An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.

Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active ß-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human ß-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a ß-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization. This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics. These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.

Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages.

Many common diseases have an important inflammatory component mediated in part by macrophages. Here we used a systems genetics strategy to examine the role of common genetic variation in macrophage responses to inflammatory stimuli. We examined genome-wide transcript levels in macrophages from 92 strains of the Hybrid Mouse Diversity Panel. We exposed macrophages to control media, bacterial lipopolysaccharide (LPS), or oxidized phospholipids. We performed association mapping under each condition and identified several thousand expression quantitative trait loci (eQTL), gene-by-environment interactions, and eQTL "hot spots" that specifically control LPS responses. We used siRNA knockdown of candidate genes to validate an eQTL hot spot in chromosome 8 and identified the gene 2310061C15Rik as a regulator of inflammatory responses in macrophages. We have created a public database where the data presented here can be used as a resource for understanding many common inflammatory traits that are modeled in the mouse and for the dissection of regulatory relationships between genes.

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis.

BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 µg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER: NCT02749630.

Postweaning cafeteria diet induces a short-term metabolic disfunction and a differential vulnerability to develop anxiety-like and depressive-like behaviors in male but not female rats.

Children and adolescents are high consumers of Western diets (rich in fat and sugars), which is a risk factor for overweight and obesity. Moreover, the presence of anxiety and depression among this population has increased significantly. This study explores in young postweaning rats the association between Western diet consumption and the development of metabolic and behavioral disturbances. At postnatal day (PN) 24, Wistar rats of both sexes were weaned and assigned to a control or cafeteria diet (CAF) group. After short-term exposure, a group of rats was euthanized at PN31 to obtain abdominal fat pads and blood samples. Another group of rats was tested in the open-field test, splash test, anhedonia test, and social play across 11 days (PN32-42). The CAF groups exhibited a significantly high level of body fat, serum glucose, triglycerides, leptin, and HOMA index when compared to the control groups. Only CAF males exhibited anxiety-like and depression-like behavior. Present results indicate that postweaning short-term exposure to a CAF diet has immediate detrimental effects on metabolism in both sexes. However, only CAF males showed mood disturbances. This study provides evidence that a CAF diet exerts immediate effects on behavior and metabolism in the postweaning period and that sexes present differential vulnerability.

"I left my shyness behind": Sustainable community-led development and processes of motivation among rural Nicaraguan women.

This paper explores motivational changes of Nicaraguan women involved in sustainable community-led development. Sustainability is the goal of many organizations engaged with capacity development interventions. Research on what such sustainability entails point to a correlation between sustained action by communities, postintervention, and high levels of social capital, collective agency, and efficacy. But what factors motivate people to develop the social capital, self-efficacy, and agency that enable them to sustain their actions towards their communities' well-being? Using Self-Determination Theory as framework, and drawing from interview data, this qualitative paper explores the psychosocial processes rural Nicaraguan women undergo when initially engaging in, and eventually committing to community-led projects. Types of motivation in combination with shifts from initial to more sustained forms of motivation, we conclude, can inform current and future community development interventions on the role motivation plays toward establishing agency, efficacy, and relationships-that is, essential components of sustainable community development.

Systems genomics in age-related macular degeneration.

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.

Social inequalities shape diet composition among urban Colombians: The Colombian Nutritional Profiles cross-sectional study.

OBJECTIVE: To explore the influence of socioeconomic position on habitual dietary intake in Colombian cities. DESIGN: We conducted a cross-sectional, population-based study in five Colombian cities. Dietary intake was assessed with a 157-item semi-quantitative food frequency questionnaire previously developed for the Colombian population. Nutrient analysis was performed using national and international food composition tables. Socioeconomic position was assessed with two indicators: a government-defined, asset-based, household-level index called socioeconomic stratum (SES) and, among adults, highest educational level attained. SETTING: The five main urban centers of Colombia: Bogotá, Medellin, Barranquilla, Cali and Bucaramanga. PARTICIPANTS: Probabilistic, multistage sample of 1865 participants (n=1491 for analyses on education). RESULTS: For both sexes, increasing SES was associated with a lower consumption of energy (p-trend <0.001 in both sexes), carbohydrates (p-trend ˂0.001 in both sexes), sodium (p-trend=0.005 in males, <0.001 in females), saturated fatty acids (p-trend <0.001 in both sexes) and among females, cholesterol (p-trend=0.002). More educated men consumed significantly less energy and carbohydrates (p-trend=0.036 and ˂0.001, respectively). Among men, intake of trans fats increased monotonically with educational level, being 21% higher among college graduates relative to those with only elementary education (p-trend=0.023). Among women, higher educational level was associated with higher MUFA intake (p-trend=0.027). CONCLUSIONS: SES and educational level are strong correlates of the usual diet of urban Colombians. Economically deprived and less educated segments of society display dietary habits that make them vulnerable to chronic diseases and should be the primary target of public health nutrition policies.

Ultrasound in situ characterization of hybrid additively manufactured Ti6Al4V.

A major barrier for the full utilization of metal additive manufacturing (AM) technologies is quality control. Additionally, in situ real time nondestructive monitoring is desirable due to the typical high value and low volume of components manufactured with metal AM. Depending on the application, characteristics such as the geometrical accuracy, porosity, defect size and content, and material properties are quantities of interest for in situ nondestructive evaluation (NDE). In particular, functionally tailored components made with hybrid processing require quantitative NDE of their microstructure and elastic properties. Ultrasonic NDE is able to quantify these relevant characteristics. In this work, an ultrasonic measurement system is used to collect in situ real time measurements during the manufacturing of samples made with a hybrid process, which combines directed energy deposition with milling. In addition to quantifying ultrasonic properties, the measurements are used to gather insight on other geometry, material, and process effects. The results show the utility of ultrasound to evaluate relevant properties during manufacturing of a functionalized material domain, while providing perspective on additional material evolution information obtained from ultrasonic signals.

Isolation and phenotypic characterization of tumor cells of patients with a diagnosis of ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related deaths. It causes approximately 125,000 deaths per year worldwide; its diagnosis is made in advanced stages resulting in a high mortality rate. The objective of the study was optimizing the isolation of cells obtained from the solid tumor and ascitic fluid of patients with ovarian cancer and the phenotype with markers related to the epithelial-mesenchymal transition. For this, the solid tumor tissue was disaggregated and cultivated with different methodologies. As a result, cell growth was obtained and epi-immunofluorescence was performed using antibodies against E-cadherin, EpCAM, N-cadherin, vimentin, CD133, and CD44. The primary culture from the solid tumor was obtained using Dispase II and DMEM/F12. Finally, heterogeneity was detected in terms of the expression of mesenchymal and epithelial type markers in the two types of isolated cells. Additionally, CD133 and CD44 expression was detected, proteins associated with the tumor stem cells phenotype.

Epigenome-wide association in adipose tissue from the METSIM cohort.

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabolic syndrome traits, we profiled global methylation levels in subcutaneous abdominal adipose tissue. We measured association between 32 clinical traits related to diabetes and obesity in 201 people from the Metabolic Syndrome in Men cohort. We performed epigenome-wide association studies between DNA methylation levels and traits, and identified associations for 13 clinical traits in 21 loci. We prioritized candidate genes in these loci using expression quantitative trait loci, and identified 18 high confidence candidate genes, including known and novel genes associated with diabetes and obesity traits. Using methylation deconvolution, we examined which cell types may be mediating the associations, and concluded that most of the loci we identified were specific to adipocytes. We determined whether the abundance of cell types varies with metabolic traits, and found that macrophages increased in abundance with the severity of metabolic syndrome traits. Finally, we developed a DNA methylation-based biomarker to assess type 2 diabetes risk in adipose tissue. In conclusion, our results demonstrate that profiling DNA methylation in adipose tissue is a powerful tool for understanding the molecular effects of metabolic syndrome on adipose tissue, and can be used in conjunction with traditional genetic analyses to further characterize this disorder.

Components of the transitional care model (TCM) to reduce readmission in geriatric patients: a systematic review.

BACKGROUND: Demographic changes are taking place in most industrialized countries. Geriatric patients are defined by the European Union of Medical Specialists as aged over 65 years and suffering from frailty and multi-morbidity, whose complexity puts a major burden on these patients, their family caregivers and the public health care system. To counteract negative outcomes and to maintain consistency in care between hospital and community dwelling, the transitional of care has emerged over the last several decades. Our objectives were to identify and summarize the components of the Transitional Care Model implemented with geriatric patients (aged over 65 years, with multi-morbidity) for the reduction of all-cause readmission. Another objective was to recognize the Transitional Care Model components' role and impact on readmission rate reduction on the transition of care from hospital to community dwelling (not nursing homes). METHODS: Randomized controlled trials (sample size ≥50 participants per group; intervention period ≥30 days), with geriatric patients were included. Electronic databases (MEDLINE, CINAHL, PsycINFO and The Cochrane Central Register of Controlled Trials) were searched from January 1994 to December 2019 published in English or German. A qualitative synthesis of the findings as well as a systematic assessment of the interventions intensities was performed. RESULTS: Three articles met the inclusion criteria. One of the included trials applied all of the nine Transitional Care Model components described by Hirschman and colleagues and obtained a high-intensity level of intervention in the intensities assessment. This and another trial reported reductions in the readmission rate (p < 0.05), but the third trial did not report significant differences between the groups in the longer follow-up period (up to 12 months). CONCLUSIONS: Our findings suggest that high intensity multicomponent and multidisciplinary interventions are likely to be effective reducing readmission rates in geriatric patients, without increasing cost. Components such as type of staffing, assessing and managing symptoms, educating and promoting self-management, maintaining relationships and fostering coordination seem to have an important role in reducing the readmission rate. Research is needed to perform further investigations addressing geriatric patients well above 65 years old, to further understand the importance of individual components of the TCM in this population.

Delays in diagnosing pulmonary tuberculosis within a context of medium incidence, Medellín, Colombia, 2017: an operational research.

BACKGROUND: Delay in tuberculosis (TB) diagnosis is one of the first obstacles for controlling the disease. Delays generate greater deterioration of the health of the patients and increase the possibilities of transmission and infection at home and in the community. The aim of the study was to identify profiles and individual variables associated with patient delays and health care system delays in patients with pulmonary tuberculosis (PTB) in Medellín, Colombia, a city that notifies 1400 new cases per year. METHODS: A retrospective cohort study in adults with PTB was conducted from May to September of 2017. Sociodemographic, health care-seeking behaviour, and clinical variables were measured. The outcomes were patient delay and health care system delay. The data were obtained from records of the local TB program, and a questionnaire was applied by the health care team that performs routine field visits. Simple correspondence analysis was used to identify groups (profiles), and their characteristics. Cox's proportional hazards model was carried out to identify the variables associated with the delays. RESULTS: The study included 183 patients. The total delay median was 101 days (IQR: 64-163). Patient delay was of 35 days (IQR: 14-84), the profile with greater delay belonged to consumers of psychoactive substances. The health care system delay was of 27 days (IQR: 7-89), the attributes of the profile with greater delay were being a female, having more than two consultations before the diagnosis, and having prescribed antibiotics. Basic-medium educational level [HRa = 0.69; 95% CI (0.49-0.97)] and having a TB home contact [HRa = 0.68; 95% CI (0.48-0.96)] were associated with greater patient delay. Having negative acid-fast bacilli (AFB) smear [HRa = 0.64; 95% CI (0.45-0.92)] and more than two consultations before the diagnosis [HRa = 0.33; 95% CI (0.22-0.49)] was associated with greater health care system delay. CONCLUSIONS: Data from epidemiological surveillance allowed locating risk groups with delays in TB diagnosis which requires the prioritisation of the local TB control program to promote early detection and prevention of adverse outcomes.

Diesel exhaust particles dysregulate multiple immunological pathways in murine macrophages: Lessons from microarray and scRNA-seq technologies.

Exposure to ambient particulate matter has been shown to promote a variety of disorders, including cardiovascular diseases predominantly of ischemic etiology. However, the mechanisms linking inhaled particulates with systemic vascular effects, resulting in worsened atherosclerosis, are not well defined. We assessed the potential role of macrophages in translating these effects by analyzing gene expression patterns in response to diesel exhaust particles (DEP) at the average cell level, using Affymetrix microarrays in peritoneal macrophages in culture (in vitro), and at the individual cell level, using single-cell RNA sequencing (scRNA-seq) in alveolar macrophages collected from exposed mice (in vivo). Peritoneal macrophages were harvested from C57BL/6J mice and treated with 25 µg/mL of a DEP methanol extract (DEPe). These cells exhibited significant (FDR < 0.05) differential expression of a large number of genes and enrichment in pathways, especially engaged in immune responses and antioxidant defense. DEPe led to marked upregulation of heme oxygenase 1 (Hmox1), the most significantly upregulated gene (FDR = 1.75E-06), and several other antioxidant genes. For the in vivo work, C57BL/6J mice were subjected to oropharyngeal aspiration of 200 µg of whole DEP. The gene expression profiles of the alveolar macrophages harvested from these mice were analyzed at the single-cell level using scRNA-seq, which showed significant dysregulation of a broad number of genes enriched in immune system pathways as well, but with a large heterogeneity in how individual alveolar macrophages responded to DEP exposures. Altogether, DEP pollutants dysregulated immunological pathways in macrophages that may mediate the development of pulmonary and systemic vascular effects.

Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci.

Folate B12-dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway-catalyzed by betaine-homocysteine methyltransferase (BHMT)-for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J Bhmt (betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk (N = 8) and observed elevation of S-adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione S-transferase and cytokeratin 8-18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed. Of these DMCs, 52% were located in one 15.5-Mb locus on chromosome 13, which encompassed the Bhmt gene and defined a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel data, which consisted of 100 inbred strains of mice, we identified 97 DMCs that were affected by Bhmt genetic variation in the same region, with 7 overlapping those found in Bhmt-null mice (P < 0.001). At all time points, we found a hypomethylated region mapping to Iqgap2 (IQ motif-containing GTPase activating protein 2) and F2rl2 (proteinase-activated receptor-3), 2 genes that were also silenced and underexpressed, respectively.-Lupu, D. S., Orozco, L. D., Wang, Y., Cullen, J. M., Pellegrini, M., Zeisel, S. H. Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci.

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States.

RATIONALE: Only a small portion of the known heritability of cardiovascular diseases, such as heart failure, can be explained based on single-gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in noncoding regions may affect cellular function and response to disease, but the mechanisms are unknown. OBJECTIVE: We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure. METHODS AND RESULTS: BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure, respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylomes in the basal state between strains and then after isoproterenol treatment. Single-base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression before environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of comethylated genes displayed correlation with other protein-based epigenetic marks, supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart. CONCLUSIONS: This study provides the first single-base resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.

Pediatric Inpatient and Emergency Dermatology Consultations: A 5-Year Retrospective Analysis.

OBJECTIVE: To characterize and analyze the inpatient and emergency pediatric dermatology consults in our academic hospital center. METHODS: We reviewed 485 consultations that were done by the University of Puerto Rico Department of Dermatology from July 2007 to June 2012. The date, patient age and gender, consulting service, presumptive diagnosis, final diagnosis, and diagnostic procedures performed were documented for each consult. RESULTS: The patients' ages ranged from newborn to 18 years; the 13 to 18 years age group was the most common (29%). Dermatology consults were requested by the general pediatrics ward, primarily (32%), followed by the emergency room (25%). In 236 cases (48.6%), a vague diagnostic impression was provided by the consulting service, whereas in 249 (51.4%) cases, a specific or differential diagnosis was provided. The dermatology service changed the diagnosis in 12% (58/249) of the evaluated cases. The most common misdiagnoses were allergic contact dermatitis, drug eruption, papular urticaria, nutritional deficiency, atopic dermatitis, seborrheic dermatitis, cellulitis, and herpes infection. The most common diagnoses encountered were inflammatory skin conditions, infectious diseases, and drug eruptions. Skin biopsy was the most common procedure performed. In 30% of the cases, more than 1 procedure was performed as part of the evaluation work-up. CONCLUSION: Our study demonstrates the important role of the dermatologist in the diagnosis and management of pediatric patients with dermatological diseases. The information contained within this manuscript should contribute to raising the awareness of pediatricians regarding the most common dermatological diagnoses in this patient population.

A Cross-Sectional Survey of the Zika Virus and its Prevention: The Knowledge, Thoughts, and Beliefs of a Community of Residents in Caguas, Puerto Rico.

