Intensified pulmonary tuberculosis case finding among HIV-infected new entrants of a prison in Malaysia: implications for a holistic approach to control tuberculosis in prisons.

PURPOSE: This intensified case finding study aimed to evaluate the prevalence of tuberculosis (TB) disease among people with HIV entering the largest prison in Malaysia. DESIGN/METHODOLOGY/APPROACH: The study was conducted in Kajang prison, starting in July 2013 in the men's prison and June 2015 in the women's prison. Individuals tested positive for HIV infection, during the mandatory HIV testing at the prison entry, were consecutively recruited over five months at each prison. Consented participants were interviewed using a structured questionnaire and asked to submit two sputum samples that were assessed using GeneXpert MTB/RIF (Xpert) and culture, irrespective of clinical presentation. Factors associated with active TB (defined as a positive result on either Xpert or culture) were assessed using regression analyses. FINDINGS: Overall, 214 incarcerated people with HIV were recruited. Most were men (84.6%), Malaysians (84.1%) and people who inject drugs (67.8%). The mean age was 37.5 (SD 8.2) years, and median CD4 lymphocyte count was 376 cells/mL (IQR 232-526). Overall, 27 (12.6%) TB cases were identified, which was independently associated with scores of five or more on the World Health Organization clinical scoring system for prisons (ARR 2.90 [95% CI 1.48-5.68]). ORIGINALITY/VALUE: Limited data exists about the prevalence of TB disease at prison entry, globally and none from Malaysia. The reported high prevalence of TB disease in the study adds an important and highly needed information to design comprehensive TB control programmes in prisons.

Healthcare Seeking and Access to Care for Pneumonia, Sepsis, Meningitis, and Malaria in Rural Gambia.

Children with acute infectious diseases may not present to health facilities, particularly in low-income countries. We investigated healthcare seeking using a cross-sectional community survey, health facility-based exit interviews, and interviews with customers of private pharmacies in 2014 in Upper River Region (URR) The Gambia, within the Basse Health & Demographic Surveillance System. We estimated access to care using surveillance data from 2008 to 2017 calculating disease incidence versus distance to the nearest health facility. In the facility-based survey, children and adult patients sought care initially at a pharmacy (27.9% and 16.7% respectively), from a relative (23.1% and 28.6%), at a local shop or market (13.5% and 16.7%), and on less than 5% of occasions with a community-based health worker, private clinic, or traditional healer. In the community survey, recent symptoms of pneumonia or sepsis (15% and 1.5%) or malaria (10% and 4.6%) were common in children and adults. Rates of reported healthcare-seeking were high with families of children favoring health facilities and adults favoring pharmacies. In the pharmacy survey, 47.2% of children and 30.4% of adults had sought care from health facilities before visiting the pharmacy. Incidence of childhood disease declined with increasing distance of the household from the nearest health facility with access to care ratios of 0.75 for outpatient pneumonia, 0.82 for hospitalized pneumonia, 0.87 for bacterial sepsis, and 0.92 for bacterial meningitis. In rural Gambia, patients frequently seek initial care at pharmacies and informal drug-sellers rather than community-based health workers. Surveillance underestimates disease incidence by 8-25%.

Changes in Transcript, Metabolite, and Antibody Reactivity During the Early Protective Immune Response in Humans to Mycobacterium tuberculosis Infection.

BACKGROUND: Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. In this study, we aimed to identify correlates of protection against Mtb infection. METHODS: Two groups of Mtb-exposed contacts of tuberculosis (TB) patients were recruited and classified according to their Mtb infection status using the tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2). A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time points classified TST or QFT nonconverters. Ribonucleic acid sequencing, Mtb proteome arrays, and metabolic profiling were performed. RESULTS: Several genes were found to be differentially expressed at baseline between converters and nonconverters. Gene set enrichment analysis revealed a distinct B-cell gene signature in TST nonconverters compared to converters. When infection status was defined by QFT, enrichment of type I interferon was observed. A remarkable area under the curve (AUC) of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST nonconverters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (vitamin B5) was significantly increased in TST nonconverters compared to converters at baseline (q = 0.0060). CONCLUSIONS: These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection, including vitamin B5 supplementation.Analysis of blood from highly exposed household contacts from The Gambia who never develop latent Mycobacterium tuberculosis infection shows distinct transcriptomic, antibody, and metabolomic profiles compared to those who develop latent tuberculosis infection but prior to any signs of infection.

