betAS: intuitive analysis and visualization of differential alternative splicing using beta distributions.

Next-generation RNA sequencing allows alternative splicing (AS) quantification with unprecedented resolution, with the relative inclusion of an alternative sequence in transcripts being commonly quantified by the proportion of reads supporting it as percent spliced-in (PSI). However, PSI values do not incorporate information about precision, proportional to the respective AS events' read coverage. Beta distributions are suitable to quantify inclusion levels of alternative sequences, using reads supporting their inclusion and exclusion as surrogates for the two distribution shape parameters. Each such beta distribution has the PSI as its mean value and is narrower when the read coverage is higher, facilitating the interpretability of its precision when plotted. We herein introduce a computational pipeline, based on beta distributions accurately modeling PSI values and their precision, to quantitatively and visually compare AS between groups of samples. Our methodology includes a differential splicing significance metric that compromises the magnitude of intergroup differences, the estimation uncertainty in individual samples, and the intragroup variability, being therefore suitable for multiple-group comparisons. To make our approach accessible and clear to both noncomputational and computational biologists, we developed betAS, an interactive web app and user-friendly R package for visual and intuitive differential splicing analysis from read count data.

Identifying biologically implausible values in big longitudinal data: an example applied to child growth data from the Brazilian food and nutrition surveillance system.

BACKGROUND: Several strategies for identifying biologically implausible values in longitudinal anthropometric data have recently been proposed, but the suitability of these strategies for large population datasets needs to be better understood. This study evaluated the impact of removing population outliers and the additional value of identifying and removing longitudinal outliers on the trajectories of length/height and weight and on the prevalence of child growth indicators in a large longitudinal dataset of child growth data. METHODS: Length/height and weight measurements of children aged 0 to 59 months from the Brazilian Food and Nutrition Surveillance System were analyzed. Population outliers were identified using z-scores from the World Health Organization (WHO) growth charts. After identifying and removing population outliers, residuals from linear mixed-effects models were used to flag longitudinal outliers. The following cutoffs for residuals were tested to flag those: -3/+3, -4/+4, -5/+5, -6/+6. The selected child growth indicators included length/height-for-age z-scores and weight-for-age z-scores, classified according to the WHO charts. RESULTS: The dataset included 50,154,738 records from 10,775,496 children. Boys and girls had 5.74% and 5.31% of length/height and 5.19% and 4.74% of weight values flagged as population outliers, respectively. After removing those, the percentage of longitudinal outliers varied from 0.02% (<-6/>+6) to 1.47% (<-3/>+3) for length/height and from 0.07 to 1.44% for weight in boys. In girls, the percentage of longitudinal outliers varied from 0.01 to 1.50% for length/height and from 0.08 to 1.45% for weight. The initial removal of population outliers played the most substantial role in the growth trajectories as it was the first step in the cleaning process, while the additional removal of longitudinal outliers had lower influence on those, regardless of the cutoff adopted. The prevalence of the selected indicators were also affected by both population and longitudinal (to a lesser extent) outliers. CONCLUSIONS: Although both population and longitudinal outliers can detect biologically implausible values in child growth data, removing population outliers seemed more relevant in this large administrative dataset, especially in calculating summary statistics. However, both types of outliers need to be identified and removed for the proper evaluation of trajectories.

Evaluating the relationship between conditional cash transfer programme on preterm births: a retrospective longitudinal study using the 100 million Brazilian cohort.

BACKGROUND: Preterm births increase mortality and morbidity during childhood and later life, which is closely associated with poverty and the quality of prenatal care. Therefore, income redistribution and poverty reduction initiatives may be valuable in preventing this outcome. We assessed whether receipt of the Brazilian conditional cash transfer programme - Bolsa Familia Programme, the largest in the world - reduces the occurrence of preterm births, including their severity categories, and explored how this association differs according to prenatal care and the quality of Bolsa Familia Programme management. METHODS: A retrospective cohort study was performed involving the first live singleton births to mothersenrolled in the 100 Million Brazilian Cohort from 2004 to 2015, who had at least one child before cohort enrollment. Only the first birth during the cohort period was included, but born from 2012 onward. A deterministic linkage with the Bolsa Familia Programme payroll dataset and a similarity linkage with the Brazilian Live Birth Information System were performed. The exposed group consisted of newborns to mothers who received Bolsa Familia from conception to delivery. Our outcomes were infants born with a gestational age < 37 weeks: (i) all preterm births, (ii) moderate-to-late (32-36), (iii) severe (28-31), and (iv) extreme (< 28) preterm births compared to at-term newborns. We combined propensity score-based methods and weighted logistic regressions to compare newborns to mothers who did and did not receive Bolsa Familia, controlling for socioeconomic conditions. We also estimated these effects separately, according to the adequacy of prenatal care and the index of quality of Bolsa Familia Programme management. RESULTS: 1,031,053 infants were analyzed; 65.9% of the mothers were beneficiaries. Bolsa Familia Programme was not associated with all sets of preterm births, moderate-to-late, and severe preterm births, but was associated with a reduction in extreme preterm births (weighted OR: 0.69; 95%CI: 0.63-0.76). This reduction can also be observed among mothers receiving adequate prenatal care (weighted OR: 0.66; 95%CI: 0.59-0.74) and living in better Bolsa Familia management municipalities (weighted OR: 0.56; 95%CI: 0.43-0.74). CONCLUSIONS: An income transfer programme for pregnant women of low-socioeconomic status, conditional to attending prenatal care appointments, has been associated with a reduction in extremely preterm births. These programmes could be essential in achieving Sustainable Development Goals.

Ethnoracial disparities in childhood growth trajectories in Brazil: a longitudinal nationwide study of four million children.

BACKGROUND: The literature contains scarce data on inequalities in growth trajectories among children born to mothers of diverse ethnoracial background in the first 5 years of life. OBJECTIVE: We aimed to investigate child growth according to maternal ethnoracial group using a nationwide Brazilian database. METHODS: A population-based retrospective cohort study employed linked data from the CIDACS Birth Cohort and the Brazilian Food and Nutrition Surveillance System (SISVAN). Children born at term, aged 5 years or younger who presented two or more measurements of length/height (cm) and weight (kg) were followed up between 2008 and 2017. Prevalence of stunting, underweight, wasting, and thinness were estimated. Nonlinear mixed effect models were used to estimate childhood growth trajectories, among different maternal ethnoracial groups (White, Asian descent, Black, Pardo, and Indigenous), using the raw measures of weight (kg) and height (cm) and the length/height-for-age (L/HAZ) and weight-for-age z-scores (WAZ). The analyses were also adjusted for mother's age, educational level, and marital status. RESULTS: A total of 4,090,271 children were included in the study. Children of Indigenous mothers exhibited higher rates of stunting (26.74%) and underweight (5.90%). Wasting and thinness were more prevalent among children of Pardo, Asian, Black, and Indigenous mothers than those of White mothers. Regarding children's weight (kg) and length/height (cm), those of Indigenous, Pardo, Black, and Asian descent mothers were on average shorter and weighted less than White ones. Regarding WAZ and L/HAZ growth trajectories, a sharp decline in average z-scores was evidenced in the first weeks of life, followed by a period of recovery. Over time, z-scores for most of the subgroups analyzed trended below zero. Children of mother in greater social vulnerability showed less favorable growth. CONCLUSION: We observed racial disparities in nutritional status and childhood growth trajectories, with children of Indigenous mothers presenting less favorable outcomes compared to their White counterparts. The strengthening of policies aimed at protecting Indigenous children should be urgently undertaken to address systematic ethnoracial health inequalities.

Impacts of mining disasters on the ambulatory care of the Brazilian national health system: the cases of Mariana and Brumadinho/Brazil.

BACKGROUND: Disasters are events that bring with them effects that contribute to the disruption of the normality of a population and thus highlight the vulnerabilities of the health system. In Mariana and Brumadinho, the collapse of the dam of ore tailings brought with it several impacts that were felt in the short term and will be felt in the medium and long term. And that by being intensely intertwined with issues of economic and productive nature, has as its meaning an uninterrupted result of its activities. METHODS: Through the DATASUS database, two specific variables were chosen to perform the analysis: the approved amount and the approved value. For this research, a methodological device, the segmented regression line, was used to observe the influences that the disasters that occurred in Mariana and Brumadinho had on the ambulatory health systems. RESULTS: The results of the segmented regression line show that, with Mariana, the amount approved continued to grow throughout the period, which shows that there was no change because of the disaster. There was a reduction in spending. In Brumadinho, regarding the amount approved, there was an upward trend in the disaster's month, which did not change immediately afterwards, and regarding expenditure, the growth pattern was maintained in all three periods. Corroborating this data, the relative and absolute base elements show an increase in the amount approved and in the number of services provided at various posts compared with Minas Gerais. CONCLUSIONS: Based on the findings, it was possible to understand that although disasters exert an influence that may have some effect on the health system, the lack of significance sometimes cannot be interpreted as a lack of impact on the disaster. The segmented regression line outlines some effects that are not conclusive but indicative of a numerical interpretation and a trend interpretation.

Naringen's Effects on Diuresis and Prevention of Urolithiasis in Hypertensive Rats.

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.

Translation, Cultural Adaptation, and Psychometric Validation of the European Portuguese Version of the Iceland-Expressive Family Functioning Questionnaire (ICE-EFFQ).

A family's experience of mental illness can change the family's functioning. In clinical contexts, valid and reliable instruments that assess family functioning, therapeutic changes, and the effects of family nursing interventions are needed. This study focuses on the linguistic and cultural adaptation of the Iceland-Expressive Family Functioning Questionnaire (ICE-EFFQ) to European Portuguese and examines the psychometric properties of this instrument. A non-random sample of 121 Portuguese depressed patients and their relatives completed the questionnaire. Principal components analysis extracted 4 factors, explaining 55.58% of the total variance. Confirmatory factor analysis revealed acceptable adjustment quality indices. Cronbach's alpha coefficient was adequate for the global scale α = .86 and for the 4 subscales: communication α = .79, expression of emotions α = .68, problem-solving α = .71, and cooperation α = .61. The Portuguese version of ICE-EFFQ is a sensitive, valid, and reliable instrument for use with Portuguese families with adult members with depression and can be valuable in assessing these families' expressive functioning, before and after intervention.

The homeless, seizures, and epilepsy: a review.

This review aims to estimate the prevalence of seizures and epilepsy among homeless people in current literature as well as understand the main adversities that this group withstands. We conducted a search for "epilep*", "seizur*", and "homeles*" in titles and abstracts of articles in PubMed. Overall, 25 articles met the final inclusion criteria and warranted analyses. This study suggests that the prevalence of epilepsy in the homeless population is between 2 and 30%, whereas the prevalence of homelessness in people with epilepsy is between 2 and 4%. Every study included in this review corroborates the increased prevalence of seizures and epilepsy among the homeless, which puts them at risk for worse outcomes related to this condition and numerous associated comorbidities. Further evidence is needed to clarify the distinction of primary and secondary seizures in this group, which shows a high rate of confounding factors for seizures like substance abuse or withdrawal and head injury, and to decrease the burden of epilepsy and homelessness in an already resource-deficient community.

Dipeptidyl peptidase 4 (DPP4) in fecal samples: validation of the extraction methodology and stability in short-term storage conditions.

OBJECTIVES: This study assesses the clinical relevance of dipeptidyl peptidase 4 (DPP4) membrane exopeptidase as a biomarker of inflammatory bowel disease (IBD). A spike-and-recovery approach of DPP4 in fecal samples was used to compare two different methods for protein extraction, followed by a stability assessment. METHODS: Fecal samples of healthy volunteers spiked with known concentrations of recombinant DPP4 were processed using a standard manual extraction protocol and the CALEX® protocol. The two methods were compared by quantification of fecal DPP4 by ELISA, followed by Bland-Altman analysis. For the stability assays DPP4 was extracted from fecal samples and stored under different conditions of temperature and time after collection. RESULTS: In general, the levels of spiked DPP4 in stool samples were lower with the manual protocol than in those obtained with the CALEX® method; this trend was corroborated by Bland-Altman analysis. Nonetheless, variability was within the acceptable limits for both protocols. In the stability assessment, no statistically significant differences were found between the results obtained under the different storage conditions. CONCLUSIONS: Both manual and CALEX® protocols provided equal extraction ability of DPP4 from stool samples. In addition, DPP4 provided flexibility in terms of sample storage enabling the accurate assessment of samples delivered up to a week before analysis.

Mapping the structural trends in zinc aluminosilicate glasses.

The structure of zinc aluminosilicate glasses with the composition (ZnO)x(Al2O3)y(SiO2)1-x-y, where 0 ≤ x < 1, 0 ≤ y < 1, and x + y < 1, was investigated over a wide composition range by combining neutron and high-energy x-ray diffraction with 27Al magic angle spinning nuclear magnetic resonance spectroscopy. The results were interpreted using an analytical model for the composition-dependent structure in which the zinc ions do not act as network formers. Four-coordinated aluminum atoms were found to be in the majority for all the investigated glasses, with five-coordinated aluminum atoms as the main minority species. Mean Al-O bond distances of 1.764(5) and 1.855(5) Å were obtained for the four- and five-coordinated aluminum atoms, respectively. The coordination environment of zinc was not observed to be invariant. Instead, it is dependent on whether zinc plays a predominantly network-modifying or charge-compensating role and, therefore, varies systematically with the glass composition. The Zn-O coordination number and bond distance were found to be 4.36(9) and 2.00(1) Å, respectively, for the network-modifying role vs 5.96(10) and 2.08(1) Å, respectively, for the charge-compensating role. The more open coordination environment of the charge-compensator is related to an enhanced probability of zinc finding bridging oxygen atoms as nearest-neighbors, reflecting a change in the connectivity of the glass network comprising four-coordinated silicon and aluminum atoms as the alumina content is increased.

Cesarean sections and early-term births according to Robson classification: a population-based study with more than 17 million births in Brazil.

BACKGROUND: Cesarean section (CS) rates are increasing worldwide and are associated with negative maternal and child health outcomes when performed without medical indication. However, there is still limited knowledge about the association between high CS rates and early-term births. This study explored the association between CSs and early-term births according to the Robson classification. METHODS: A population-based, cross-sectional study was performed with routine registration data of live births in Brazil between 2012 and 2019. We used the Robson classification system to compare groups with expected high and low CS rates. We used propensity scores to compare CSs to vaginal deliveries (1:1) and estimated associations with early-term births using logistic regression. RESULTS: A total of 17,081,685 live births were included. Births via CS had higher odds of early-term birth (OR 1.32; 95% CI 1.32-1.32) compared to vaginal deliveries. Births by CS to women in Group 2 (OR 1.50; 95% CI 1.49-1.51) and 4 (OR 1.57; 95% CI 1.56-1.58) showed the highest odds of early-term birth, compared to vaginal deliveries. Increased odds of an early-term birth were also observed among births by CS to women in Group 3 (OR 1.30, 95% CI 1.29-1.31), compared to vaginal deliveries. In addition, live births by CS to women with a previous CS (Group 5 - OR 1.36, 95% CI 1.35-1.37), a single breech pregnancy (Group 6 - OR 1.16; 95% CI 1.11-1.21, and Group 7 - OR 1.19; 95% CI 1.16-1.23), and multiple pregnancies (Group 8 - OR 1.46; 95% CI 1.40-1.52) had high odds of an early-term birth, compared to live births by vaginal delivery. CONCLUSIONS: CSs were associated with increased odds of early-term births. The highest odds of early-term birth were observed among those births by CS in Robson Groups 2 and 4.

Time trends and social inequalities in infant and young child feeding practices: national estimates from Brazil's Food and Nutrition Surveillance System, 2008-2019.

OBJECTIVE: To describe the time trends and socio-economic inequalities in infant and young child feeding practices in accordance with the Brazilian deprivation index (BDI). DESIGN: This time-series study analysed the prevalence of multiple breast-feeding and complementary feeding indicators based on data from the Brazilian Food and Nutrition Surveillance System, 2008-2019. Prais-Winsten regression models were used to analyse time trends. Annual percent change (APC) and 95 % CI were calculated. SETTING: Primary health care services, Brazil. PARTICIPANTS: Totally, 911 735 Brazilian children under 2 years old. RESULTS: Breast-feeding and complementary feeding practices differed between the extreme BDI quintiles. Overall, the results were more favourable in the municipalities with less deprivation (Q1). Improvements in some complementary feeding indicators were observed over time and evidenced such disparities: minimum dietary diversity (Q1: Δ 47·8-52·2 %, APC + 1·44, P = 0·006), minimum acceptable diet (Q1: Δ 34·5-40·5 %, APC + 5·17, P = 0·004) and consumption of meat and/or eggs (Q1: Δ 59·7-80·3 %, APC + 6·26, P < 0·001; and Q5: Δ 65·7-70·7 %, APC + 2·20, P = 0·041). Stable trends in exclusive breast-feeding and decreasing trends in the consumption of sweetened drinks and ultra-processed foods were also observed regardless the level of the deprivation. CONCLUSIONS: Improvements in some complementary food indicators were observed over time. However, the improvements were not equally distributed among the BDI quintiles, with children from the municipalities with less deprivation benefiting the most.

Notifications of work-related injuries and diseases: an observational study on a mining disaster.

INTRODUCTION: Accidents at work are events that endanger the health and life of workers. They are considered a public health problem, being the object of studies and actions in the Brazilian health system. The collapsed of the ore tailings dam in the municipality of Brumadinho, Brazil, in January 2019, shocked the world due to the proportion of environmental and human damage caused. In this context, concern for the health of workers gained prominence. This paper evaluated the impact of the collapse of the mining tailings dam in Brumadinho, on notifications of occupational health problems before and after the disaster. METHODS: An observational, longitudinal and retrospective study, of the time series type with a statistical approach was carried out on notifications of work-related injuries and diseases, available in the local database of the Notifiable Diseases Information System between January 2017 and December 2021. RESULTS: During the study period, 520 notifications of work-related injuries and conditions were registered. Of this total, 67.3% were serious work accidents, 26.0% mental disorders, 12.3% accidents with biological material and 2.9% repetitive strain injuries/musculoskeletal disorders, occupational dermatoses and induced hearing loss by noise. Occurrences were more frequent in 2019, the year in which the mining disaster occurred, recording 65.2% of total notifications. Regarding the volume of notifications after the disaster, there was a statistically significant reduction (p < 0.001) for accidents with biological material; significant increase for severe work accident and mental disorder. The average time between the occurrence of the injury and the notification showed a statistically significant reduction for accidents involving biological material (p = 0.001) and a significant increase for serious accidents at work (p = 0.016). CONCLUSIONS: It was demonstrated that there were changes in the number of notifications when comparing the period before and after the mining disaster, with a consequent impact on the health of workers, which may persist over the years.

Microparticles in the Development and Improvement of Pharmaceutical Formulations: An Analysis of In Vitro and In Vivo Studies.

Microparticulate systems such as microparticles, microspheres, microcapsules or any particle in a micrometer scale (usually of 1-1000 µm) are widely used as drug delivery systems, because they offer higher therapeutic and diagnostic performance compared to conventional drug delivery forms. These systems can be manufactured with many raw materials, especially polymers, most of which have been effective in improving the physicochemical properties and biological activities of active compounds. This review will focus on the in vivo and in vitro application in the last decade (2012 to 2022) of different active pharmaceutical ingredients microencapsulated in polymeric or lipid matrices, the main formulation factors (excipients and techniques) and mostly their biological activities, with the aim of introducing and discussing the potential applicability of microparticulate systems in the pharmaceutical field.

Cell transplantation and secretome based approaches in spinal cord injury regenerative medicine.

The axonal growth-restrictive character of traumatic spinal cord injury (SCI) makes finding a therapeutic strategy a very demanding task, due to the postinjury events impeditive to spontaneous axonal outgrowth and regeneration. Considering SCI pathophysiology complexity, it has been suggested that an effective therapy should tackle all the SCI-related aspects and provide sensory and motor improvement to SCI patients. Thus, the current aim of any therapeutic approach for SCI relies in providing neuroprotection and support neuroregeneration. Acknowledging the current SCI treatment paradigm, cell transplantation is one of the most explored approaches for SCI with mesenchymal stem cells (MSCs) being in the forefront of many of these. Studies showing the beneficial effects of MSC transplantation after SCI have been proposing a paracrine action of these cells on the injured tissues, through the secretion of protective and trophic factors, rather than attributing it to the action of cells itself. This manuscript provides detailed information on the most recent data regarding the neuroregenerative effect of the secretome of MSCs as a cell-free based therapy for SCI. The main challenge of any strategy proposed for SCI treatment relies in obtaining robust preclinical evidence from in vitro and in vivo models, before moving to the clinics, so we have specifically focused on the available vertebrate and mammal models of SCI currently used in research and how can SCI field benefit from them.

Differences in risk factors for incident and recurrent preterm birth: a population-based linkage of 3.5 million births from the CIDACS birth cohort.

BACKGROUND: Preterm birth (PTB) is a syndrome resulting from a complex list of underlying causes and factors, and whether these risk factors differ in the context of prior PTB history is less understood. The aim of this study was to explore whether PTB risk factors in a second pregnancy were different in women with versus without previous PTB. METHODS: We conducted a population-based cohort study using data from the birth cohort of the Center for Data and Knowledge Integration for Health (CIDACS) for the period 2001 to 2015. We used longitudinal transition models with multivariate logistic regression to investigate whether risk factors varied between incident and recurrent PTB. RESULTS: A total of 3,528,050 live births from 1,764,025 multiparous women were analyzed. We identified different risk factors (Pdifference <0.05) between incident and recurrent PTB. The following were associated with an increased chance for PTB incidence, but not recurrent: household overcrowding (OR 1.09), maternal race/ethnicity [(Black/mixed-OR 1.04) and (indigenous-OR 1.34)], young maternal age (14 to 19 years-OR 1.16), and cesarean delivery (OR 1.09). The following were associated with both incident and recurrent PTB, respectively: single marital status (OR 0.85 vs 0.90), reduced number of prenatal visits [(no visit-OR 2.56 vs OR 2.16) and (1 to 3 visits-OR 2.44 vs OR 2.24)], short interbirth interval [(12 to 23 months-OR 1.04 vs OR 1.22) and (<12 months, OR 1.89, 95 vs OR 2.58)], and advanced maternal age (35-49 years-OR 1.42 vs OR 1.45). For most risk factors, the point estimates were higher for incident PTB than recurrent PTB. CONCLUSIONS: The risk factors for PTB in the second pregnancy differed according to women's first pregnancy PTB status. The findings give the basis for the development of specific prevention strategies for PTB in a subsequent pregnancy.

Dehydroepiandrosterone sulphate levels at 7 years old are positively associated with more advanced pubertal development between 10 and 13 years old in girls.

OBJECTIVE: We aimed to explore the association between dehydroepiandrosterone sulphate (DHEAS) levels at age 7, pubertal development between ages 10 and 13, and age at menarche. DESIGN AND PARTICIPANTS: This is a longitudinal study of 603 individuals (301 girls, 302 boys) from the Generation XXI cohort. MEASUREMENTS: Evaluation of the participants at ages 7, 10 and 13 included anthropometry and Tanner staging. Pubertal development between ages 10 and 13 was categorized using latent class analysis, based on Tanner stages. The association between DHEAS at age 7 and pubertal development between ages 10 and 13 was conducted with binomial logistic regression, adjusted for BMI z-score. The variation of age at menarche in relation to DHEAS levels at age 7, controlling for maternal age at menarche, birth weight z-score and BMI z-score, was estimated fitting a linear regression model. RESULTS: Pubertal development at ages 10-13 was categorized into two classes-Class 1 had a higher probability for the lower Tanner stage (less advanced sexual maturation) and Class 2 had a higher probability for the higher Tanner stage (more advanced sexual maturation). In girls, taking Class 1 as a reference, Class 2 was positively associated with BMI z-score and DHEAS. In boys, Class 2 was positively associated with BMI, but not with DHEAS. DHEAS levels at age 7 were negatively associated with age at menarche, after adjustment for maternal age at menarche, birth weight and BMI. CONCLUSION: In girls, but not in boys, DHEAS at age 7 was positively associated with more advanced pubertal development between ages 10 and 13, and with earlier age at menarche.

Persistent weight gain between 0 and 4 years of age is associated with higher dehydroepiandrosterone sulphate levels at 7 years old: Data from the Generation XXI birth cohort.

OBJECTIVE: To assess the influence of longitudinal weight gain from 0 to 4 years old on dehydroepiandrosterone sulphate (DHEAS) levels at 7 years old. DESIGN: DHEAS levels were measured at 7 years old in a subsample of 587 children from the Generation XXI birth cohort. Weight trajectories (0-4 years of age) were identified using model-based clustering and categorized as "normal weight gain," "weight gain during infancy," "weight gain during childhood" and "persistent weight gain." MEASUREMENTS: Differences in DHEAS levels at age 7 between the four weight trajectories were analysed through analysis of covariance (ANCOVA), adjusted for birth weight (BW) and body mass index (BMI). RESULTS: In the crude analysis, compared with the "normal weight gain" trajectory (5.53 (95% CI: 5.10-5.98] µmol/L), DHEAS levels were significantly higher in children in the "persistent weight gain" (8.75 [95% CI: 7.23-10.49] µmol/L, p < .001] and in children in the "weight gain during infancy" trajectories (7.68 [95% CI: 6.22-9.49] µmol/L, p = .021] and marginally significantly higher in children in the "weight gain during childhood" trajectory (6.89 (95% CI: 5.98-8.00) µmol/L; p = .052). In BW- and BMI-adjusted model, a statistically significant difference in DHEAS levels was found between the "persistent weight gain" (7.93 [95% CI: 6.43-9.86] µmol/L) and the "normal weight gain" trajectories ([5.75 [95% CI: 5.32-6.23] µmol/L; p = .039). CONCLUSION: Higher DHEAS levels are found in 7-year-old children following a trajectory of persistent weight gain from 0 to 4 years, independently of their BW or current BMI, highlighting the impact of exposure to overweight in the first years of life on prepubertal adrenal androgen production.

Dorsal root ganglia CX3CR1 expressing monocytes/macrophages contribute to arthritis pain.

Pain is a persistent symptom of Rheumatoid Arthritis, and the K/BxN serum transfer model recapitulates both association and dissociation between pain and joint inflammation in RA. Furthermore, this model features monocyte/macrophage infiltration in joints and lumbar dorsal root ganglia (DRG), where these immune cells are close to nociceptive neurons. We focussed on CX3CR1-monocyte/macrophage trafficking and show that at peak paw swelling associated with nociception, CX3CR1 deletion altered neither swelling nor macrophage infiltration/phenotype in paws. However, acute nociception and DRG non-classical monocyte numbers were reduced in CX3CR1GFP/GFP (KO) compared to CX3CR1+/GFP (WT). Nociception that persisted despite swelling had resolved was attenuated in KO and correlated with DRG macrophages displaying M2-like phenotype. Still in the DRG, neurons up-regulated neuropeptide CGRP and olcegepant treatment reduced acute swelling, nociception, and leukocyte infiltration in paws and DRG. We delineate in-vitro a signalling pathway showing that CGRP liberates the CX3CR1 ligand fractalkine (FKN) from endothelium, and in bone marrow-derived macrophages, FKN promotes activation of intracellular kinases, polarisation towards M1-like phenotype and release of pro-nociceptive IL-6. These data implicate non-classical CX3CR1-expressing monocyte and macrophage recruitment into the DRG in initiation and maintenance of arthritis pain.

Association of dehydroepiandrosterone sulfate, birth size, adiposity and cardiometabolic risk factors in 7-year-old children.

BACKGROUND: Low birth size (BS) and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in childhood, insulin acting as a mediator, despite contradictory findings. To further explore these issues, we studied the associations between DHEAS, BS, adiposity, maternal characteristics, and cardiometabolic risk indicators, in participants of Generation XXI, a population-based birth cohort. METHODS: A sample of 700 children (mean age 7.1 yr) was randomly selected. Data on maternal characteristics, BS, body mass index (BMI), waist-to-height ratio, body fat (dual-energy X-ray absorptiometry), insulin, lipid profile, and high-sensitivity C-reactive protein were analyzed in relation to DHEAS. RESULTS: DHEAS was negatively associated with BS and positively associated with all adiposity indicators, with no sex differences. DHEAS was positively associated with insulinemia independently of the child's BS or BMI. No significant association was found between DHEAS, maternal characteristics, lipid profile, or high-sensitivity C-reactive protein. Including insulin in the model did not affect the association between BS and DHEAS but reduced the magnitude of the BMI effect by 24% for boys and 30% for girls. CONCLUSION: Higher DHEAS levels at 7 years old were associated with lower BS and higher adiposity. DHEAS levels were positively associated with insulinemia independently of BS or BMI. IMPACT: Low birth weight and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in prepuberty. Insulin has been suggested as a mediator, despite previous studies failing to show an association between DHEAS and insulin levels. In a randomly selected population of 700 7-year-old children from the Generation XXI birth cohort, higher DHEAS levels were associated with a lower birth size and higher adiposity, with no sex differences. DHEAS was positively related to insulinemia independently of the child's birth size or body mass index. No association was found between DHEAS and other cardiometabolic risk factors.