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Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

BACKGROUND: Most of the data regarding the burden of hypertension in low-income and middle-income countries comes from cross-sectional surveys instead of longitudinal studies. We estimated the incidence of, and risk factors for, hypertension in four study sites with different degree of urbanisation and altitude. METHODS: Data from the CRONICAS Cohort Study, conducted in urban, semiurban and rural areas in Peru, was used. An age-stratified and sex-stratified random sample of participants was taken from the most updated census available in each site. Hypertension was defined as systolic blood pressure >/=140 mm Hg, or diastolic blood pressure >/=90 mm Hg, or self-report physician diagnosis and current treatment. The exposures were study site and altitude as well as modifiable risk factors. Incidence, incidence rate ratios (IRRs), 95% CIs and population-attributable fractions (PAFs) were estimated using generalised linear models. RESULTS: Information from 3237 participants, mean age 55.8 (SD+/-12.7) years, 48.4% males, was analysed. Overall baseline prevalence of hypertension was 19.7% (95% CI 18.4% to 21.1%). A total of 375 new cases of hypertension were recorded, including 5266 person-years of follow-up, with an incidence of 7.12 (95% CI 6.44 to 7.88) per 100 person-years. Individuals from semiurban site were at higher risk of hypertension compared with highly urbanised areas (IRR=1.76; 95% CI 1.39 to 2.23); however, those from high-altitude sites had a reduced risk (IRR=0.74; 95% CI 0.58 to 0.95). Obesity was the leading risk factor for hypertension with a great variation according to study site with PAF ranging from 12.5% to 42.4%. CONCLUSIONS: Our results suggest heterogeneity in the progression towards hypertension depending on urbanisation and site altitude.

BACKGROUND: The study aims were to estimate the incidence and risk factors for T2D in four settings with different degree of urbanization and altitude in Peru. METHODS: Prospective cohort study conducted in urban, semi-urban, and rural areas in Peru. An age- and sex-stratified random sample of participants was taken from the most updated census. T2D was defined as fasting blood glucose 7.0mmol/L or taking anti-diabetes medication. Exposures were divided into two groups: geographical variables (urbanization and altitude), and modifiable risk factors. Incidence, relative risks (RR), 95% confidence intervals (95%CI), and population attributable fractions (PAF) were estimated. RESULTS: Data from 3135 participants, 48.8% males, mean age 55.6years, was analyzed. Overall baseline prevalence of T2D was 7.1% (95%CI 6.2-8.0%). At follow-up, including 6207 person-years of follow-up, a total of 121 new T2D cases were accrued, equating to an incidence of 1.95 (95%CI 1.63-2.33) per 100 person-years. There was no urban to rural gradient in the T2D incidence; however, compared to sea level sites, participants living in high altitude had a higher incidence of diabetes (RR=1.58; 95%CI 1.01-2.48). Obesity had the highest attributable risk for developing T2D, although results varied by setting, ranging from 14% to 80% depending on urbanization and altitude. CONCLUSIONS: Our results suggest that the incidence of T2D was greater in high altitude sites. New cases of diabetes were largely attributed to obesity, but with substantial variation in the contribution of obesity depending on the environment. These findings can inform appropriate context-specific strategies to reduce the incidence of diabetes.

Background The epidemiological impact and cost-effectiveness of social protection and biomedical interventions for tuberculosis-affected households might be improved by risk stratification. We therefore derived and externally validated a household-level risk score to predict tuberculosis among contacts of patients with tuberculosis. Methods In this prospective cohort study, we recruited tuberculosis-affected households from 15 desert shanty towns in Ventanilla and 17 urban communities in Callao, Lima, Peru. Tuberculosis-affected households included index patients with a new diagnosis of tuberculosis and their contacts who reported being in the same house as the index patient for more than 6 h per week in the 2 weeks preceding index patient diagnosis. Tuberculosis-affected households were not included if the index patient had no eligible contacts or lived alone. We followed contacts until 2018 and defined household tuberculosis, the primary outcome, as any contact having any form of tuberculosis within 3 years. We used logistic regression to identify characteristics of index patients, contacts, and households that were predictive of household tuberculosis, and used these to derive and externally validate a household-level score. Findings Between Dec 12, 2007, and Dec 31, 2015, 16 505 contacts from 3 301 households in Ventanilla were included in a derivation cohort. During the 3-year follow-up, tuberculosis occurred in contacts of index patients in 430 (13%, 95% CI 12–14) households. Index patient predictors were pulmonary tuberculosis and sputum smear grade, age, and the maximum number of hours any contact had spent with the index patient while they had any cough. Household predictors were drug use, schooling of the female head of a household, and lower food spending. Contact predictors were if any of the contacts were children, number of lower-weight (body-mass index [BMI]

