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2.  Emergence of Acinetobacter baumannii international clone II in Brazil: reflection of a global expansion 
The aim of this study was to investigate the occurrence of carbapenem-resistant Acinetobacter baumannii international clones (IC) in Curitiba, Brazil, using multilocus sequence typing and trilocus PCR-based typing schemes. IC2 was the first emerging clone. This IC was detected in an isolate from 2003 of a PFGE type spread in at least two hospitals since 1999. Subsequently, IC2 waned while IC1 and clonal complex 15/104 prevailed. This is the first description of IC2 in Brazil and Latin America.
PMCID: PMC3856948  PMID: 24121023
Acinetobacter baumannii; multilocus sequence typing; trilocus PCR-based typing; international clone; molecular epidemiology
3.  Distribution of Strain Type and Antimicrobial Susceptibility of Escherichia coli Isolates Causing Meningitis in a Large Urban Setting in Brazil 
Journal of Clinical Microbiology  2014;52(5):1418-1422.
The clinical management of meningitis caused by Escherichia coli is greatly complicated when the organism becomes resistant to broad-spectrum antibiotics. We sought to characterize the antimicrobial susceptibilities, sequence types (ST), and presence of known drug resistance genes of E. coli isolates that caused meningitis between 1996 and 2011 in Salvador, Brazil. We then compared these findings to those for E. coli isolates from community-acquired urinary tract infections (UTI) that occurred during the same time period and in the same city. We found that 19% of E. coli isolates from cases of meningitis and less than 1% of isolates from UTI were resistant to third-generation cephalosporins. The sequence types of E. coli isolates from cases of meningitis included ST131, ST69, ST405, and ST62, which were also found among isolates from UTI. Additionally, among the E. coli isolates that were resistant to third-generation cephalosporins, we found genes that encode the extended-spectrum beta-lactamases CTX-M-2, CTX-M-14, and CTX-M-15. These observations demonstrate that compared to E. coli strains isolated from cases of community-acquired UTI, those isolated from cases of meningitis are more resistant to third-generation cephalosporins, even though the same sequence types are shared between the two forms of extraintestinal infections.
PMCID: PMC3993653  PMID: 24523478
4.  High prevalence of Staphylococcus aureus and methicillin-resistant S. aureus colonization among healthy children attending public daycare centers in informal settlements in a large urban center in Brazil 
BMC Infectious Diseases  2014;14(1):538.
In the past decade methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly prevalent in community settings. Attending a daycare center (DCC) is a known risk factor for colonization with MRSA. Brazil operates free, public DCCs for low-income families, some of which are located in census tracts defined by the Brazilian Census Bureau as informal settlements (aglomerados subnormais, AGSN). Physical and demographic characteristics of AGSNs suggest that S. aureus colonization prevalence would be higher, but little is known about the prevalence of MRSA in these settings.
We conducted a cross-sectional study to assess risk factors for S. aureus and MRSA colonization among children attending DCCs located in AGSN vs non-AGSN. Nasal swabs were collected from children aged three months to six years in 23 public DCCs in Niterói, Brazil between August 2011 and October 2012.
Of 500 children enrolled in the study, 240 (48%) were colonized with S. aureus and 31 (6.2%) were colonized with MRSA. Children attending DCCs in AGSNs were 2.32 times more likely to be colonized with S. aureus (95% CI: 1.32, 4.08), and 3.27 times more likely to be colonized with MRSA than children attending non-AGSN DCCs (95% CI: 1.52, 7.01), adjusted for confounding variables.
S. aureus and MRSA colonization prevalence among children attending DCCs in informal settlement census tracts was higher than previously reported in healthy pre-school children in Latin America. Our data suggest that transmission may occur more frequently in DCCs rather than at home, highlighting the importance of DCCs in AGSNs as potential MRSA reservoirs. This finding underscores the importance of local epidemiologic surveillance in vulnerable AGSN communities.