Evaluation of Xpert MTB-RIF guided diagnosis and treatment of rifampicin-resistant tuberculosis in Indonesia: A retrospective cohort study.

BACKGROUND: Rifampicin-resistant tuberculosis (RR-TB) is largely underdetected in Indonesia. Xpert MTB/RIF (Xpert) has recently been introduced, prioritizing patients at risk of RR-TB, followed by phenotypic drug-susceptibility (DST) if rifampicin resistance is detected. OBJECTIVE: This study investigated Xpert-based management of presumptive RR-TB cases under routine practice in West Java, Indonesia. METHODS: We examined all records of patients tested with Xpert in the referral hospital for West Java in 2015-2016. We measured loss across a limited cascade of care, time to Xpert diagnosis and the commencement of initial second-line treatment, and identified factors associated with diagnostic and treatment delay. Additionally, we analyzed the appropriateness of treatment according to DST results. RESULTS: Of 3415 patients with presumptive RR-TB, 3215 (94%) were tested by Xpert, of whom 339 (10.5%) were diagnosed as RR-TB. 288 (85%) of 339 RR-TB patients started initial second-line TB treatment, with 48 (14%) patients being lost between diagnosis and pre-treatment assessment. Second-line treatment was commenced at a median of 41 days (IQR 29-70) after RR-TB diagnosis. Delays in both diagnosis and treatment initiation were observed in 104 (52%) of 201 RR-TB patients with identifiable referral date. Rural residence was associated with delay to diagnosis (adjusted OR 2.7; 95%CI 1.5-5.2) and treatment initiation (adjusted OR 2.0; 1.2-3.4). Of 162 patients with available DST result, 107 (66%) had multidrug-resistant tuberculosis (MDR-TB) and 32 (20%) had either pre-extensively drug resistant (pre-XDR) or extensively drug resistant tuberculosis (XDR-TB). We estimated that with the current algorithm 41% of pre-XDR or XDR-TB patients are diagnosed, and 33% of them started on an appropriate treatment regimen. CONCLUSIONS: Many patients with Xpert-diagnosed RR-TB either do not start MDR-TB treatment or encountered diagnostic and treatment delays under programmatic conditions in Indonesia, and most pre-XDR and XDR-TB cases remain undiagnosed. Further expansion and ongoing quality improvement of RR-TB services are urgently needed.

Feasibility study of strengthening the public-private partnership for tuberculosis case detection in Bandung City, Indonesia.

OBJECTIVE: Private practitioner's (PPs) collaboration for detection, diagnosis and treatment of tuberculosis (TB) is recommended by the World Health Organization and encouraged by the Indonesian National TB control programme. TB case management by PPs, however, are mostly not in line with current guidelines. Therefore, we developed an intervention package for PPs comprising of TB training, implementation of a mobile phone application for notification of TB cases and a 6-month regular follow-up with PPs. This study aimed to evaluate the feasibility of the intervention package to increase TB case detection and notification rates among PPs in five community health centre areas in Bandung City, Indonesia. RESULTS: A total of 87 PPs were registered within the study area of whom 17 attended the training and 12 had the mobile phone application successfully installed. The remaining five PPs had phones that did not support the application. During the follow-up period, five PPs registered patients with TB symptoms and cases into the application. A total of 36 patients with TB symptoms were identified and 17 were confirmed TB positive.

Effect of micronutrient sprinkles on reducing anemia: a cluster-randomized effectiveness trial.