OBJECTIVE: The objective of this study was to explore the knowledge, thoughts, and beliefs regarding the Zika virus and its prevention in a community of residents in the municipality of Caguas, Puerto Rico, and elicit their concerns and perceptions of risk. METHODS: A quantitative, non experimental, descriptive, cross-sectional correlational study was conducted in a community in Caguas, Puerto Rico. A structured questionnaire was administered to a sample of 158 residents, aged 21 and older, who participated voluntarily. The data were analyzed using SPSS version 17 via univariate and bivariate analysis. RESULTS: Of 158 surveyed, 64.6% were women; with a population average of 53.85 years. Of the respondents who believed that they would be affected in some way if they were infected by the Zika virus, over half (52.3%) felt that the virus represented a significant threat to their emotional stability. Of those who perceived emotional threat, 39.5% (n=32) continued to study after completing high school (X2=9.217, p=0.027), 57.9% (n=55) had private health insurance (X2=6.325; p=0.042), and 67.9% (n=55) reported it was little or unlikely to become infected (X2= 6.783; p=0.034). Out of those concerned, 57.4% (n=54) considered Zika very or extremely severe (X2=22.827, p<0.001) and 98.9% (n=93) clean the house surroundings as a preventive measure (X2 = 4.951, p=0.026). Lack of interest was the most common reason identified for not complying with preventive actions by the residents (89.2%). CONCLUSION: The underestimation both of the risk concerning the Zika virus and of its consequences was evident. This study reaffirms the need to develop a network that effectively and constantly communicates risk estimates, doing so while addressing the specific needs within the communities served by that network. Community interventions aimed at improving the benefits of and reducing the risks associated with and the perceived barriers to preventive behaviors are needed.

Dissonant health transition in the states of Mexico, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: Child and maternal health outcomes have notably improved in Mexico since 1990, whereas rising adult mortality rates defy traditional epidemiological transition models in which decreased death rates occur across all ages. These trends suggest Mexico is experiencing a more complex, dissonant health transition than historically observed. Enduring inequalities between states further emphasise the need for more detailed health assessments over time. The Global Burden of Diseases, Injuries, and Risk Factors Study 2013 (GBD 2013) provides the comprehensive, comparable framework through which such national and subnational analyses can occur. This study offers a state-level quantification of disease burden and risk factor attribution in Mexico for the first time. METHODS: We extracted data from GBD 2013 to assess mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) in Mexico and its 32 states, along with eight comparator countries in the Americas. States were grouped by Marginalisation Index scores to compare subnational burden along a socioeconomic dimension. We split extracted data by state and applied GBD methods to generate estimates of burden, and attributable burden due to behavioural, metabolic, and environmental or occupational risks. We present results for 306 causes, 2337 sequelae, and 79 risk factors. FINDINGS: From 1990 to 2013, life expectancy from birth in Mexico increased by 3·4 years (95% uncertainty interval 3·1-3·8), from 72·1 years (71·8-72·3) to 75·5 years (75·3-75·7), and these gains were more pronounced in states with high marginalisation. Nationally, age-standardised death rates fell 13·3% (11·9-14·6%) since 1990, but state-level reductions for all-cause mortality varied and gaps between life expectancy and years lived in full health, as measured by HALE, widened in several states. Progress in women's life expectancy exceeded that of men, in whom negligible improvements were observed since 2000. For many states, this trend corresponded with rising YLL rates from interpersonal violence and chronic kidney disease. Nationally, age-standardised YLL rates for diarrhoeal diseases and protein-energy malnutrition markedly decreased, ranking Mexico well above comparator countries. However, amid Mexico's progress against communicable diseases, chronic kidney disease burden rapidly climbed, with age-standardised YLL and DALY rates increasing more than 130% by 2013. For women, DALY rates from breast cancer also increased since 1990, rising 12·1% (4·6-23·1%). In 2013, the leading five causes of DALYs were diabetes, ischaemic heart disease, chronic kidney disease, low back and neck pain, and depressive disorders; the latter three were not among the leading five causes in 1990, further underscoring Mexico's rapid epidemiological transition. Leading risk factors for disease burden in 1990, such as undernutrition, were replaced by high fasting plasma glucose and high body-mass index by 2013. Attributable burden due to dietary risks also increased, accounting for more than 10% of DALYs in 2013. INTERPRETATION: Mexico achieved sizeable reductions in burden due to several causes, such as diarrhoeal diseases, and risks factors, such as undernutrition and poor sanitation, which were mainly associated with maternal and child health interventions. Yet rising adult mortality rates from chronic kidney disease, diabetes, cirrhosis, and, since 2000, interpersonal violence drove deteriorating health outcomes, particularly in men. Although state inequalities from communicable diseases narrowed over time, non-communicable diseases and injury burdens varied markedly at local levels. The dissonance with which Mexico and its 32 states are experiencing epidemiological transitions might strain health-system responsiveness and performance, which stresses the importance of timely, evidence-informed health policies and programmes linked to the health needs of each state. FUNDING: Bill & Melinda Gates Foundation, Instituto Nacional de Salud Pública.