Parental body mass index and blood pressure are associated with higher body mass index and blood pressure in their adult offspring: a cross-sectional study in a resource-limited setting in northern Peru.

OBJECTIVES: High body mass index (BMI) and blood pressure (BP) are major contributors to the high burden of non-communicable diseases in adulthood. Individual high-risk and population approaches for prevention require newer strategies to target these risk factors and focusing on the family to introduce prevention initiatives appears as a promising scenario. Characterisation of the relationship between BMI and BP among the adult members of a given family merits evaluation. We conducted a secondary analysis of an implementation study in Tumbes, Peru, benefiting from data derived from families with at least one adult offspring. METHODS: The exposures of interest were the BMI, systolic BP (SBP) and diastolic BP (DBP) of the mother and father. The outcomes were the BMI, SBP and DBP of the offspring. Mixed-effects linear regression models were conducted. RESULTS: The mean age of the offspring, mothers and fathers was 29 (SD: 9.5), 54 (SD: 11.8) and 59 (SD: 11.6) years, respectively. Father's BMI was associated with a quarter-point increase in offspring BMI, regardless of the sex of the offspring. Mother's BMI had a similar effect on the BMI of her sons, but had no significant effect on her daughters'. Mother's SBP was associated with almost one-tenth of mmHg increase in the SBP of the adult offspring. There was no evidence of an association for DBP. CONCLUSIONS: In families with adult members, the higher the parents' BMI and SBP, the higher their adult offspring's levels will be.

Towards sustainable partnerships in global health: the case of the CRONICAS Centre of Excellence in Chronic Diseases in Peru.

Human capital requires opportunities to develop and capacity to overcome challenges, together with an enabling environment that fosters critical and disruptive innovation. Exploring such features is necessary to establish the foundation of solid long-term partnerships. In this paper we describe the experience of the CRONICAS Centre of Excellence in Chronic Diseases, based at Universidad Peruana Cayetano Heredia in Lima, Peru, as a case study for fostering meaningful and sustainable partnerships for international collaborative research. The CRONICAS Centre of Excellence in Chronic Diseases was established in 2009 with the following Mission: "We support the development of young researchers and collaboration with national and international institutions. Our motivation is to improve population's health through high quality research." The Centre's identity is embedded in its core values - generosity, innovation, integrity, and quality- and its trajectory is a result of various interactions between multiple individuals, collaborators, teams, and institutions, which together with the challenges confronted, enables us to make an objective assessment of the partnership we would like to pursue, nurture and support. We do not intend to provide a single example of a successful partnership, but in contrast, to highlight what can be translated into opportunities to be faced by research groups based in low- and middle-income countries, and how these encounters can provide a strong platform for fruitful and sustainable partnerships. In defiant contexts, partnerships require to be nurtured and sustained. Acknowledging that all partnerships are not and should not be the same, we also need to learn from the evolution of such relationships, its key successes, hurdles and failures to contribute to the promotion of a culture of global solidarity where mutual goals, mutual gains, as well as mutual responsibilities are the norm. In so doing, we will all contribute to instil a new culture where expectations, roles and interactions among individuals and their teams are horizontal, the true nature of partnerships.

Discovery of dipiperidines as new antitubercular agents.

As part of our ongoing research effort to develop new therapeutics for treatment of tuberculosis (TB), we synthesized a combinatorial library of 10,358 compounds on solid support using a pool-and-split technique and tested the resulting compounds for activity against Mycobacteriumtuberculosis. Structure-activity relationship (SAR) evaluation identified new compounds with antitubercular activity, including a novel hit series that is structurally unrelated to any existing antitubercular drugs, dipiperidines. Dipiperidine representatives exhibited MIC values as low as 7.8microM, the ability to induce promoter Rv0341 activated in response to cell wall biosynthesis inhibition, relatively low nonspecific cellular toxicity in the range of 30-162microM, and logP values less than 4.

Effect of salt substitution on community-wide blood pressure and hypertension incidence.