PMCID: PMC4287590  PMID: 25287855
Community-associated; Methicillin-resistant; Staphylococcus aureus; Nasal colonization; Risk factors; Slum; Informal settlements; Favelas
5.  A comparative effectiveness trial of postoperative management for lumbar spine surgery: changing behavior through physical therapy (CBPT) study protocol 
The United States has the highest rate of lumbar spine surgery in the world, with rates increasing over 200% since 1990. Medicare spends over $1 billion annually on lumbar spine surgery. Despite surgical advances, up to 40% of patients report chronic pain and disability following surgery. Our work has demonstrated that fear of movement is a risk factor for increased pain and disability and decreased physical function in patients following lumbar spine surgery for degenerative conditions. Cognitive-behavioral therapy and self-management treatments have the potential to address psychosocial risk factors and improve outcomes after spine surgery, but are unavailable or insufficiently adapted for postoperative care. Our research team developed a cognitive-behavioral based self-management approach to postoperative rehabilitation (Changing Behavior through Physical Therapy (CBPT)). Pilot testing of the CBPT program demonstrated greater improvement in pain, disability, physical and mental health, and physical performance compared to education. The current study compares which of two treatments provided by telephone – a CBPT Program or an Education Program about postoperative recovery - are more effective for improving patient-centered outcomes in adults following lumbar spine surgery for degenerative conditions.
A multi-center, comparative effectiveness trial will be conducted. Two hundred and sixty patients undergoing lumbar spine surgery for degenerative conditions will be recruited from two medical centers and community surgical practices. Participants will be randomly assigned to CBPT or Education at 6 weeks following surgery. Treatments consist of six weekly telephone sessions with a trained physical therapist. The primary outcome will be disability and secondary outcomes include pain, general health, and physical activity. Outcomes will be assessed preoperatively and at 6 weeks, 6 months and 12 months after surgery by an assessor masked to group allocation.
Effective rehabilitation treatments that can guide clinicians in their recommendations, and patients in their actions will have the potential to effect change in current clinical practice.
Trial registration
PMCID: PMC4192328  PMID: 25273991
Comparative effectiveness research; Cognitive-behavioral therapy; Self-management; Rehabilitation; Postoperative pain; Spine surgery
6.  Comparison of Interferon-γ Release Assay to Two Cut-Off Points of Tuberculin Skin Test to Detect Latent Mycobacterium tuberculosis Infection in Primary Health Care Workers 
PLoS ONE  2014;9(8):e102773.
An interferon-γ release assay, QuantiFERON-TB (QFT) test, has been introduced an alternative test for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). Here, we compared the performance of QFT with tuberculin skin test (TST) measured at two different cut-off points among primary health care work (HCW) in Brazil.
A cross-sectional study was carried out among HCWs in four Brazilian cities with a known history of high incidence of TB. Results of the QFT were compared to TST results based on both ≥5 mm and ≥10 mm as cut-off points.
We enrolled 632 HCWs. When the cut-off value of ≥10 mm was used, agreement between QFT and TST was 69% (k = 0.31), and when the cut-off of ≥5 mm was chosen, the agreement was 57% (k = 0.22). We investigated possible factors of discordance of TST vs QFT. Compared to the TST−/QFT− group, risk factors for discordance in the TST+/QFT− group with TST cut-off of ≥5 mm included age between 41–45 years [OR = 2.70; CI 95%: 1.32–5.51] and 46–64 years [OR = 2.04; CI 95%: 1.05–3.93], BCG scar [OR = 2.72; CI 95%: 1.40–5.25], and having worked only in primary health care [OR = 2.30; CI 95%: 1.09–4.86]. On the other hand, for the cut-off of ≥10 mm, BCG scar [OR = 2.26; CI 95%: 1.03–4.91], being a household contact of a TB patient [OR = 1.72; CI 95%: 1.01–2.92] and having had a previous TST [OR = 1.66; CI 95%: 1.05–2.62], were significantly associated with the TST+/QFT− group. No statistically significant associations were found among the TST−/QFT+ discordant group with either TST cut-off value.
Although we identified BCG vaccination to contribute to the discordance at both TST cut-off measures, the current Brazilian recommendation for the initiation of LTBI treatment, based on information gathered from medical history, TST, chest radiograph and physical examination, should not be changed.
PMCID: PMC4138087  PMID: 25137040
7.  Treatment Outcomes in Tuberculosis Patients with Diabetes: A Polytomous Analysis Using Brazilian Surveillance System 
PLoS ONE  2014;9(7):e100082.
The impact of non-communicable diseases on tuberculosis incidence has received significant attention. It has been suggested that the risk of tuberculosis is higher among subjects with diabetes and these subjects also has poor TB treatment outcomes.This study was aimed at assessing the socio-demographic and clinical factors that may influence different outcome of TB in patients with DM (TB-DM) identified in the Brazilian national database from 2001 to 2011.
TB-DM cases reported in the Brazilian information system were identified and compared.Covariates associated with the outcomes of interest (cure, default, deaths, and development of TB MDR) were included in a hierarchical regression model.
TB-DM cases increased from 380/100,000/year in 2001 to 6,150/100,000/year in 2011. Some of the main associations found are pointed. The odds of default was higher among those in the age group 20–39 years (OR = 2.07, 95%CI 1.32–3.24); alcoholics (OR = 2.17, 95%CI 1.86–2.54), and HIV/AIDS (OR = 2.16, 95%CI 1.70–2.74);positive monitoring smear (OR = 1.94, 95%CI 1.55–2.43); prior default (OR = 5.41, 95%CI 4.47–6.54), and unknown type of treatment (OR = 3.33, 95%CI 1.54–7.22). The odds of death was greater for subjects ≥60 years old (OR = 2.74, 95%CI 1.74–4.29); institutionalized in shelter (OR = 2.69, 95%CI 1.07–6.77); alcoholics (OR = 2.70, 95%CI 2.27–3.22); HIV/AIDS (OR = 2.87, 95%CI 2.13–3.86); pulmonary+extrapulmonary TB (OR = 2.49, 95%CI 1.79–3.46); with unknown type of treatment (OR = 14.12, 95%CI 7.04–28.32).Development of MDR TB was more related to relapse (OR = 9.60, 95%CI 6.07–15.14);previous default (OR = 17.13, 95%CI 9.58–30.63); and transfer of treatment center (OR = 7.87, 95%CI 4.74–13.07).
Older subjects and those with comorbidities and with a previous treatment of TB had poorest outcomes. TB control program in Brazil will need to expand efforts to focus on treatment of TB-DM patients to improve their cure rates in order to achieve the goals of tuberculosis elimination.
PMCID: PMC4086729  PMID: 25003346
8.  Distribution of superantigens in group A streptococcal isolates from Salvador, Brazil 
BMC Infectious Diseases  2014;14:294.
Group A streptococcus (GAS) causes invasive disease, superficial disease, and can asymptomatically colonize humans. Superantigens are one virulence factor found in GAS. Previous studies found associations between the genes that encode superantigens and emm type of GAS. It is unknown if these associations are due to underlying biological factors that limit the distribution of superantigens or, alternatively, if these associations are due to the expansion of local GAS linages where these studies took place. To further address this question we screened GAS isolates collected from Salvador, Brazil for 11 known superantigen genes.
Seventy-seven GAS isolates were screened by PCR for superantigen genes. These superantigen genes were speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa, and smeZ. We used Fisher’s two-sided exact test to identify associations between superantigens and GAS emm type. We then compared our results to previous reports of superantigen prevalence and superantigen association with emm type.
In our collection we found several emm type and superantigen genotype combinations that have previously been reported in isolates from Europe and Australia. We also found that speA was significantly associated with emm type 1, and that speC was significantly associated with emm type 12.
Our study reports superantigen genotypes of GAS from a region of the world that is lacking this information. We found evidence of common GAS superantigen genotypes that are spread worldwide as well as novel superantigen genotypes that, so far, are unique to Brazil.
PMCID: PMC4045995  PMID: 24885209
Streptococcus pyogenes; Streptococcal superantigens; Group A streptococcus; Emm types
9.  Longitudinal surveillance for meningitis by Acinetobacter in a large urban setting in Brazil 
The study aim was to describe the emergency of carbapenem resistance and clonal complexes (CC), defined by multilocus sequence typing (MLST), in Acinetobacter baumannii in a surveillance system for meningitis. Starting in 1996 at an urban setting of Brazil, surveillance detected meningitis by Acinetobacter sp for the first time in 2002. Until 2008, 35 isolates were saved. Carbapenem resistance emerged in 2006, reaching 70% of A. baumannii isolates in 2008, including one colistin-resistant. A. baumannii belonged to CC113/79 (University of Oxford/ Institute Pasteur schemes), CC235/162 and CC103/15. Dissemination of infections resistant to all antimicrobial agents may occur in the future.