Background: Kidney health needs to be studied in low- and middle-income countries with populations living at high altitude and undergoing urbanization. We studied whether greater level of urbanization was associated with worse kidney function and higher hemoglobin was associated with worse kidney function at high altitude. Methods: Cross-sectional analysis of population-based studies in Peru including five sites at different altitude above the sea level and urbanization level (in decreasing order of urbanization): Lima (sea level), Arequipa (2335 m), urban Puno (3825 m), Tumbes (sea level), and rural Puno (3825 m). The exposures were urbanization and altitude as per study site, and hemoglobin (g/dL). The outcome was the estimated glomerular filtration rate (eGFR). Results: Four thousand two hundred eight people were studied: mean age was 57.4 years (standard deviation: 12.4) and 51.9% were women. In comparison to rural Puno, eGFR was similar in Lima; in comparison to rural Puno, Arequipa, urban Puno, and Tumbes had worse eGFR, for example, in Arequipa, beta = -8.07 (95% confidence interval [CI]: -10.90 to -5.24). Intermediate (beta = -8.60; 95% CI: -10.55 to -6.66) and high (beta = -11.21; 95% CI: -14.19 to -8.24) altitude were negatively correlated with eGFR when only urban places were analyzed. At high altitude, there was a trend for a negative association between hemoglobin and eGFR: beta = -1.09 (95% CI: -2.22 to 0.04). Conclusions: Apparently, higher altitude and level of urbanization, except for one highly urbanized site, were associated with worse kidney function. Our findings suggest that some of the adverse impact of high altitude on kidney function has been balanced by the lower risk conferred by rural environments.

Aims. Prognostic thresholds to identify new type 2 diabetes mellitus (T2DM) cases using the HOMA-IR have not been defined. We studied the HOMA-IR performance to identify incident T2DM cases and to assess if the thresholds varied according to urbanization and altitude in Peru. Methods. Longitudinal analysis. The outcome was incident T2DM cases: self-report diagnosis and fasting glucose. The exposure was the HOMA-IR. Receiver operating characteristic (ROC) curves were plotted, and the area under the ROC curve (AUC) was estimated with 95% confidence intervals (95% CIs). Results are presented overall and stratified by study site (Lima, Tumbes, urban Puno, and rural Puno), rurality (urban, semiurban, and rural), and altitude (low and high). Results. A total of 3120 participants (mean age: 55.6 years, 51.2% females) contributed data to this analysis. The median baseline HOMA-IR was 1.7 (IQR 1.0–2.9), with median values ranging from 1.1 in rural Puno to 2.0 in Lima and Tumbes (). Overall for incident T2DM, the AUC was 0.69 (95% CI: 0.64–0.74) with an empirical threshold of 2.8 yielding a positive likelihood ratio of 2.30 and a negative one of 0.61; the positive and negative predictive values were 14.6% and 95.7%, respectively. The empirical thresholds varied within the variables of interest, for example, from 0.9 in urban Puno to 2.9 in Lima. Conclusions. Using the HOMA-IR to identify incident T2DM cases seems to yield moderate accuracy. The HOMA-IR could help improve identifying people at high risk of T2DM.

In this study, 132 patients with lymphadenopathy were investigated. Fifty-two (39.4%) were diagnosed with tuberculosis (TB). The microscopic observation drug susceptibility (MODS) assay provided rapid (13 days), accurate diagnosis (sensitivity, 65.4%) and reliable drug susceptibility testing (DST). Despite its lower sensitivity than that of other methods, its faster results and simultaneous DST are advantageous in resource-poor settings, supporting the incorporation of MODS into diagnostic algorithms for extrapulmonary TB.

