A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

The Use of Wearable Technology to Objectively Measure Sleep Quality and Physical Activity Among Pregnant Women in Urban Lima, Peru: A Pilot Feasibility Study.

INTRODUCTION: Sleep quality and physical activity can affect the mental and physical health of pregnant women and their babies in utero. METHODS: We investigated the feasibility of objectively assessing sleep quality and physical activity among resource-constrained, pregnant women in urban Lima, Peru. Twenty pregnant women were asked to complete written sleep logs and wear ActiSleep, a wristwatch-like device that records sleep quality (consecutive minutes of uninterrupted sleep) and physical activity (steps), for seven consecutive days. Sociodemographic data and pregnancy characteristics were also collected. RESULTS: Of twenty women, 13 (65%) had sufficient data collected for analysis. The mean age of study participants was 26.3 years (SD = 3.9), with a mean sleep duration of 6.9 h (SD = 1.4). The median time for sleep onset was 21:15. The mean time for sleep latency was 17.3 min; and wake after sleep onset was 116 min. The mean number of awakenings was 20.4 (SD = 6.7); and sleep efficiency was 77.9%. For physical activity, participants averaged of 6,029 steps per day (SD = 3,087). DISCUSSION: Objective assessment of sleep quality and physical activity among pregnant women in a resource-constrained setting was promising, despite modest data collection completeness. Wearable technology could be used in health interventions to improve sleep quality and physical activity among this population.

Correction to: Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology.

Following publication of the original article [1]. The authors reported that there is a mistake in Fig. 1: the number of patients in the control group its 449 patients, instead of 455.

Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology.

BACKGROUND: Rapid and accurate diagnosis of childhood tuberculosis (TB) is challenging because children are often unable to produce the sputum sample required for conventional tests. Stool is an alternative sample type that is easy to collect from children, and studies investigating the use of stool for molecular detection of Mycobacterium tuberculosis (Mtb) have led to promising results. Our objective was to evaluate stool as an alternative specimen to sputum for Mtb detection in children. We did so using the TruTip workstation (Akonni Biosystems), a novel automated lysis and extraction platform. METHODS: We tested stool samples from 259 children aged 0-14 years old, in Lima, Peru who presented with TB symptoms. Following extraction with TruTip, we detected the presence of Mtb DNA by IS6110 real-time PCR. We calculated assay sensitivity in two groups: (1) children with culture confirmed TB (N = 22); and (2) children with clinically-diagnosed unconfirmed TB (N = 84). We calculated specificity among children in whom TB was ruled out (N = 153). Among children who were diagnosed with TB, we examined factors associated with a positive stool test. RESULTS: Assay sensitivity was 59% (95% confidence interval [CI]: 39-80%) and 1.2% (95% CI: 0.0-6.5%) in children with culture-confirmed and clinically-diagnosed unconfirmed TB, respectively, and specificity was 97% (95% CI: 93-99%). The assay detected Mtb in stool of 7/7 children with smear-positive TB (100% sensitivity; 95% CI: 59-100%), and in 6/15 of children with smear-negative, culture-confirmed TB (40% sensitivity; 95% CI: 16-68%). Older age, smear positivity, culture positivity, ability to produce sputum and cavitary disease were associated with a positive stool result. CONCLUSION: Testing of stool samples with the TruTip workstation and IS6110 amplification yielded sensitivity and specificity estimates comparable to other tests such as Xpert. Future work should include detection of resistance using the TruTip closed amplification system and assay optimization to improve sensitivity in children with low bacillary loads.

Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.

RATIONALE: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. OBJECTIVES: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. METHODS: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. MEASUREMENTS AND MAIN RESULTS: Each 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). CONCLUSIONS: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Feasibility of the string test for tuberculosis diagnosis in children between 4 and 14 years old.

BACKGROUND: The enteric string test can be used to obtain a specimen for microbiological confirmation of tuberculosis in children, but it is not widely used for this. The aim of this analysis to evaluate this approach in children with tuberculosis symptoms. METHODS: We conducted a cross-sectional study to assess children's ability to complete the test (feasibility), and self-reported pain (tolerability). We examined caregivers' and children's willingness to repeat the procedure (acceptability) and described the diagnostic yield of cultures for diagnostic tools. We stratified estimates by age and compared metrics to those derived for gastric aspirate (GA). RESULTS: Among 148 children who attempted the string test, 34% successfully swallowed the capsule. Feasibility was higher among children aged 11-14 than in children 4-10 years (83% vs 22% respectively, p < 0.0001). The string test was better tolerated than GA in both age groups; however, guardians and older children reported higher rates of willingness to repeat GA than the string test (86% vs. 58% in children; 100% vs. 83% in guardians). In 9 children with a positive sputum culture, 6 had a positive string culture. The one children with a positive gastric aspirate culture also had a positive string culture. CONCLUSION: Although the string test was generally tolerable and accepted by children and caregivers; feasibility in young children was low. Reducing the capsule size may improve test success rates in younger children.

Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial.

BACKGROUND: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. METHODS/DESIGN: The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. DISCUSSION: Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011.

Adolescent, caregiver and provider perspectives on tuberculosis treatment adherence: a qualitative study from Lima, Peru.

OBJECTIVES: To understand the perspectives of adolescents (10-19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents. DESIGN: We conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)'s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis. SETTING: Between August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru. PARTICIPANTS: We interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months' experience supervising TB treatment. RESULTS: Participants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment. CONCLUSION: Our findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers' ability to support adolescents.

Impact of prolonged isolation on adolescents with drug-susceptible tuberculosis in Lima, Peru: a qualitative study.

OBJECTIVES: Patients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects. METHODS: This study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews. RESULTS: We interviewed 85 participants: 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents' mental health. CONCLUSION: Prolonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents' rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

Is exclusive breastfeeding for six-months protective against pediatric tuberculosis?

Experts recommend exclusive breastfeeding from birth to six months because it protects against deadly childhood illness, including respiratory tract infections and diarrhea. We hypothesized that exclusive breastfeeding would decrease the risk of active tuberculosis (TB) in children. We analyzed cross-sectional data from 279 children in Lima, Peru aged 6 to 59 months with TB symptoms and a close adult contact with TB. Mothers self-reported breastfeeding, and children were evaluated for TB per national guidelines. To quantify the association between exclusive breastfeeding and TB, we estimated prevalence ratios using a generalized linear model with a log link, binomial distribution, and robust variance. Twenty-two percent of children were diagnosed with TB and 72% were exclusively breastfed for six months. We found no evidence that six months of exclusive breastfeeding was associated with TB disease in either bivariate analyses (prevalence ratio [PR] = 1.5; 95%CI = 0.8-2.5) or multivariable analyses adjusting for sex and socioeconomic status (adjusted PR = 1.6; 95%[CI] = 0.9-2.7). In post hoc analyses among children whose close TB contact was their mother, we found evidence of a weak positive association between breastfeeding and TB (aPR = 2.1; 95%[CI] = 0.9-4.9). This association was not apparent among children whose close contact was not the mother (aPR = 1.2; 95%[CI] = 0.6-2.4). Our results raise the possibility that children who are breastfed by mothers with TB may be at increased risk for TB, given the close contact. Due to the cross-sectional study design, these results should be interpreted with caution. If these findings are confirmed in longitudinal analyses, future interventions could aim to minimize TB transmission from mothers with TB to breastfeeding infants.

Incident Tuberculosis Diagnoses in Children at High Risk for Disease.

We followed 35 children meeting a research definition for unconfirmed tuberculosis (TB) but in whom a pediatric pulmonologist did not diagnose or treat TB. After a median follow-up of 16.4 months, most children were not diagnosed with TB following a comprehensive evaluation. However, 2 were diagnosed with TB, demonstrating high TB risk (6%; exact 95% CI, 1%-19%). In some contexts, researchers may wish to supplement these research definitions with clinical decision data and longitudinal follow-up in order to improve specificity.

Molecular detection of Mycobacterium tuberculosis from buccal swabs among adult in Peru.

Tuberculosis (TB) diagnosis relies on a sputum sample, which cannot be easily obtained from all symptomatic patients. Mycobacterium tuberculosis DNA can be detected from oral swabs, a noninvasive, safe alternative sample type; however, reported sensitivities have been variable and likely depend on sample collection, processing procedures and host characteristics. We analyzed three buccal swab samples from 123 adults with culture-confirmed TB in Lima, Peru. We compared the sensitivity and specificity of two sample collection devices (OmniSwab and EasiCollect FTA cards) and examined factors associated with detection. DNA was extracted with a commercially available kit and detected via real-time PCR IS6110 amplification. Overall sensitivity for buccal samples was 51% (95% Confidence Interval [CI] 42-60%). Specificity from a single sample among healthy controls was 96.7% (95% CI 83-99.9%). Positive sputum smear and cavitary disease, correlates of disease burden, were associated with detection via buccal swab. Although we observed higher sensitivities with the Omniswab samples, this appeared to be due primarily to differences in patient characteristics (e.g., cavitary disease). Overall, our findings support the potential for a buccal sample-based TB assay. Future work should focus on assay optimization and streamlining the assay workflow.