PMCID: PMC3625502  PMID: 23398654
Acinetobacter baumannii; bacterial meningitis; carbapenem-resistance; multilocus sequence typing; clonal complexes
10.  Mycobacterium tuberculosis DNA fingerprint clusters and its relationship with RDRio genotype in Brazil 
Mycobacterium tuberculosis (Mtb) strains designated as RDRio are responsible for a large cluster of new cases of tuberculosis (TB) in Rio de Janeiro. They were previously shown to be associated with severe manifestations of TB. Here, we used three genotyping methods (IS6110 RFLP, spoligotyping, and multiplex PCR) to characterize RDRio and non-RDRio strains from the metropolitan area of Vitória, State of Espirito Santo in southeast Brazil to determine strain diversity and transmission patterns. Strains with identical IS6110 RFLP patterns were considered to belong to a cluster indicative of recent transmission. Between 2000 and 2010, we identified 5470 new TB patients and genotyped 981 Mtb strains. Of these, 376 (38%) were RDRio. By RFLP, 180 (48%) of 376 RDRio strains and 235 (40%) of 593 non-RDRio strains belonged to RFLP cluster pattern groups (p = 0.023). Simpson’s diversity index based on RFLP patterns was 0.96 for RDRio and 0.98 for non-RDRio strains. Thus, although RDRio strains appear to be comprised of a fewer number of RFLP genotypes, they represent a heterogeneous group. While TB cases caused by RDRio appear more likely to be due to recent transmission than cases caused by non-RDRio strains, the difference is small. These observations suggest that factors other than inherent biological characteristic of RDRio lineages are more important in determining recent transmission, and that public health measures to interrupt new transmissions need to be emphasized for TB control in Vitória.
PMCID: PMC3734852  PMID: 23232111
Tuberculosis; DNA fingerprinting; Mycobacterium tuberculosis; Epidemiologic surveillance; RDRio
11.  Dissemination of Acinetobacter nosocomialis Clone among Critically Ill Patients and the Environment 
Journal of Clinical Microbiology  2013;51(8):2707-2709.
We examined the environmental dissemination of Acinetobacter nosocomialis multilocus sequence typing clonal complex 260/71 in Rio de Janeiro, Brazil, including water from a dam and food samples. The increasing use of sequence based methods has demonstrated a large, previously unpredicted, dissemination of bacteria that may serve as opportunistic pathogens.
PMCID: PMC3719634  PMID: 23698521
12.  Incidence and transmission patterns of tuberculosis among indigenous populations in Brazil 
Memórias do Instituto Oswaldo Cruz  2013;109(1):108-113.
Approximately 10% of the Brazilian indigenous population lives in the state of Mato Grosso do Sul (MS), where a large number of new cases of tuberculosis (TB) are reported. This study was conducted to assess TB occurrence, transmission and the utility of TB diagnosis based on the Ogawa-Kudoh (O-K) culture method in this remote population. The incidence of TB was estimated by a retrospective review of the surveillance data maintained by the Notifiable Diseases Surveillance System for the study region. The TB transmission pattern among indigenous people was assessed by genotyping Mycobacterium tuberculosis isolates using the IS 6110 restriction fragment length polymorphism (RFLP) technique. Of the 3,093 cases identified from 1999-2001, 610 (~20%) were indigenous patients (average incidence: 377/100,000/year). The use of the O-K culture method increased the number of diagnosed cases by 34.1%. Of the genotyped isolates from 52 indigenous patients, 33 (63.5%) belonged to cluster RFLP patterns, indicating recently transmitted TB. These results demonstrate high, on-going TB transmission rates among the indigenous people of MS and indicate that new efforts are needed to disrupt these current transmissions.
PMCID: PMC4005523  PMID: 24270999
tuberculosis; genotyping; microbiology; molecular epidemiology; South American indigenous people
13.  Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model 
Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011.
Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informações de Agravo de Notificação - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson’s chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model.
A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 – 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 – 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 – 0.57) and mental illness (OR 0.88; 95% CI 0.82 – 0.95) were associated with PTB.
Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil.
PMCID: PMC3893400  PMID: 24400848
14.  Obesity in the United States – Dysbiosis from Exposure to Low-Dose Antibiotics? 
The rapid increase in obesity prevalence in the United States in the last 20 years is unprecedented and not well explained. Here, we explore a hypothesis that the obesity epidemic may be driven by population-wide chronic exposures to low-residue antibiotics that have increasingly entered the American food chain over the same time period. We propose this hypothesis based on two recent bodies of published reports – (1) those that provide evidence for the spread of antibiotics into the American food chain, and (2) those that examine the relationship between the gut microbiota and body physiology. The livestock use of antimicrobial agents has sharply increased in the US over the same 20-year period of the obesity epidemic, especially with the expansion of intensified livestock production, such as the concentrated animal feeding operations. Observational and experimental studies support the idea that changes in the intestinal microbiota exert a profound effect on body physiology. We propose that chronic exposures to low-residue antimicrobial drugs in food could disrupt the equilibrium state of intestinal microbiota and cause dysbiosis that can contribute to changes in body physiology. The obesity epidemic in the United States may be partly driven by the mass exposure of Americans to food containing low-residue antimicrobial agents. While this hypothesis cannot discount the impact of diet and other factors associated with obesity, we believe studies are warranted to consider this possible driver of the epidemic.
PMCID: PMC3867737  PMID: 24392444
obesity; antibiotic residues; intestinal microbiota; food chain; CAFOs; animal husbandry; polysaccharide diet
15.  Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis 
Nature medicine  2013;19(6):704-712.
Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for osteoarthritis due to limited understanding of osteoarthritis pathogenesis. We show that TGF–β1 is activated in the subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) osteoarthritis mouse model. TGF–β1 concentrations also increased in human osteoarthritis subchondral bone. High concentrations of TGF–β1 induced formation of nestin+ mesenchymal stem cell (MSC) clusters leading to aberrant bone formation accompanied by increased angiogenesis. Transgenic expression of active TGF–β1 in osteoblastic cells induced osteoarthritis. Inhibition of TGF–β activity in subchondral bone attenuated degeneration of osteoarthritis articular cartilage. Notably, knockout of the TGF–β type II receptor (TβRII) in nestin+ MSCs reduced development of osteoarthritis in ACLT mice. Thus, high concentrations of active TGF–β1 in the subchondral bone initiated the pathological changes of osteoarthritis, inhibition of which could be a potential therapeutic approach.
PMCID: PMC3676689  PMID: 23685840
16.  Identification of novel antimicrobial resistance genes from microbiota on retail spinach 
BMC Microbiology  2013;13:272.
Drug resistance genes and their mobile genetic elements are frequently identified from environmental saprophytic organisms. It is widely accepted that the use of antibiotics in animal husbandry selects for drug resistant microorganisms, which are then spread from the farm environment to humans through the consumption of contaminated food products. We wished to identify novel drug resistance genes from microbial communities on retail food products. Here, we chose to study the microbial communities on retail spinach because it is commonly eaten raw and has previously been associated with outbreaks of bacterial infections.
We created metagenomic plasmid libraries from microbiota isolated from retail spinach samples. We identified five unique plasmids that increased resistance to antimicrobial drugs in the E. coli host. These plasmids were identified in E. coli that grew on plates that contained ampicillin (pAMP), aztreonam (pAZT), ciprofloxacin (pCIP), trimethoprim (pTRM), and trimethoprim-sulfamethoxazole (pSXT). We identified open reading frames with similarity to known classes of drug resistance genes in the DNA inserts of all 5 plasmids. These drug resistance genes conferred resistance to fluoroquinolones, cephalosporins, and trimethoprim, which are classes of antimicrobial drugs frequently used to treat human Gram negative bacterial infections. These results show that novel drug resistance genes are found in microbiota on retail produce items.
Here we show that microbiota of retail spinach contains DNA sequences previously unidentified as conferring antibiotic resistance. Many of these novel sequences show similarity to genes found in species of bacteria, which have previously been identified as commensal or saprophytic bacteria found on plants. We showed that these resistance genes are capable of conferring clinically relevant levels of resistance to antimicrobial agents. Food saprophytes may serve as an important reservoir for new drug-resistance determinants in human pathogens.
PMCID: PMC3890574  PMID: 24289541
Antibiotic resistance; Gram negative bacteria; Metagenomic library
17.  Extrapulmonary Tuberculosis: Mycobacterium tuberculosis Strains and Host Risk Factors in a Large Urban Setting in Brazil 
PLoS ONE  2013;8(10):e74517.
Factors related to the development of extrapulmonary forms of tuberculosis (EPTB) are still poorly understood, particularly in high-endemic countries like Brazil. The objective of the paper is to determine host and Mycobacterium tuberculosis (MTB) strain-related factors associated with the development of EPTB in Espírito Santo state, Brazil.