BACKGROUND: Cough frequency, and its duration, is a biomarker that can be used in low-resource settings without the need of laboratory culture and has been associated with transmission and treatment response. Radiologic characteristics associated with increased cough frequency may be important in understanding transmission. The relationship between cough frequency and cavitary lung disease has not been studied. METHODS: We analyzed data in 41 adults who were HIV negative and had culture-confirmed, drug-susceptible pulmonary TB throughout treatment. Cough recordings were based on the Cayetano Cough Monitor, and sputum samples were evaluated using microscopic observation drug susceptibility broth culture; among culture-positive samples, bacillary burden was assessed by means of time to positivity. CT scans were analyzed by a US-board-certified radiologist and a computer-automated algorithm. The algorithm evaluated cavity volume and cavitary proximity to the airway. CT scans were obtained within 1 month of treatment initiation. We compared small cavities (≤ 7 mL) and large cavities (> 7 mL) and cavities located closer to (≤ 10 mm) and farther from (> 10 mm) the airway to cough frequency and cough cessation until treatment day 60. RESULTS: Cough frequency during treatment was twofold higher in participants with large cavity volumes (rate ratio [RR], 1.98; P = .01) and cavities located closer to the airway (RR, 2.44; P = .001). Comparably, cough ceased three times faster in participants with smaller cavities (adjusted hazard ratio [HR], 2.89; P = .06) and those farther from the airway (adjusted HR, 3.61;, P = .02). Similar results were found for bacillary burden and culture conversion during treatment. CONCLUSIONS: Cough frequency during treatment is greater and lasts longer in patients with larger cavities, especially those closer to the airway.

SETTING: There remains a lack of effective and inexpensive diagnostic tools for active tuberculosis (TB) disease. Testing immune responses to proteins secreted by Mycobacterium tuberculosis, such as MPT64, may be a diagnostic option. OBJECTIVE: To evaluate the sensitivity and specificity of a patch test using MPT64 for the diagnosis of active TB disease. DESIGN: This randomised, double-blind, placebo-controlled, prospective study in Lima, Peru, involved 55 healthy controls and 457 symptomatic individuals referred for routine TB testing by the National TB Control Programme. All subjects underwent a comprehensive diagnostic workup, and received an active patch on one arm and a placebo patch on the opposite arm, which were read after 4 days. RESULTS: Eighty-one (18%) of the symptomatic participants were classified as having definite TB, while an additional 98 (21%) had probable TB. The patch tests performed the same in both groups, with a sensitivity of 27% and specificity of 74%. The area under the receiver operating characteristic curve was 0.495 (95%CI 0.425-0.565). CONCLUSIONS: Contrary to existing literature, the MPT64 patch was not sensitive and specific to detect active TB. Given the potential of the test, understanding possible differences in the protein source or underlying genetic factors should be explored further.

Despite the negative effects of high sodium and low potassium consumption on cardiovascular health, their consumption has not been quantified in sites undergoing urbanization. We aimed to determine the sodium and potassium consumption in a semi-urban area in Peru with a cross-sectional study. 24-h urine samples were collected. The outcomes were mean consumption of sodium and potassium, as well as adherence to their consumption recommendation

Background Chronic Kidney Disease (CKD) represents a great burden for the patient and the health system, particularly if diagnosed at late stages. Consequently, tools to identify patients at high risk of having CKD are needed, particularly in limited-resources settings where laboratory facilities are scarce. This study aimed to develop a risk score for prevalent undiagnosed CKD using data from four settings in Peru: a complete risk score including all associated risk factors and another excluding laboratory-based variables. Methods Cross-sectional study. We used two population-based studies: one for developing and internal validation (CRONICAS), and another (PREVENCION) for external validation. Risk factors included clinical- and laboratory-based variables, among others: sex, age, hypertension and obesity; and lipid profile, anemia and glucose metabolism. The outcome was undiagnosed CKD: eGFR

Background The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis. Methods We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta-analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression. Findings We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1·6, 95% CI 1·3–1·9, p

Congenital Trypanosoma cruzi transmission is now estimated to account for 22% of new infections, representing a significant public health problem across Latin America and internationally. Treatment during infancy is highly efficacious and well tolerated, but current assays for early detection fail to detect >50% of infected neonates and 9 month follow-up is low. : Women presenting for delivery in two urban hospitals in Santa Cruz department, Bolivia were screened by rapid test. Specimens from infants of infected women were tested by microscopy (micromethod), quantitative PCR (qPCR) and IgM trypomastigote excreted-secreted antigen (TESA)-blots at birth and 1 month, and by IgG serology at 6 and 9 months. : Among 487 infants of 476 seropositive women, congenital T. cruzi infection was detected in 38 infants of 35 mothers (7.8%). In cord blood, qPCR, TESA-blot and micromethod sensitivities/specificities were 68.6%/99.1%, 58.3%/99.1% and 16.7%/100%, respectively. When birth and 1 month results were combined, cumulative sensitivities reached 84.2%, 73.7% and 34.2%, respectively. Low birth weight and/or respiratory distress were reported in 11 (29%) infected infants. Infants with clinical signs had higher parasite loads and were significantly more likely to be detected by micromethod. : The proportion of T. cruzi infected infants with clinical signs has fallen from the 1990s, but symptomatic congenital Chagas disease still represents a significant, albeit increasingly challenging to detect, public health problem. Molecular methods could facilitate earlier diagnosis and circumvent loss to follow-up but remain logistically and economically prohibitive for routine screening in resource-limited settings.