Replacement of regular salt with potassium-enriched substitutes reduces blood pressure in controlled situations, mainly among people with hypertension. We report on a population-wide implementation of this strategy in a stepped-wedge cluster randomized trial (NCT01960972). The regular salt in enrolled households was retrieved and replaced, free of charge, with a combination of 75% NaCl and 25% KCl. A total of 2,376 participants were enrolled in 6 villages in Tumbes, Peru. The fully adjusted intention-to-treat analysis showed an average reduction of 1.29 mm Hg (95% confidence interval (95% CI) (-2.17, -0.41)) in systolic and 0.76 mm Hg (95% CI (-1.39, -0.13)) in diastolic blood pressure. Among participants without hypertension at baseline, in the time- and cluster-adjusted model, the use of the salt substitute was associated with a 51% (95% CI (29%, 66%)) reduced risk of developing hypertension compared with the control group. In 24-h urine samples, there was no evidence of differences in sodium levels (mean difference 0.01; 95% CI (0.25, -0.23)), but potassium levels were higher at the end of the study than at baseline (mean difference 0.63; 95% CI (0.78, 0.47)). Our results support a case for implementing a pragmatic, population-wide, salt-substitution strategy for reducing blood pressure and hypertension incidence.

The solution structure of antigen MPT64 from Mycobacterium tuberculosis defines a new family of beta-grasp proteins.

The MPT64 protein and its homologs form a highly conserved family of secreted proteins with unknown function that are found within the pathogenic Mycobacteria genus. The founding member of this family from Mycobacterium tuberculosis (MPT64 or protein Rv1980c) is expressed only when Mycobacteria cells are actively dividing. By virtue of this relatively unique expression profile, Rv1980c is currently under phase III clinical trials to evaluate its potential to replace tuberculin, or purified protein derivative, as the rapid diagnostic of choice for detection of active tuberculosis infection. We describe here the NMR solution structure of Rv1980c. This structure reveals a previously undescribed fold that is based upon a variation of a beta-grasp motif most commonly found in protein-protein interaction domains. Examination of this structure in conjunction with multiple sequence alignments of MPT64 homologs identifies a candidate ligand-binding site, which may help guide future studies of Rv1980c function. The work presented here also suggests structure-based approaches for increasing the antigenic potency of a Rv1980c-based diagnostic.

Sodium and Potassium Consumption in a Semi-Urban Area in Peru: Evaluation of a Population-Based 24-Hour Urine Collection.

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: <2 g/day and ≥3.51 g/day, respectively. Bivariate analyses were conducted to identify socio-economic and clinical variables associated with the consumption recommendations of 602 participants, complete urine samples were found in 409: mean age of participants was 45.7 (standard deviation (SD): 16.2) years and 56% were women. The mean sodium and potassium consumption was 4.4 (SD: 2.1) and 2.0 (SD: 1.2) g/day. The sodium and potassium recommendation was met by 7.1% and 13.7% of the study sample; none of the participants met both recommendations. People not adherent to the sodium recommendation had higher diastolic (73.1 mmHg vs. 68.2 mmHg, p = 0.015) and systolic (113.1 mmHg vs. 106.3 mmHg, p = 0.047) blood pressure than those who comply with the recommendation. Public health actions ought to be implemented in areas undergoing urbanization to improve sodium and potassium consumption at the population level.

Implementation of foot thermometry plus mHealth to prevent diabetic foot ulcers: study protocol for a randomized controlled trial.

BACKGROUND: Diabetic foot neuropathy (DFN) is one of the most important complications of diabetes mellitus; its early diagnosis and intervention can prevent foot ulcers and the need for amputation. Thermometry, measuring the temperature of the feet, is a promising emerging modality for diabetic foot ulcer prevention. However, patient compliance with at-home monitoring is concerning. Delivering messages to remind patients to perform thermometry and foot care might be helpful to guarantee regular foot monitoring. This trial was designed to compare the incidence of diabetic foot ulcers (DFUs) between participants who receive thermometry alone and those who receive thermometry as well as mHealth (SMS and voice messaging) over a year-long study period. METHODS/DESIGN: This is an evaluator-blinded, randomized, 12-month trial. Individuals with a diagnosis of type 2 diabetes mellitus, aged between 18-80 years, having a present dorsalis pedis pulse in both feet, are in risk group 2 or 3 using the diabetic foot risk classification system (as specified by the International Working Group on the Diabetic Foot), have an operating cell phone or a caregiver with an operating cell phone, and have the ability to provide informed consent will be eligible to participate in the study. Recruitment will be performed in diabetes outpatient clinics at two Ministry of Health tertiary hospitals in Lima, Peru. INTERVENTIONS: participants in both groups will receive education about foot care at the beginning of the study and they will be provided with a thermometry device (TempStat™). TempStat™ is a tool that captures a thermal image of the feet, which, depending on the temperature of the feet, shows different colors. In this study, if a participant notes a single yellow image or variance between one foot and the contralateral foot, they will be prompted to notify a nurse to evaluate their activity within the previous 2 weeks and make appropriate recommendations. In addition to thermometry, participants in the intervention arm will receive an mHealth component in the form of SMS and voice messages as reminders to use the thermometry device, and instructions to promote foot care. OUTCOMES: the primary outcome is foot ulceration, evaluated by a trained nurse, occurring at any point during the study. DISCUSSION: This study has two principal contributions towards the prevention of DFU. First, the introduction of messages to promote self-management of diabetes foot care as well as using reminders as a strategy to improve adherence to daily home-based measurements. Secondly, the implementation of a thermometry-based strategy complemented by SMS and voice messages in an LMIC setting, with wider implications for scalability. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov: Identifier NCT02373592 .

Training and Capacity Building in LMIC for Research in Heart and Lung Diseases: The NHLBI-UnitedHealth Global Health Centers of Excellence Program.

Stemming the tide of noncommunicable diseases (NCDs) worldwide requires a multipronged approach. Although much attention has been paid to disease control measures, there is relatively little consideration of the importance of training the next generation of health-related researchers to play their important role in this global epidemic. The lack of support for early stage investigators in low- and middle-income countries interested in the global NCD field has resulted in inadequate funding opportunities for research, insufficient training in advanced research methodology and data analysis, lack of mentorship in manuscript and grant writing, and meager institutional support for developing, submitting, and administering research applications and awards. To address this unmet need, The National Heart, Lung, and Blood Institute-UnitedHealth Collaborating Centers of Excellence initiative created a Training Subcommittee that coordinated and developed an intensive, mentored health-related research experience for a number of early stage investigators from the 11 Centers of Excellence around the world. We describe the challenges faced by early stage investigators in low- and middle-income countries, the organization and scope of the Training Subcommittee, training activities, early outcomes of the early stage investigators (foreign and domestic) and training materials that have been developed by this program that are available to the public. By investing in the careers of individuals in a supportive global NCD network, we demonstrate the impact that an investment in training individuals from low- and middle-income countries can have on the preferred future of or current efforts to combat NCDs.

Applying the Triangle Taste Test to Assess Differences between Low Sodium Salts and Common Salt: Evidence from Peru.

BACKGROUND: In resourced-constrained settings, daily cooking practices are still the norm. Replacing sodium in regular salt to produce potassium-enriched salts are potential alternative routes to reduce sodium intake, paired with the benefit associated with potassium intake. This change would likely have effects on palatability and taste of prepared foods, yet a threshold to discriminate sensorial changes can be determined. The main goal of this study was to assess if the use of potassium-enriched salt substitutes lead to perceived differences in taste utilizing a sensory discrimination test. METHODS AND RESULTS: A triangle taste test was conducted and participants were offered samples of cooked rice prepared with different salts. The only ingredient that differed in the preparation was the salt used: 100%NaCl (regular salt) and salts where sodium was replaced by 50%, 33% or 25% KCl (potassium-enriched salt). Comparisons were carried out according to the minimum number of correct judgments. A total of 156 subjects, 49% males, mean age 41.0 years (SD±15.5) years, participated in the study. Samples using 25% potassium-enrichment were indistinguishable in terms of taste from regular salt, whereas samples with 33% and 50% potassium-enrichment were distinguishable. Results were consistent when stratified by sex and age. Less than 10% of participants attributed the differences to bitterness or metallic flavor. CONCLUSIONS: The 25% potassium-enriched salt is indistinguishable from regular salt. These findings suggest a potential to achieve sodium intake reduction strategies in cooking practices by substituting regular salt with potassium-enriched salt without affecting palatability.

Building a platform for translational research in chronic noncommunicable diseases to address population health: lessons from NHLBI supported CRONICAS in Peru.

The CRONICAS Centre of Excellence in Chronic Diseases, based at Universidad Peruana Cayetano Heredia, was created in 2009 with support from the U.S. National Heart, Lung, and Blood Institute (NHLBI). The vision of CRONICAS is to build a globally recognized center of excellence conducting quality and innovative research and generating high-impact evidence for health. The center's identity is embedded in its core values: generosity, innovation, integrity, and quality. This review has been structured to describe the development of the CRONICAS Centre, with a focus on highlighting the ongoing translational research projects and capacity-building strategies. The CRONICAS Centre of Excellence is not a risk-averse organization: it benefits from past experiences, including past mistakes, and improves upon them and thus challenges traditional research approaches. This ethos and environment are key to fostering innovation in research.

New tuberculosis vaccine development.

Tuberculosis (TB) is a devastating disease that kills more than three million people each year. Of these, 0.9 million are co-infected with HIV and numbers of infections and death continue to rise with the global spread of HIV. A new vaccine is desperately needed to control this epidemic that threatens to kill 90 million people over the next 3 decades. Outstanding work in research laboratories, combined with the success of genome sequencing, has resulted in a variety of candidate TB vaccines, many of which are sufficiently promising to advance into clinical trials. This review discusses the array of new candidate TB vaccines and the clinical studies that are currently planned.

Launching a salt substitute to reduce blood pressure at the population level: a cluster randomized stepped wedge trial in Peru.

BACKGROUND: Controlling hypertension rates and maintaining normal blood pressure, particularly in resource-constrained settings, represent ongoing challenges of effective and affordable implementation in health care. One of the strategies being largely advocated to improve high blood pressure calls for salt reduction strategies. This study aims to estimate the impact of a population-level intervention based on sodium reduction and potassium increase - in practice, introducing a low-sodium, high-potassium salt substitute - on adult blood pressure levels. METHODS/DESIGN: The proposed implementation research study includes two components: Phase 1, an exploratory component, and Phase 2, an intervention component. The exploratory component involves a triangle taste test and a formative research study designed to gain an understanding of the best implementation methods. Phase 2 involves a pragmatic stepped wedge trial design where the intervention will be progressively implemented in several clusters starting the intervention randomly at different times. In addition, we will evaluate the implementation strategy using a cost-effectiveness analysis. DISCUSSION: This is the first project in a Latin-American setting to implement a salt substitution intervention at the population level to tackle high blood pressure. Data generated and lessons learnt from this study will provide a strong platform to address potential interventions applicable to other similar low- and middle-income settings. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov NCT01960972.

Diabetic peripheral neuropathy in ambulatory patients with type 2 diabetes in a general hospital in a middle income country: a cross-sectional study.

AIM: We aimed to estimate the morbidity rate and associated factors for diabetic peripheral neuropathy (DPN) in a low-middle income country setting. METHODS: Cross-sectional study, data was gathered at Peru's Ministry of Health national specialized hospital for endocrinological conditions through standardized interviews, anthropometric measurements and blood tests for glycated haemoglobin (HbA1c). DPN was evaluated using two techniques: the Semmes-Weinstein monofilament test and the diabetic neuropathy symptom score. Overall prevalence and 95% confidence intervals (95% CI) were calculated. Potential factors related to DPN explored included body mass index, years with disease (<10 vs. ≥10 years), glycaemic control (HbA1c <7% vs. ≥7%), microalbuminuria, retinopathy, and current pharmacological treatment. Multivariable analysis was performed using Poisson analysis to calculate prevalence ratios. RESULTS: DPN was observed in 73/129 (56.6%) patients. In multivariable analysis adjusted by age and sex, the prevalence ratio of neuropathy was 1.4 times higher (95% CI 1.07-1.88) in patients who took insulin plus metformin compared to patients who used one treatment alone, and 1.4 higher (95% CI 1.02-1.93) in patients with ≥10 years of disease compared to those with a shorter duration of disease. Also we found some characteristics in foot evaluation associated to neuropathy such as deformities (p<0.001), onychomycosis (p = 0.012), abnormal Achilles reflex (p<0.001), pain perception (p<0.001) and vibration perception (p<0.001). CONCLUSION: DPN is highly frequent among patients with diabetes in a national specialized facility from Peru. Associated factors to DPN included being a diabetic patient for over ten years, and receiving insulin plus metformin.

Generation of a novel nucleic acid-based reporter system to detect phenotypic susceptibility to antibiotics in Mycobacterium tuberculosis.

UNLABELLED: We designed, constructed, and evaluated a prototype novel reporter system comprised of two functional cassettes: (i) the SP6 RNA polymerase gene under transcriptional control of a promoter active in mycobacteria and (ii) the consensus SP6 polymerase promoter that directs expression of an otherwise unexpressed sequence. We incorporated the reporter system into a mycobacteriophage for delivery into viable Mycobacterium tuberculosis, and introduction led to synthesis of an SP6 polymerase-dependent surrogate marker RNA that we detected by reverse transcriptase PCR (RT-PCR). The reporter confirmed the susceptibility profile of both drug-susceptible and drug-resistant M. tuberculosis strains exposed to first-line antitubercular drugs and required as little as 16 h of exposure to antibacterial agents targeting bacterial metabolic processes to accurately read the reaction. The reporter system translated the bacterial phenotype into a language interpretable by rapid and sensitive nucleic acid detection. As a phenotypic assay that works only on viable M. tuberculosis, it could be used to rapidly assess resistance to any drug, including drugs for which the mechanism of resistance is unknown or which result from many potential known (and unknown) genetic alterations. IMPORTANCE: The ability to detect antibiotic resistance of slow-growing bacteria (i.e., Mycobacterium tuberculosis) is hampered by two factors, the time to detection (weeks to months) and the resistance mechanism (unknown for many drugs), delaying the appropriate treatment of patients with drug-resistant or multidrug-resistant tuberculosis (TB). The novel technique described in this article uses a unique surrogate nucleic acid marker produced by phage that infects M. tuberculosis to record phenotypic antibiotic susceptibility in less than a day.

Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action.

Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.

Preclinical study of new TB drugs and drug combinations in mouse models.

Tuberculosis (TB) remains one of the leading infectious killers in the world. New anti-TB drugs and more effective drug combinations are urgently needed, particularly given the increasing incidence of drug-resistant TB and HIV-TB co-infection. This review describes the available mouse models of TB and describes their utility in the evaluation of new TB drug candidates and in the evaluation of the efficacy of new TB drug combinations. Some of the most recent patents on promising TB drug-candidates are also mentioned here.

Design and optimization of a recombinant system for large-scale production of the MPT64 antigen from Mycobacterium tuberculosis.

Early clinical trials of a potential new tuberculosis (TB) diagnostic, the Patch Test for Active TB (PTAT), used MPB64 protein that was purified from the spent medium of Bacillus Calmette-Guérin (BCG) Tokyo 172 vaccine production. The yield was poor, 0.05 mg/L, and the process for purification of the protein was complex, requiring four chromatographic steps. The combination of yield and purification complexity compromised the ability to produce the PTAT diagnostic in quantities sufficient for larger clinical trials and commercialization. We report here a highly efficient method for the overexpression and purification of recombinant MPT64 from Escherichia coli (rMPT64) based upon a mild insolubility of rMPT64 following induction, and scalable anion-exchange and gel filtration chromatographies. Yields of protein were improved substantially to approximately 250 mg/L, and resulted in a preparation greater than 98% pure. Quantitative release assays were developed and used with MALDI-TOF mass spectrometry to confirm the identity of rMPT64. Using a guinea pig model of active TB, we found that rMPT64 elicited a specific immune response indistinguishable from that of MPB64 purified from BCG Tokyo culture filtrates. These results describe the first efficient and scalable protocol for production of rMPT64, demonstrate its activity in an animal model of active TB, and lay the foundation of ongoing and future use of the PTAT in clinical settings.