Methods and Findings
We conducted a retrospective laboratory-based surveillance study of new tuberculosis (TB) cases diagnosed in Espírito Santo state, Brazil between 1998 and 2007. We genotyped 612 isolates of MTB from 606 TB patients using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing and compared sociodemographic and clinical characteristics of patients with pulmonary TB (PTB) and EPTB. Among 606 patients, 464 (77%) had PTB, 79 (13%) had EPTB, 51 (8%) had both, and 12 (2%) had miliary TB. The IS6110 RFLP analysis demonstrated that 250 (41%) isolates belonged to clustered RFLP patterns, 27 (11%) of which were from EPTB. We identified 73 clusters including 35 (48%) composed of 2 isolates each. By spoligotyping, 506 (83%) MTB isolates fell into known patterns and 106 (17%) fell into patterns with no family assignment; 297 (48%) isolates belonged to the Latin-American Mediterranean family. Higher school level (4-7 years OR: 0.16 95% CI 0.34-0.73 and > 8 years of education, OR 0.06 95% CI 0.009-0.50) white ethnicity (OR: 2.54 95% CI 1.03-6.25) and HIV infection (OR: 16.83 95% CI 5.23-54.18) were associated with EPTB. No specific strain lineage or percentage of clustering was associated with EPTB.
These results demonstrate that risk factors for EPTB are related more to host than to MTB strain lineage characteristics.
PMCID: PMC3788772  PMID: 24098337
18.  Blood Cells and Interferon-Gamma Levels Correlation in Latent Tuberculosis Infection 
ISRN pulmonology  2013;2013:256148.
The Mycobacterium tuberculosis (M. tb) infection is largely spread in world’s population. Most infected individuals develop latent tuberculosis infection (LTBI). Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are the available tests to detect the infection. It has been reported that some individuals take a longer period of time to develop the infection than others with the same exposure level. It is suggested that the innate immunity, in which neutrophils have an important protective role, is responsible for this. Many hematologic abnormalities have been described as common findings during severe disease. To investigate if these changes are related to LTBI development and if they interfere in TST and IFN-γ production, we recruited 88 household contacts of tuberculosis (TB) pulmonary patients and compared blood cell counts with these tests’ results. There were no statistically significant changes in hemoglobin, hematocrit, platelets, global leukocyte, neutrophils, basophils, eosinophils, typical lymphocytes, atypical lymphocytes, and monocytes counts between infected and noninfected individuals. Also, there was no correlation between TST or IGRA and blood cell counts. These results suggest that blood cell counts are not LTBI markers and do not interfere in TST results or IFN-γ levels obtained by IGRA.
PMCID: PMC3769793  PMID: 24040564
19.  Prevalence and patterns of multimorbidity among tuberculosis patients in Brazil: a cross-sectional study 
The number of subjects with tuberculosis (TB) presenting with co-occurrence of multiple chronic medical conditions, or multimorbidity (MM) is increasing in Brazil. This manuscript aimed to characterize subjects with TB, according to their MM status and to analyse factors associated with TB treatment outcomes.
This is a cross-sectional study that included 39,881 TB subjects reported in Brazil, in 2011. MM were defined as any (two or more) occurrence of chronic medical conditions in a TB patient (TB–MM). Data analysis was performed by hierarchical logistic regression models comparing TBMM with those with only TB.
Of the reported TB cases in 2011, 454 (1.14%) had MM. The subjects in the age group 40–59 years (OR: 17.89; 95% CI, 5.71-56.03) and those ≥ 60 years (OR: 44.11; 95% CI, 14.09-138.06) were more likely to develop TB–MM. The TB–MM subjects were less likely to be male (OR: 0.63; 95% CI, 0.52-0.76), institutionalized (OR: 0.59; 95% CI, 0.23-0.80) and live in rural areas (OR: 0.63; 95% CI, 0.42-0.95). Death from causes other than TB was higher among TB–MM subjects (OR: 1.76; 95% CI, 1.36-2.28). Of 454 TB–MM subjects 302 (66.5%) were cured and 152 (33.5%) were not cured. The odds of not being cured was 1.55 (95% CI, 1.04-2.32) among males, 2.85 (95% CI, 1.12-7.28) among institutionalized subjects, and 3.93 (IC 95%, 1.86-8.30) among those who were infected with HIV. TB retreatment after previous abandonment (OR: 7.53; 95% CI, 2.58-21.97) and transfer from a treatment site (OR: 2.76; 95% CI, 1.20-6.38) were higher for subjects not cured compared to those who were cured.
While TB is well recognized to be a disease engendered by social inequity, we found that even among TB patients, those who have MM have greater inequity in terms of socioeconomic status and adverse clinical outcomes. Addressing the problem of TB and TB–MM requires a multisectorial approach that includes health and social service organizations.