Background: Cough is the major determinant of tuberculosis transmission. Despite this, there is a paucity of information regarding characteristics of cough frequency throughout the day and in response to tuberculosis therapy. Here we evaluate the circadian cycle of cough, cough frequency risk factors, and the impact of appropriate treatment on cough and bacillary load. Methods: We prospectively evaluated human immunodeficiency virus-negative adults (n = 64) with a new diagnosis of culture-proven, drug-susceptible pulmonary tuberculosis immediately prior to treatment and repeatedly until treatment day 62. At each time point, participant cough was recorded (n = 670) and analyzed using the Cayetano Cough Monitor. Consecutive coughs at least 2 seconds apart were counted as separate cough episodes. Sputum samples (n = 426) were tested with microscopic-observation drug susceptibility broth culture, and in culture-positive samples (n = 252), the time to culture positivity was used to estimate bacillary load. Results: The highest cough frequency occurred from 1 pm to 2 pm, and the lowest from 1 am to 2 am (2.4 vs 1.1 cough episodes/hour, respectively). Cough frequency was higher among participants who had higher sputum bacillary load (P < .01). Pretreatment median cough episodes/hour was 2.3 (interquartile range [IQR], 1.2-4.1), which at 14 treatment days decreased to 0.48 (IQR, 0.0-1.4) and at the end of the study decreased to 0.18 (IQR, 0.0-0.59) (both reductions P < .001). By 14 treatment days, the probability of culture conversion was 29% (95% confidence interval, 19%-41%). Conclusions: Coughs were most frequent during daytime. Two weeks of appropriate treatment significantly reduced cough frequency and resulted in one-third of participants achieving culture conversion. Thus, treatment by 2 weeks considerably diminishes, but does not eliminate, the potential for airborne tuberculosis transmission.

Background: Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss. Methods: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB. Results: Overall, 147/1,545 (9.5 %) subjects had culture-positive TB, of which 32 (21.8 %) had DR-TB (MDR, 13.6 %; isoniazid mono-resistant, 7.5 %; rifampicin mono-resistant, 0.7 %). A total of 553 subjects (35.8 %) reported one or more MDR-TB risk factors; of these, 506 (91.5 %; 95 % CI, 88.9–93.7 %) did not have TB, 32/553 (5.8 %; 95 % CI, 3.4–8.1 %) had drug-susceptible TB, and only 15/553 (2.7 %; 95 % CI, 1.5–4.4 %) had DR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2 %; 95 % CI, 34.7–70.9). Conclusions: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority.

Accurate noninvasive tests for diagnosing Helicobacter pylori infection in very young children are strongly required. We investigated the agreement between the [¹³C] urea breath test ([¹³C]UBT) and a monoclonal ELISA (HpSA) for detection of H. pylori antigen in stool. From October 2007 to July 2011, we enrolled 414 infants (123 from Brazil and 291 from Peru) of ages 6 to 30 months. Breath and stool samples were obtained at intervals of at least 3 months from Brazilian (n = 415) and Peruvian (n = 908) infants. [¹³C]UBT and stool test results concurred with each other in 1,255 (94.86%) cases (kappa coefficient = 0.90; 95% confidence interval [CI] = 0.87 to 0.92). In the H. pylori-positive group, delta-over-baseline (DOB) and optical density (OD) values were positively correlated (r = 0.62; P < 0.001). The positivity of the tests was higher (P < 0.001; odds ratio [OR] = 6.01; 95% CI = 4.50 to 8.04) in Peru (546/878; 62.2%) than in Brazil (81/377; 21.5%) and increased with increasing age in Brazil (P = 0.02), whereas in Peru it decreased with increasing age (P < 0.001). The disagreement between the test results was associated with birth in Brazil and female gender but not with age and diarrhea. Our results suggest that both [¹³C]UBT and the stool monoclonal test are reliable for diagnosing H. pylori infection in very young children, which will facilitate robust epidemiological studies in infants and toddlers.

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N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent.