line anti-TB drug. METHODS: The quinolone resistance determining region (QRDR) of gyrA/gyrB genes and the drug resistance associated fragment of rrs gene from 80 isolates were sequenced and investigated for presence of drug resistance mutations. Of the 80 isolates, 40 were MDR, of which 28 (70%) were resistant to a second-line anti-TB injectable drug, 18 (45%) were levofloxacin resistant while 12 (30%) were extensively drug resistant (XDR). The remaining 40 isolates were susceptible to anti-TB drugs. MIRU-VNTR analysis was performed for M/XDR isolates. RESULTS: We successfully sub-cultured 38 of the 40 M/XDR isolates. The gyrA resistance mutations (Gly88Ala/Cys/Ala, Ala90Val, Ser91Pro, Asp94Gly/Asn) and gyrB resistance mutations (Asp500His, Asn538Asp) were detected in 72.2% (13/18) and 22.2% (4/18) of the MDR and levofloxacin resistant isolates, respectively. Overall, drug resistance mutations in gyrA/gyrB QRDRs occurred in 77.8% (14/18) of the MDR and levofloxacin resistant isolates. Furthermore, drug resistance mutations a1401g and g1484 t in rrs occurred in 64.3% (18/28) of the MDR isolates resistant to a second-line anti-TB injectable drug. Drug resistance mutations were not detected in drug susceptible isolates. CONCLUSIONS: The frequency of resistance mutations to second-line anti-TB drugs in MDR-TB isolates resistant to second line anti-TB drugs from eSwatini, Somalia and Uganda is high, implying that rapid molecular tests are useful in detecting second-line anti-TB drug resistance in those countries. Relatedly, the frequency of fluoroquinolone resistance mutations in gyrB/QRDR is high relative to global estimates, and they occurred independently of gyrA/QRDR mutations implying that their absence in panels of molecular tests for detecting fluoroquinolone resistance may yield false negative results in our setting.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Mutação , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Amicacina/uso terapêutico , Antituberculosos/uso terapêutico , Capreomicina/uso terapêutico , Estudos Transversais , Essuatíni/epidemiologia , Fluoroquinolonas/uso terapêutico , Frequência do Gene , Humanos , Canamicina/uso terapêutico , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Análise de Sequência de DNA , Somália/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Uganda/epidemiologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-31171965

RESUMO

Background: Methicillin resistant Staphylococcus aureus (MRSA) strains were once confined to hospitals however, in the last 20 years MRSA infections have emerged in the community in people with no prior exposure to hospitals. Strains causing such infections were novel and referred to as community-associated MRSA (CA-MRSA). The aim of this study was to determine the MRSA carriage rate in children in eastern Uganda, and to investigate coexistence between CA-MRSA and hospital-associated (HA-MRSA). Methods: Between February and October 2011, nasopharyngeal samples (one per child) from 742 healthy children under 5 years in rural eastern Uganda were processed for isolation of MRSA, which was identified based on inhibition zone diameter of ≤19 mm on 30 µg cefoxitin disk. SCCmec and spa typing were performed for MRSA isolates. Results: A total of 140 S. aureus isolates (18.9%, 140/742) were recovered from the children of which 5.7% (42/742) were MRSA. Almost all (95.2%, 40/42) MRSA isolates were multidrug resistant (MDR). The most prevalent SCCmec elements were types IV (40.5%, 17/42) and I (38.1%, 16/42). The overall frequency of SCCmec types IV and V combined, hence CA-MRSA, was 50% (21/42). Likewise, the overall frequency of SCCmec types I, II and III combined, hence HA-MRSA, was 50% (21/42). Spa types t002, t037, t064, t4353 and t12939 were detected and the most frequent were t064 (19%, 8/42) and t037 (12%, 5/42). Conclusion: The MRSA carriage rate in children in eastern Uganda is high (5.7%) and comparable to estimates for Mulago Hospital in Kampala city. Importantly, HA-MRSA (mainly of spa type t037) and CA-MRSA (mainly of spa type t064) coexist in children in the community in eastern Uganda, and due to high proportion of MDR detected, outpatient treatment of MRSA infection in eastern Uganda might be difficult.


Assuntos
Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/epidemiologia , Antibacterianos/farmacologia , Técnicas de Tipagem Bacteriana , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Pré-Escolar , Estudos Transversais , Farmacorresistência Bacteriana Múltipla , Feminino , Genótipo , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Nasofaringe/microbiologia , População Rural , Uganda/epidemiologia
14.
Am J Trop Med Hyg ; 100(2): 386-391, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30594259

RESUMO

Understanding risk factors for tuberculosis (TB) and their prevalence helps guide early diagnosis. We determined their prevalence among bacteriologically negative and bacteriologically confirmed TB patients in five regional referral hospitals in Uganda. This cross-sectional study considered 1,862 adult presumptive TB participants. We performed fluorescent microscopy, Xpert MTB/RIF (Xpert), Lowenstein-Jensen culture, human immunodeficiency virus, and random blood sugar testing on recruited patients. Prevalence and prevalence ratios of risk factors were compared among bacteriologically negative and confirmed cases. Odds ratios and 95% confidence interval (CI) were determined for significant risk factors in bacteriologically confirmed patients. Of the 1,862 participants, 978 (55%) were male and the median age of the participants was 36 years (interquartile range: 27-48). Up to 273 (15%) had a positive result on all three TB tests. Most prevalent risk factors (prevalence ratio [PR] > 1.0) among bacteriologically negative and positive TB patients were cigarette smoking (9.3% versus 2.1%; PR = 2.1), biosmoke (24% versus 39.7%; PR = 1.7), contact (4.2% versus 6.5%; PR = 1.6), male gender (51.4% versus 72.5%; PR = 1.4), alcohol use (17.2% versus 24.4%; PR = 1.4), diabetes (0.7% versus 0.9%; PR = 1.3), and family history of TB (12.1% versus 13.7%; PR = 1.1). The risk factors and their adjusted prevalence rate ratios (95% CI) of being bacteriologically positive were male (1.8 [1.4-2.4]), biosmoke exposure (1.5 [1.2-2.0]), and history of cigarette smoking (1.6 [1.1-2.4]). Among bacteriologically confirmed patients in Uganda, cigarette smoking, biosmoke exposure, contact, male gender, alcohol use, diabetes, and family history of TB are important risk factors for TB. Interventions for TB control in people with these risk factors would help in TB control efforts.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Fumar Cigarros/fisiopatologia , Diabetes Mellitus/fisiopatologia , Infecções por HIV/epidemiologia , Lesão por Inalação de Fumaça/fisiopatologia , Tuberculose Pulmonar/epidemiologia , Adulto , Glicemia/metabolismo , Coinfecção , Estudos Transversais , Feminino , HIV/crescimento & desenvolvimento , HIV/patogenicidade , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , Hospitais , Humanos , Masculino , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Mycobacterium tuberculosis/fisiologia , Prevalência , Fatores de Risco , Fatores Sexuais , Escarro/microbiologia , Escarro/virologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Uganda/epidemiologia
15.
ACS Infect Dis ; 5(3): 353-364, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30585483

RESUMO

The evaluation of new tuberculosis (TB) therapies is limited by the paucity of biomarkers to monitor treatment response. Previous work detected an uncharacterized urine metabolite with a molecular mass of 874.3547 Da that showed promise as a biomarker for successful TB treatment. Using mass spectrometry combined with enzymatic digestions, the metabolite was structurally characterized as a seryl-leucine core 1 O-glycosylated peptide (SLC1G) of human origin. Examination of SLC1G in urine revealed a significant abundance increase in individuals with active TB versus their household contacts and healthy controls. Moreover, differential decreases in SLC1G levels were observed by week one in TB patients during successful treatment versus those that failed treatment. The SLC1G levels were also associated with clinical parameters used to measure bacterial burden (GeneXpert) and inflammation (positron emission tomography-computed tomography (PET-CT)). These results demonstrate the importance of metabolite identification and provide strong evidence for applying SLC1G as a biomarker of TB treatment response.


Assuntos
Antituberculosos/uso terapêutico , Glicopeptídeos/urina , Tuberculose/tratamento farmacológico , Adulto , Biomarcadores/urina , Monitoramento de Medicamentos , Feminino , Humanos , Leucina , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Tuberculose/urina , Urina/química , Adulto Jovem
16.
BMC Infect Dis ; 18(1): 498, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30285648

RESUMO

BACKGROUND: Ebolavirus and Marburgvirus are genera of the virus family Filoviridae. Filoviruses cause rare but fatal viral hemorrhagic fevers (VHFs) in remote villages of equatorial Africa with potential for regional and international spread. Point-of-care (POC) rapid diagnostic tests (RDTs) are critical for early epidemic detection, reponse and control. There are 2 RDTs for Zaire ebolavirus (EBOV), but not other Ebolavirus spp. or Marburg marburgvirus (MARV). We validate 3 conserved B cell epitopes of filovirus glycoprotein (GP) using ebola virus diseases (EVD) survivor samples, towards devising pan-filovirus RDTs. METHODS: In-silico Immuno-informatics:- (a) multiple and basic local alignments of amino-acid sequences of filovirus (4 Ebolavirus spp. & MARV) Gp1, 2 and epitope prediction and conservation analyses within context of ClusterW, BLAST-P and the immune epitope database analysis resource (IEDB-AR); alongside (b) in-vitro enzyme immuno-assays (EIAs) for SUDV Gp1, 2 antigen and host-specific antibodies (IgM and IgG) among 94 gamma irradiated EVD survivor serum and 9 negative controls. RESULTS: Linear B cell epitopes were present across the entire length of all Gp1, 2, most lying in the region between amino acids positioned 350 and 500. Three seperate epitopes 97/80_GAFFLYDRLAST, 39_YEAGEWAENCY and 500_CGLRQLANETTQALQLFLRATTELR (designated UG-Filo-Peptide- 1, 2 and 3 respectively) were conserved within all studied filovirus species Gp1, 2. Gp1, 2 host specific IgM levels were comparably low (av. ODs < 0.04 [95% CI: 0.02837 to 0.04033]) among the 9 negative controls and 57 survivor samples analyzed. Host specific IgG levels, on the other hand, were elevated (av. ODs > 1.7525 [95% CI: 0.3010 to 3.1352]) among the 92 survivor samples relative to the 9 negative controls (av. ODs < 0.2.321 [95% CI: -0.7596 to 0.5372]). Filovirus Gp1, 2 antigen was not detected [av. ODs < 0.20] within EVD survivor serum relative to recombinant protein positive controls [av. ODs = 0.50]. CONCLUSIONS: These conserved B cell epitopes of filovirus Gp1, 2 and their derivative antibodies are promising for research and development of RDTs for EVD, with potential for extension to detect MVD.


Assuntos
Ebolavirus/imunologia , Epitopos de Linfócito B/imunologia , Glicoproteínas/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/imunologia , Sequência Conservada , Doença pelo Vírus Ebola/diagnóstico , Doença pelo Vírus Ebola/virologia , Humanos , Imunoglobulina G , Imunoglobulina M , Doença do Vírus de Marburg/diagnóstico , Doença do Vírus de Marburg/virologia , Marburgvirus/imunologia , Kit de Reagentes para Diagnóstico , Proteínas Virais/genética , Proteínas Virais/imunologia
17.
J Acquir Immune Defic Syndr ; 79(3): 394-398, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063647

RESUMO

BACKGROUND: Throughout the world, there are antiretroviral therapy-naive HIV+ individuals who maintain elevated peripheral CD4 T-cell counts, historically referred to as long-term nonprogressors (LTNPs). With recent improvements in viral load (VL) detection methods to levels as low as 20 copies per milliliter, 2 subsets of LTNPs have been defined: elite controllers (ECs), with undetectable VLs for at least 6-12 months, and viremic controllers (VCs), with VLs between 200 and 2000 copies per milliliter. ECs and VCs have been extensively studied in the developed world to determine underlying mechanisms responsible for virologic control. In sub-Saharan Africa, most studies have characterized LTNPs based on immunologic criteria making it difficult to compare findings with the Western cohorts, which use virologic criteria. Here, we describe a cohort of Uganda ECs and VCs attending a large HIV ambulatory center in Kampala, Uganda, based initially on CD4 counts and confirmed by repeated VL measurements. METHODS: A cross-sectional study was conducted among 14,492 HIV-infected, antiretroviral therapy-naive individuals aged 18 years and older under care for at least 5 years with serial peripheral CD4 counts ≥500 cells/µL. Among those, we determined the frequency of individuals with VLs <2000 copies per milliliter for at least 6 months. RESULTS: We report a prevalence of 0.26% (38/14,492) of HIV controllers in the clinic. We identified 36 ECs and 2 VCs. These individuals were middle-aged with an average CD4 count of 858 ± 172 (mean ± SD, 95% confidence interval: 795 to 921). Their average duration in HIV care was 7.4 ± 2.1 years (mean ± SD, 95% confidence interval: 6.6 to 8.1). The majority of EC/VCs were women (87%, 33/38), reflecting the demographics of the urban clinic. CONCLUSIONS: For the first time, this study demonstrates the frequency of EC/VCs in a large urban clinic in Uganda. Further study of these East African subjects may provide insights into how some individuals are able to control HIV in the absence of medications.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Carga Viral , Adulto , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Uganda
18.
PLoS One ; 13(6): e0199638, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953491

RESUMO

INTRODUCTION: Although Sensititre Mycobacterium tuberculosis (MYCOTB) plate offers both drug susceptibility testing (DST) and minimum inhibitory concentration (MIC) results, it has not been evaluated against both Lowenstein Jensen (LJ) and Middlebrook 7H10 (MB7H10) DST methods at standard critical concentrations. MATERIALS AND METHODS: We analyzed 76 M. tuberculosis isolates consisting of 54 isolates from the Uganda National TB drug resistance survey done December 2009-February 2011 and 22 isolates from the World Health Organization External Quality Assessment panel for the year 2011. All isolates were tested for LJ, MB7H10 and MYCOTB plate based DSTs for streptomycin, isoniazid, rifampicin and ethambutol anti-tuberculosis drugs. The agreement of MB7H10 with LJ and accuracy of MYCOTB plate using either LJ-DST or MB7H10 as a reference standard were determined. RESULTS: The agreement (kappa) of MB7H10 with LJ was; 0.687 for rifampicin, 0.498 for isoniazid, 0.275 for streptomycin and 0.082 for ethambutol which as almost similar when compared with MYCOTB plate. The sensitivity (95% confidence interval; CI) of MYCOTB plate when LJ was used as a reference standard was higher for streptomycin 87.5% (81.6-98.4) followed by isoniazid 75.9% (65.1-95.6) and rifampicin 73.1% (52.2-88.4). When MB7H10 was used as reference standard, the sensitivity of MYCOTB plate improved significantly; isoniazid 96.2% (80.3-99.9), rifampicin 94.0 (83.4-98.7) and 93.8% (69.7-99.8). There was good agreement between MYCOTB plate and MB7H10; 1.00 for ethambutol, 0.959 for streptomycin, 0.915 for rifampicin and 0.778 for isoniazid. CONCLUSIONS: The performance of the two culture-based reference standards for phenotypic first-line drug susceptibility testing methods, LJ and MB7H10, varied much even with acceptable MYCOTB plate MICs. There was acceptable agreement and accuracy of MYCOTB plate for drug susceptibility testing when MB7H10 was used as reference standard than with LJ-DST. Results from MIC information makes the MYCOTB plate more suitable for guiding clinicians on the choice of the most appropriate TB treatment regimen as well as limits of detection for TB drug resistance.


Assuntos
Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana/instrumentação , Mycobacterium tuberculosis/efeitos dos fármacos , Farmacorresistência Bacteriana , Humanos , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Mycobacterium tuberculosis/isolamento & purificação , Padrões de Referência , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
19.
PLoS One ; 13(5): e0198091, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29847567