Detection of Mycobacterium Tuberculosis DNA in Buccal Swab Samples from Children in Lima, Peru.

We examined Mycobacterium tuberculosis DNA detection from buccal swab samples collected from children in Lima, Peru. DNA was extracted and amplified via real-time polymerase chain reaction. Sensitivity was 21% (95% confidence interval [CI]: 7%-42%) in 24 culture-confirmed tuberculosis cases and 4.6% (95% CI: 1%-13%) in 65 clinically diagnosed unconfirmed cases. Sensitivity was highest for smear-positive tuberculosis. Specificity was 99% in the 199 controls (95% CI: 96%-100%).

Diagnostic accuracy of molecular detection of Mycobacterium tuberculosis in pediatric stool samples: A systematic review and meta-analysis.

BACKGROUND: Stool is a promising specimen option to diagnose pediatric tuberculosis (TB), but studies have reported a wide range of test sensitivities. We conducted a meta-analysis to assess the accuracy of Xpert MTB/RIF or 'in-house' molecular tests on stool samples against culture or Xpert MTB/RIF on respiratory samples or clinically-diagnosed unconfirmed TB and aimed to identify factors that contribute to the heterogeneity of reported sensitivity. METHODS: We searched EMBASE and Pubmed databases and conference abstract books for studies reporting molecular stool testing against a clinical or microbiological reference standard among children. RESULTS: We identified 16 studies that included 2,481 children in stool test analyses. Pooled specificity was 98% [95%CI: 96-99], pooled sensitivity was 57% [95%CI: 40-72] against culture and 3% [95%CI: 2-6] among children with clinically-diagnosed, unconfirmed TB. There was much heterogeneity. Sensitivity was higher among children with a smear-positive sputum test. Rifampin resistance in stool was reported in two studies and detected in 5/14 children (36%). CONCLUSION: Our results suggest molecular stool tests have potential as diagnostic rule-in tests, but it is challenging to optimize sensitivity due to between-study variation in methodology and test procedures. Therefore, we recommend future research with rigorous study design and standardized results reporting.

Mycobacterium tuberculosis detection from oral swabs with Xpert MTB/RIF ULTRA: a pilot study.

OBJECTIVE: Diagnostic testing for tuberculosis depends on microbiological detection of Mycobacterium tuberculosis (Mtb) in sputum. For patients unable to expectorate sputum, such as children and individuals living with HIV, this poses barriers to rapid diagnosis and treatment initiation. Therefore, this study aimed to use oral swabs as an alternative sample type for Mtb detection via molecular testing. RESULTS: In a pilot study, we aimed to evaluate sensitivity of Mtb detection via oral swabs using Xpert MTB/RIF ULTRA. We enrolled 33 TB cases and 30 controls from Lima, Peru, and detected Mtb from oral swabs with a sensitivity of 45% (95% confidence interval (CI) 29-62%) and specificity of 100% (95% CI 89-100%) using liquid culture of sputum as reference test. Our current protocol will need optimization, but these results support future exploration of the use of oral swabs for Mtb detection.

Introducing solid foods: validity of report among mothers who do not adhere to recommended US guidelines.

BACKGROUND: Introducing solids foods to infants before 6 months has been associated with adverse long-term health outcomes. Studies and surveys frequently use maternal report to identify the age when infants start solid foods. OBJECTIVE: To address the accuracy of maternal report at 1 year postpartum regarding introduction of solid foods. METHODS: Between 2008 and 2009, the authors enrolled mothers of healthy term singletons at an urban Boston hospital within 72 hours of giving birth. We called mothers monthly for 6 months and asked if they had given their baby solid foods in the previous month. At 1 year, we contacted mothers again and asked when they first gave solid foods; answers at 1 year were compared with the data collected monthly. RESULTS: The authors analyzed data on 157 women, all of whom had, according to monthly responses, started solid foods before 6 months. At 1 year, only 14% (22/157) of reports matched data recorded monthly. Although 100% of women introduced solids before 6 months, at 1 year, 41.4% reported starting solids at 6 months. CONCLUSIONS: Among women who started feeding solids before 6 months, most did not give an accurate response at 1 year. Most said they started giving solids later than they did. Maternal report may not be the best way to collect such data, and health outcomes based on such data may be biased toward the null.