OBJECTIVE: To evaluate the effectiveness of Sprinkles alongside infant and young child feeding (IYCF) education compared with IYCF education alone on anemia, deficiencies in iron, vitamin A, and zinc, and growth in Cambodian infants. DESIGN: Cluster-randomized effectiveness study. SETTING: Cambodian rural health district. PARTICIPANTS: Among 3112 infants aged 6 months, a random subsample (n = 1350) was surveyed at baseline and 6-month intervals to age 24 months. INTERVENTION: Daily micronutrient Sprinkles alongside IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months. MAIN OUTCOME MEASURES: Prevalence of anemia; iron, vitamin A, and zinc deficiencies; and growth via biomarkers and anthropometry. RESULTS: Anemia prevalence (hemoglobin level <11.0 g/dL [to convert to grams per liter, multiply by 10.0]) was reduced in the intervention arm compared with the control arm by 20.6% at 12 months (95% CI, 9.4-30.2; P = .001), and the prevalence of moderate anemia (hemoglobin level <10.0 g/dL) was reduced by 27.1% (95% CI, 21.0-31.8; P < .001). At 12 and 18 months, iron deficiency prevalence was reduced by 23.5% (95% CI, 15.6-29.1; P < .001) and 11.6% (95% CI, 2.6-17.9; P = .02), respectively. The mean serum zinc concentration was increased at 12 months (2.88 µg/dL [to convert to micromoles per liter, multiply by 0.153]; 95% CI, 0.26-5.42; P = .03). There was no statistically significant difference in the prevalence of zinc and vitamin A deficiencies or in growth at any time. CONCLUSIONS: Sprinkles reduced anemia and iron deficiency and increased the mean serum zinc concentration in Cambodian infants. Anemia and zinc effects did not persist beyond the intervention period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12608000069358.

Myristoylation negative msbB-mutants of probiotic E. coli Nissle 1917 retain tumor specific colonization properties but show less side effects in immunocompetent mice.

Specific colonization of solid tumors by bacteria opens the way to novel approaches in both tumor diagnosis and therapy. However, even non-pathogenic bacteria induce responses by the immune system, which could be devastating for a tumor bearing patient. As such effects are caused e.g., by the lipid A moiety of the lipopolysaccharide, a msbB-mutant of the probiotic E. coli Nissle 1917 strain was investigated. Bacteria of the mutant strain did not show any growth defects in culture media when compared to wild-type E. coli Nissle 1917 but were unable to myristoylate lipid A, had less toxic effects on immunocompetent BALB/c mice, and were still able to specifically colonize tumors. Therefore, the modification of lipid A could result in bacterial strains that might be better suited for diagnosis and therapy of tumors than the corresponding wild-type strains, even if those are not considered pathogenic or are of probiotic background.

Preventive measures in infancy to reduce under-five mortality: a case-control study in The Gambia.

OBJECTIVE: To investigate the relationship between child mortality and common preventive interventions: vaccination, trained birthing attendants, tetanus toxoid during pregnancy, breastfeeding and vitamin A supplementation. METHODS: Case-control study in a population under demographic surveillance. Cases (n = 141) were children under five who died. Each was age and sex-matched to five controls (n = 705). Information was gathered by interviewing primary caregivers. RESULTS: All but one of the interventions - whether the mother had received tetanus toxoid during pregnancy - were protective against child mortality after multivariate analysis. Having a trained person assisting at child birth (OR 0.2 95% CI 0.1-0.4), receiving all vaccinations by 9 months of age (OR 0.1; 95% CI 0.01-0.3), being breastfed for more than 12 months (Children breastfed between 13 and 24 months OR 0.1 95% CI 0.03-0.3, more than 25 months OR 0.1 95% CI 0.01-0.5) and receiving vitamin A supplementation at or after 6 months of age (OR 0.05; 95% CI 0.01-0.2) were protective against child death. CONCLUSIONS: This study confirms the value of at least four available interventions in the prevention of under-five death in The Gambia. It is now important to identify those who are not receiving them and why, and to intervene to improve coverage across the population.

Serotype and antimicrobial susceptibility patterns of isolates of Streptococcus pneumoniae causing invasive disease in The Gambia 1996-2003.

OBJECTIVES: To describe the characteristics of pneumococcal isolates obtained from patients with invasive pneumococcal disease in The Gambia. METHODS: Pneumococcal isolates were obtained from children aged < or =6 years with invasive pneumococcal disease during a Haemophilus influenzae vaccine effectiveness study (1997-2002) and from patients with invasive pneumococcal disease admitted to the MRC hospital, Fajara, for routine care (1996-2003). Isolates were identified, serotyped and tested for antibiotic susceptibility. RESULTS: Five hundred and thirty one pneumococcal isolates were obtained from 518 patients; 55 (10.6%) patients died; 415 isolates (79%) were from blood culture, 84 (16%) from CSF, and 42 (8%) from lung aspirates. Forty serogroups and serotypes were identified; six accounted for 64% and 16 for 86% of all episodes; 33.7% were of serotypes 1 and 5. 23.5% were of a 7-valent vaccine serotype, 57.1% were of a 9-valent vaccine serotype; 56% were of a 7-valent serogroup and 78% were of a 9-valent serogroup. There was a significant increase in the proportion of isolates of non-vaccine serogroup with increasing age (P < 0.0001). Antibiotic resistance had not significantly increased over time; but intermediate non-susceptibility to penicillin had risen and resistance to chloramphenicol had fallen in isolates of vaccine serotype compared with those of non-vaccine serotype. CONCLUSIONS: The majority of invasive pneumococcal disease in The Gambia is caused by pneumococci of relatively few serogroups. A conjugate vaccine would be expected to reduce the pneumococcal disease burden substantially and to have a beneficial effect on pneumococcal antibiotic resistance to penicillins.

LuxS: its role in central metabolism and the in vitro synthesis of 4-hydroxy-5-methyl-3(2H)-furanone.

Many bacteria produce extracellular molecules which function in cell-to-cell communication. One of these molecules, autoinducer 2 (AI-2), was first described as an extracellular signal produced by Vibrio harveyi to control luciferase expression. Subsequently, a number of bacteria have been shown to possess AI-2 activity in their culture supernatants, and bear the luxS gene product, which is required for AI-2 synthesis. In Porphyromonas gingivalis, luxS and pfs, encoding a 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTA/SAH'ase), form an operon, suggesting that S-adenosylhomocysteine (SAH) or 5'-methylthioadenosine (MTA) serves as a substrate for AI-2 production. Cell-free extracts of Escherichia coli MG1655, but not DH5alpha (which carries a luxS frame-shift mutation) were capable of generating AI-2 activity upon addition of SAH, but not MTA. S-Ribosyl-homocysteine (RH) derived from SAH also served as a substrate in E. coli MG1655 extracts. RH-supplemented cell-free extracts of Pseudomonas aeruginosa, a bacterium that lacks luxS, only generated AI-2 activity following the introduction of a plasmid containing the Por. gingivalis pfs-luxS operon. In addition, defined in vitro systems consisting of the purified LuxS proteins from Por. gingivalis, E. coli, Neisseria meningitidis or Staphylococcus aureus converted RH to homocysteine and a compound that exhibits AI-2 activity.4-Hydroxy-5-methyl-3(2H)-furanone was identified by mass spectrometry analysis as a major product formed in this in vitro reaction. In E. coli MG1655, expression of T3SH [the bacteriophage T3 S-adenosylmethionine (SAM) hydrolase] significantly reduced AI-2 activity in culture supernatants, suggesting that AI-2 production is limited by the amount of SAH produced in SAM-dependent transmethylase reactions. The authors suggest that the LuxS protein has an important metabolic function in the recycling of SAH. They also show that Ps. aeruginosa is capable of removing AI-2 activity, implying that this molecule may act as a nutrient. In many bacteria AI-2 may in fact represent not a signal molecule but a metabolite which is released early and metabolized in the later stages of growth.