RESUMO

BACKGROUND: Accurate diagnosis of tuberculosis, especially by using rapid molecular assays, can reduce transmission of drug resistant tuberculosis in communities. However, the frequency of resistance conferring mutations varies with geographic location of Mycobacterium tuberculosis, and this affects the efficiency of rapid molecular assays in detecting resistance. This has created need for characterizing drug resistant isolates from different settings to investigate frequencies of resistance conferring mutations. Here, we describe the prevalence and patterns of rifampicin- and isoniazid- resistance conferring mutations in isolates from Uganda, which could be useful in the management of MDR-TB patients in Uganda and other countries in sub-Saharan Africa. RESULTS: Ninety seven M. tuberculosis isolates were characterized, of which 38 were MDR, seven rifampicin-resistant, 12 isoniazid-mono-resistant, and 40 susceptible to rifampicin and isoniazid. Sequence analysis of the rpoB rifampicin-resistance determining region (rpoB/RRDR) revealed mutations in six codons: 588, 531, 526, 516, 513, and 511, of which Ser531Leu was the most frequent (40%, 18/45). Overall, the three mutations (Ser531Leu, His526Tyr, Asp516Tyr) frequently associated with rifampicin-resistance occurred in 76% of the rifampicin resistant isolates while 18% (8/45) of the rifampicin-resistant isolates lacked mutations in rpoB/RRDR. Furthermore, sequence analysis of katG and inhA gene promoter revealed mainly the Ser315Thr (76%, 38/50) and C(-15)T (8%, 4/50) mutations, respectively. These two mutations combined, which are frequently associated with isoniazid-resistance, occurred in 88% of the isoniazid resistant isolates. However, 20% (10/50) of the isoniazid-resistant isolates lacked mutations both in katG and inhA gene promoter. The sensitivity of sequence analysis of rpoB/RRDR for rifampicin-resistance via detection of high confidence mutations (Ser531Leu, His526Tyr, Asp516Tyr) was 81%, while it was 77% for analysis of katG and inhA gene promoter to detect isoniazid-resistance via detection of high confidence mutations (Ser315Thr, C(-15)T, T(-8)C). Furthermore, considering the circulating TB genotypes in Uganda, the isoniazid-resistance conferring mutations were more frequent in M. tuberculosis lineage 4/sub-lineage Uganda, perhaps explaining why this genotype is weakly associated with MDR-TB. CONCLUSION: Sequence analysis of rpoB/RRDR, katG and inhA gene promoter is useful in detecting rifampicin/isoniazid resistant M. tuberculosis isolates in Uganda however, about ≤20% of the resistant isolates lack known resistance-conferring mutations hence rapid molecular assays may not detect them as resistant.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Genótipo , Prevalência , Uganda
20.
BMC Infect Dis ; 18(1): 133, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29548281

RESUMO

BACKGROUND: Precise designation of high risk forms of latent Mycobacterium tuberculosis-M.tb infections (LTBI) is impossible. Delineation of high-risk LTBI can, however, allow for chemoprophylaxis and curtail majority cases of active tuberculosis (ATB). There is epidemiological evidence to support the view that LTBI in context of HIV-1 co-infection is high-risk for progression to ATB relative to LTBI among HIV-ve persons. We recently showed that assays of M.tb thymidylate kinase (TMKmt) antigen and host specific IgG can differentiate ATB from LTBI and or no TB (NTB, or healthy controls). In this study, we aimed to expose the differential levels of TMKmt Ag among HIV+ve co-infected LTBI relative to HIV-ve LTBI as a strategy to advance these assays for designating incipient LTBI. METHODS: TMKmt host specific IgM and IgG detection Enzyme Immuno-Assays (EIA) were conducted on 40 TB exposed house-hold contacts (22 LTBI vs. 18 no TB (NTB) by QunatiFERON-TB GOLD®); and TMKmt Ag detection EIA done on 82 LTBI (46 HIV+ve vs 36 HIV-ve) and 9 NTB (American donors). Purified recombinant TMKmt protein was used as positive control for the Ag assays. RESULTS: IgM levels were found to be equally low across QuantiFERON-TB GOLD® prequalified NTB and TB exposed house-hold contacts. Higher TMKmt host specific IgG trends were found among TB house-hold contacts relative to NTB controls. TMKmt Ag levels among HIV+ve LTBI were 0.2676 ± 0.0197 (95% CI: 0.2279 to 0.3073) relative to 0.1069 ± 0.01628 (95% CI: 0.07385 to 0.14) for HIV-ve LTBI (supporting incipient nature of LTBI in context of HIV-1 co-infection). NTB had TMKmt Ag levels of 0.1013 ± 0.02505 (5% CI: 0.0421 to 0.1606) (intimating that some were indeed LTBI). CONCLUSIONS: TMKmt Ag levels represent a novel surrogate biomarker for high-risk LTBI, while host-specific IgG can be used to designate NTB from LTBI.


Assuntos
Progressão da Doença , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/enzimologia , Núcleosídeo-Fosfato Quinase/metabolismo , Teste Tuberculínico/métodos , Adulto , Anticorpos Antibacterianos/análise , Biomarcadores/análise , Coinfecção , Feminino , Infecções por HIV/complicações , HIV-1 , Humanos , Imunoglobulina G/análise , Imunoglobulina M/análise , Tuberculose Latente/complicações , Tuberculose Latente/microbiologia , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Medição de Risco
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