PMCID: PMC3765118  PMID: 23962018
Tuberculosis; Multimorbidities; Inequity; Social determinants; Hierarchical models
20.  Clonal Composition and Community Clustering of Drug-Susceptible and -Resistant Escherichia coli Isolates from Bloodstream Infections 
Multidrug-resistant Escherichia coli strains belonging to a single lineage frequently account for a large proportion of extraintestinal E. coli infections in many parts of the world. However, limited information exists on the community prevalence and clonal composition of drug-susceptible E. coli strains. Between July 2007 and September 2010, we analyzed all consecutively collected Gram-negative bacterial isolates from patients with bloodstream infection (BSI) admitted to a public hospital in San Francisco for drug susceptibility and associated drug resistance genes. The E. coli isolates were genotyped for fimH single nucleotide polymorphisms (SNPs) and multilocus sequence types (MLSTs). Among 539 isolates, E. coli accounted for 249 (46%); 74 (30%) of them were susceptible to all tested drugs, and 129 (52%) were multidrug resistant (MDR). Only five MLST genotypes accounted for two-thirds of the E. coli isolates; the most common were ST131 (23%) and ST95 (18%). Forty-seven (92%) of 51 ST131 isolates, as opposed to only 8 (20%) of 40 ST95 isolates, were MDR (P < 0.0001). The Simpson's diversity index for drug-susceptible ST genotypes was 87%, while the index for MDR ST genotypes was 81%. ST95 strains were comprised of four fimH types, and one of these (f-6) accounted for 67% of the 21 susceptible isolates (P < 0.003). A large proportion (>70%) of both MDR and susceptible E. coli BSI isolates represented community-onset infections. These observations show that factors other than the selective pressures of antimicrobial agents used in hospitals contribute to community-onset extraintestinal infections caused by clonal groups of E. coli regardless of their drug resistance.
PMCID: PMC3535975  PMID: 23147723
21.  Association between an Emerging Disseminated form of Leishmaniasis and Leishmania (Viannia) braziliensis Strain Polymorphisms 
Journal of Clinical Microbiology  2012;50(12):4028-4034.
Leishmania (Viannia) braziliensis causes three main types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). All forms are observed among individuals of Corte de Pedra, Brazil. We previously used random amplified markers to identify a multiclonal population among L. (V.) braziliensis isolates from ATL patients, defining parasite clades associated with different clinical syndromes. Herein we compared sequences of random amplified markers to identify genotypes of L. (V.) braziliensis recovered from lesions of CL, ML, and DL patients. Six polymorphic genomic loci were sequenced from 35 parasite isolates. Single-nucleotide polymorphisms (SNPs) and insertions-deletions (indels) at each locus allowed us to segregate the L. (V.) braziliensis population according to haplotypes. Several SNPs, indels, and haplotypes were significantly associated with an increased risk of DL. Molecular genotyping may provide markers to identify L. (V.) braziliensis strains likely to cause this emerging, hard-to-treat form of ATL.
PMCID: PMC3503016  PMID: 23035200
22.  Socio-Demographic and Clinical Differences in Subjects with Tuberculosis with and without Diabetes Mellitus in Brazil – A Multivariate Analysis 
PLoS ONE  2013;8(4):e62604.
Several studies have evaluated the relationship between diabetes mellitus (DM) and tuberculosis (TB), but the nature of this relationship is not fully understood. TB incidence may be influenced by immunosuppression from DM, but this association may be confounded by other clinical and socioeconomic factors. We aimed to assess socio-demographic and clinical differences in TB patients with and without DM.
Using the Brazilian national surveillance system (SINAN), we compared 1,797 subjects with TB and DM with 29,275 subjects diagnosed with TB only in 2009. We performed multivariate analysis to identify factors associated with the presence of DM among TB patients.
Subjects with TB – DM were older; have initial positive sputum smear test (OR = 1.42, 95% CI 1.26–1.60), and were more likely to die from TB (OR = 1.44, 95% CI 1.03–2.01). They were less likely to have been institutionalized [in prison, shelter, orphanage, psychiatric hospital (OR = 0.74, 95% CI 0.60–0.93)]; developed extra pulmonary TB (OR = 0.62, 95% CI 0.51–0.75) and to return to TB treatment after abandonment (OR = 0.66, 95% CI 0.51–0.86).
Prevalence of NCD continues to rise in developing countries, especially with the rise of elderly population, the prevention and treatment of infectious diseases will be urgent. DM and TB represent a critical intersection between communicable and non-communicable diseases in these countries and the effect of DM on TB incidence and outcomes provide numerous opportunities for collaboration and management of these complex diseases in the national public health programs.
PMCID: PMC3634755  PMID: 23638123
23.  Psychometric Properties of the Patient Activation Measure among Individuals Presenting for Elective Lumbar Spine Surgery 
An individual’s propensity to engage in adaptive health and rehabilitation behaviors may account for variation in postsurgical outcome.
To determine the psychometric properties and construct validity of the recently developed Patient Activation Measure (PAM) (previously unused in spine research) in persons undergoing elective lumbar spine surgery.
We prospectively used the PAM to assess activation in 283 patients undergoing elective lumbar spine surgery. Reliability statistics were computed using repeated assessment (baseline and 1-week follow-up) before surgery. Additional psychological attributes were assessed at baseline and correlated with patient activation. Factor analysis was used to confirm the theoretical structure of patient activation.
Repeat PAM administrations had an intraclass correlation coefficient of 0.85. The PAM showed positive correlation with optimism (r = 0.75), hope (r = 0.73), self-efficacy (r = 0.65), and internal locus of control (r = 0.65) but no correlation with comorbidity (r = 0.01). Confirmatory factor analysis of the PAM items indicated reasonable fit between observed data and a three-factor patient activation model.
The PAM is a reliable, valid measure of patient activation for individuals undergoing elective lumbar spine surgery and may have clinical utility in identify those at risk for poor engagement in postsurgical rehabilitation.
PMCID: PMC3561629  PMID: 19916057
Patient Activation Measure; Validation; Positive psychology; Lumbar spine surgery
24.  Time-based distribution of Staphylococcus saprophyticus pulsed field gel-electrophoresis clusters in community-acquired urinary tract infections 
The epidemiology of urinary tract infections (UTI) by Staphylococcus saprophyticus has not been fully characterised and strain typing methods have not been validated for this agent. To evaluate whether epidemiological relationships exist between clusters of pulsed field gel-electrophoresis (PFGE) genotypes of S. saprophyticus from community-acquired UTI, a cross-sectional surveillance study was conducted in the city of Rio de Janeiro, Brazil. In total, 32 (16%) female patients attending two walk-in clinics were culture-positive for S. saprophyticus. Five PFGE clusters were defined and evaluated against epidemiological data. The PFGE clusters were grouped in time, suggesting the existence of community point sources of S. saprophyticus. From these point sources, S. saprophyticus strains may spread among individuals.
PMCID: PMC3974321  PMID: 23440118
Staphylococcus saprophyticus; PFGE genotype; UTI epidemiology
25.  An adjunctive therapeutic vaccine against reactivation and post-treatment relapse tuberculosis 
Vaccine  2011;30(2):459-465.
Preventing latently infected or inadequately treated individuals from progressing to active disease could make a major impact on tuberculosis (TB) control worldwide. The purpose of this study was to evaluate a new approach to prevent reactivation and TB relapse that combines drug treatment and vaccination. Mycobacterium tuberculosis harbors a gene called mce1R that, in vivo, negatively regulates a 13-gene cluster called the mce1 operon. In a Cornell mouse model, BALB/c mice infected with M. tuberculosis H37Rv disrupted in mce1R consistently develop latent infection and reactivation disease. We used this new mouse model to test a recombinant M. tuberculosis cell wall protein (Mce1A), encoded by a gene in the mce1 operon, for its ability to prevent post-treatment TB. At 32 weeks of follow-up, a complete sterilizing protection was observed in lungs of the vaccinated mice. Mce1A but not phosphate-buffered saline administered intraperitoneally during the period of latent infection prevented disease progression and proliferation of M. tuberculosis mce1R mutant. The only visible lung lesions in vaccinated mice included small clusters of lymphocytes, while the unvaccinated mice showed progressively enlarging granulomas comprised of foamy macrophages surrounded by lymphocytes. The combination of anti-TB drugs and a vaccine may serve as a powerful treatment modality against TB reactivation and relapse.
PMCID: PMC3246084  PMID: 22079078
tuberculosis; latent TB infection; adjunctive TB vaccine; therapeutic TB vaccine; mce1 operon; mce1R

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