Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial.

BACKGROUND: Juvenile idiopathic arthritis can be refractory to some or all treatment regimens, therefore new medications are needed to treat this population. This trial assessed the efficacy and safety of baricitinib, an oral Janus kinase 1/2-selective inhibitor, versus placebo in patients with juvenile idiopathic arthritis. METHODS: This phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial was conducted in 75 centres in 20 countries. We enrolled patients (aged 2 to <18 years) with polyarticular juvenile idiopathic arthritis (positive or negative for rheumatoid factor), extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or juvenile psoriatic arthritis, and an inadequate response (after ≥12 weeks of treatment) or intolerance to one or more conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The trial consisted of a 2-week safety and pharmacokinetic period, a 12-week open-label lead-in period (10 weeks for the safety and pharmacokinetic subcohort), and an up to 32-week placebo-controlled double-blind withdrawal period. After age-based dosing was established in the safety and pharmacokinetic period, patients received a once-daily 4 mg adult-equivalent dose of baricitinib (tablets or suspension) in the open-label lead-in period. Patients meeting Juvenile Idiopathic Arthritis-American College of Rheumatology (JIA-ACR) 30 criteria (JIA-ACR30 responders) at the end of the open-label lead-in (week 12) were eligible for random assignment (1:1) to receive placebo or continue receiving baricitinib, and remained in the double-blind withdrawal period until disease flare or up to the end of the double-blind withdrawal period (week 44). Patients and any personnel interacting directly with patients or sites were masked to group assignment. The primary endpoint was time to disease flare during the double-blind withdrawal period and was assessed in the intention-to-treat population of all randomly assigned patients. Safety was assessed in all patients who received at least one dose of baricitinib throughout the three trial periods. For adverse events in the double-blind withdrawal period, exposure-adjusted incidence rates were calculated. The trial was registered on ClinicalTrials.gov, NCT03773978, and is completed. FINDINGS: Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled and received at least one dose of baricitinib (152 [69%] girls and 68 [31%] boys; median age 14·0 years [IQR 12·0-16·0]). 219 patients received baricitinib in the open-label lead-in period, of whom 163 (74%) had at least a JIA-ACR30 response at week 12 and were randomly assigned to placebo (n=81) or baricitinib (n=82) in the double-blind withdrawal period. Time to disease flare was significantly shorter with placebo versus baricitinib (hazard ratio 0·241 [95% CI 0·128-0·453], p<0·0001). Median time to flare was 27·14 weeks (95% CI 15·29-not estimable) in the placebo group, and not evaluable for patients in the baricitinib group (<50% had a flare event). Six (3%) of 220 patients had serious adverse events during the safety and pharmacokinetic period or open-label lead-in period. In the double-blind withdrawal period, serious adverse events were reported in four (5%) of 82 patients (incidence rate [IR] 9·7 [95% CI 2·7-24·9] per 100 patient-years at risk) in the baricitinib group and three (4%) of 81 (IR 10·2 [2·1-29·7]) in the placebo group. Treatment-emergent infections were reported during the safety and pharmacokinetic or open-label lead-in period in 55 (25%) of 220 patients, and during the double-blind withdrawal period in 31 (38%) of 82 (IR 102·1 [95% CI 69·3-144·9]) in the baricitinib group and 15 (19%) of 81 (IR 59·0 [33·0-97·3]) in the placebo group. Pulmonary embolism was reported as a serious adverse event in one patient (1%; IR 2·4 [95% CI 0·1-13·3]) in the baricitinib group in the double-blind withdrawal period, which was judged to be related to study treatment. INTERPRETATION: Baricitinib was efficacious with an acceptable safety profile in the treatment of polyarticular juvenile idiopathic arthritis, extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, and juvenile psoriatic arthritis, after inadequate response or intolerance to standard therapy. FUNDING: Eli Lilly and Company under licence from Incyte.

Environmental impact of the diet of young Portuguese and its relationship with adherence to the Mediterranean Diet.

OBJECTIVE: To estimate, in a cohort of young Portuguese adults, the environmental impact (greenhouse gas (GHG) emissions, land use, energy used, acidification and potential eutrophication) of diet according to adherence to the Mediterranean Diet (MD). METHODS: Data from 1554 participants of the Epidemiologic Health Investigation of Teenagers in Porto (EPITeen) were analysed. Food intake and MD adherence were determined using validated questionnaires. The environmental impact was evaluated with the EAT-Lancet Commission tables, and the link between MD adherence and environmental impact was calculated using adjusted multivariate linear regression models. RESULTS: Higher adherence (high vs. low) to the MD was associated with lower environmental impact in terms of land use (7.8 vs. 8.5 m2, p = 0.002), potential acidification (57.8 vs. 62.4 g SO2-eq, p = 0.001) and eutrophication (21.7 vs. 23.5 g PO4-eq, p < 0.001). Energy use decreased only in the calorie-adjusted model (9689.5 vs. 10,265.9 kJ, p < 0.001), and GHG emissions were reduced only in a complementary model where fish consumption was eliminated (3035.3 vs. 3281.2 g CO2-eq, p < 0.001). Meat products had the greatest environmental impact for all five environmental factors analysed: 35.7% in GHG emissions, 60.9% in energy use, 72.8% in land use, 70% in acidification and 61.8% in eutrophication. CONCLUSIONS: Higher adherence to the MD is associated with lower environmental impact, particularly in terms of acidification, eutrophication, and land use. Reducing meat consumption can contribute to greater environmental sustainability.

Longitudinal tracking of diet quality from childhood to adolescence: The Interplay of individual and sociodemographic factors.

This study aimed to examine diet tracking from childhood to adolescence, using 4 time-points, and the influence of socioeconomic and individual characteristics in this transition. The sample included 6893 children from the Portuguese birth cohort Generation XXI with complete information on Food Frequency Questionnaire in at least one of the considered follow-ups. A Healthy Eating Index (HEI), previously developed to assess adherence to WHO's dietary recommendations, was applied at all ages (4, 7, 10 and 13y). The intraclass correlation coefficient (ICC) was used to analyse the tracking of diet quality. Linear mixed-effect models were performed to estimate the association of the child's socioeconomic and individual characteristics with the HEI score and respective trajectories over time. The overall diet quality decreased from childhood (22.2 ± 3.6 at 4y) to adolescence (18.2 ± 3.9 at 13y), with moderate tracking (ICC = 0.53), showing that children who start a healthy diet earlier might have a better diet quality as time goes by. Children of older mothers (ß = 0.079, 95%CI = 0.061-0.097) and with higher education (ß = 0.203, 95%CI = 0.178-0.229) and a higher household monthly income (ß = 0.024,95%CI = 0.007-0.041) had a higher diet quality over time. Besides family characteristics, the child's sedentary activities (ß = -0.009, 95%CI = -0.014--0.003) negatively influence diet quality throughout life. In contrast, being a girl (ß = -0.094, 95%CI = -0.132--0.056) and having higher sleep duration (ß = 0.039, 95%CI = 0.015-0.064) are associated with a higher diet quality over time. The presence of dietary tracking from childhood to adolescence implies that promoting healthy eating habits during the first years of life is crucial for a healthier diet quality during late childhood and early adolescence, focusing on maternal and individual child characteristics.

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids.

Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs' effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.

Changes in screen time from 4 to 7 years of age, dietary patterns and obesity: Findings from the Generation XXI birth cohort.

BACKGROUND AND AIMS: Increased screen exposure is associated with unhealthy eating behaviours and obesity. Screen time (ST) changes from pre-school to school age, and associations with dietary patterns (DP) and obesity remain unknown. We, therefore, analysed ST changes from 4 to 7 years of age, associated factors, and the relation with DP and obesity. METHODS AND RESULTS: We included 4531 children evaluated at 4 and 7 years, as part of the Generation XXI birth cohort (Porto, Portugal). ST was assessed for weekdays and weekend, and average daily time was estimated. Associations between covariates and ST changes, and between ST changes and 3 DP previously identified (Energy-dense foods, Snacking, and Healthier) were estimated by odds ratios (OR) and 95% confidence interval (95%CI), using adjusted multinomial regression models. From 4 to 7 years, 31.5% of the children decreased their ST, 21.8% increased, 16.5% maintained low (≤60 min), and 30.2% maintained high (61-120 min or >120 min) ST. After adjustment, lower maternal education (OR = 2.33, 95%CI:1.82-2.99) and lower family income (OR = 1.72, 95%CI:1.35-2.21) were associated with higher odds of increasing ST, while being a girl was associated with 35% decreased odds of increasing ST. Children that increased and those that maintained high ST showed greater odds of presenting a Snacking DP at 7 years (OR = 2.34, 95%CI:1.64-3.35) and (OR = 2.65, 95%CI:1.89-3.72), respectively. No statistically significant differences were found regarding changes in ST and the child's BMI. CONCLUSION: Children increasing screen exposure during this period were more frequently from lower socioeconomic strata and presented unhealthier DP.

MULT: New height references and their efficiency in multi-ethnic populations.

OBJECTIVES: To develop new height references (MULT) based on longitudinal data of multi-ethnic populations and to compare them to the height references from the Dutch Growth Study, from the Centers for Disease Control and Prevention (CDC) and from the World Health Organization (WHO). METHODS: The MUL height references were developed through the LMS method and the Generalized Additive Models for Location Scale and Shape. They were constructed based on 2611 subjects (15 292 measurements) from the advantaged quintile of the Young Lives (Younger Cohort), Millennium Cohort Study, Adolescent Nutritional Assessment Longitudinal Study, and Epidemiological Health Investigation of Teenagers in Porto studies. The M, S curves were described to compare the growth trajectory of the MULT, DUTCH, CDC and WHO height references. For the population comparative analysis, we used the total sample of the studies (91 063 observations, 17 641 subjects). The Lin's concordance correlation coefficient (CCC) and Cohen's kappa coefficient (K) were used to verify the agreement between MULT, WHO and CDC height references. RESULTS: The MULT height references showed taller boys for the periods of 61-174 months and 196-240 months and taller girls for 61-147 and 181-240 months, when compared to CDC and WHO height references. There was an almost perfect agreement between WHO and MULT height references (CCC >0.99) for the subjects aged 2 to 5 years. CONCLUSIONS: MULT height references presented a taller population and a high agreement with WHO growth charts, especially for children under 5 years, indicating that it could be useful to assess nutritional status of multi-ethnic populations.

MULT: A new BMI reference to assess nutritional status of multi-ethnic children and adolescents.

OBJECTIVES: To develop a new Body Mass Index (BMI) reference (MULT) based on longitudinal data of multi-ethnic populations and to compare it to international BMI references. METHODS: The MULT BMI reference was constructed through the LMS method and the Generalized Additive Models for Location Scale and Shape (GAMLSS), with 81 310 observations of 17 505 subjects aged 0-22 years old, from the United Kingdom, Ethiopia, Peru, India, Vietnam, Brazil, and Portugal. Outlier values were removed based on weight z-scores (population level) and based on BMI z-scores using the linear mixed effects model (individual level). The MULT M, S and L curves were compared to the ones of the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), International Obesity Task Force (IOTF), and Dutch Growth Study (DUTCH). The MULT BMI percentile cutoffs for overweight and obesity were calculated using the adult BMI values of 25 and 30 kg/m2 at 17, 18, 19, and 20 years old. RESULTS: MULT presented the lowest mean BMI values for the ages 102-240 months for boys and 114-220 months for girls. MULT S values were similar to the WHO and IOTF for children under 60 months of age and the highest during puberty, while the L curve showed to be more symmetric than the other BMI references. CONCLUSION: The MULT BMI reference was constructed based on recent data of populations from 10 countries, being a good option to assess the nutritional status of multi-ethnic populations.

Socioeconomic factors and intergenerational differences in height of Portuguese adults born in 1990: results from the EPITeen cohort.

Average adult height is an indicator of population health and a marker of socioeconomic inequalities. This study aimed to assess how socioeconomic differences affect intergenerational height increase between adults born in 1990 and their parents. Data from a population-based cohort of subjects born in 1990 (EPITeen) were analysed. Participants' adult height was objectively measured. Parental height, education, and occupation were reported by the parents. The height difference between daughters and their mothers (n=707), and sons and their fathers (n=647) was calculated. A generalised linear model was used to assess the association between parental education and occupation, separately, and the intergenerational height difference, adjusted for maternal age at birth, smoking during pregnancy, birthweight adjusted for gestational age, and birth order. Females were on average 1.46cm (SD=6.62) taller than their mothers, and males 3.00cm (SD=7.26) taller than their fathers. The highest height gain was shown in those with less advantaged socioeconomic background. In the adjusted model, sons whose mothers had 0-6 years of education grew 3.9cm taller (ß=3.894; 95%CI:2.345;5.443) and daughters 1.5cm taller (ß=1.529; 95%CI:0.180;2.878) (compared to >12y maternal education); for paternal education, sons and daughters grew 3.5cm (ß=3.480; 95%CI:1.913;5.047) and 1.9cm taller (ß=1.895; 95%CI:0.526;3.265), respectively. A higher height increase was found in participants with less advantaged maternal and paternal occupational level. Adults born in 1990 are taller than their parents, and height gain was higher in males than females. Adults from a lower socioeconomic status experienced the highest height gain, suggesting a reduction in height inequality.

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids.

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2-31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32-61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Localized Therapeutic Approaches Based on Micro/Nanofibers for Cancer Treatment.

Cancer remains one of the most challenging health problems worldwide, and localized therapeutic approaches based on micro/nanofibers have shown potential for its treatment. Micro/nanofibers offer several advantages as a drug delivery system, such as high surface area, tunable pore size, and sustained release properties, which can improve drug efficacy and reduce side effects. In addition, functionalization of these fibers with nanoparticles can enhance their targeting and therapeutic capabilities. Localized delivery of drugs and/or other therapeutic agents via micro/nanofibers can also help to overcome the limitations of systemic administration, such as poor bioavailability and off-target effects. Several studies have shown promising results in preclinical models of cancer, including inhibition of tumor growth and improved survival rates. However, more research is needed to overcome technical and regulatory challenges to bring these approaches to clinical use. Localized therapeutic approaches based on micro/nanofibers hold great promise for the future of cancer treatment, providing a targeted, effective, and minimally invasive alternative to traditional treatments. The main focus of this review is to explore the current treatments utilizing micro/nanofibers, as well as localized drug delivery systems that rely on fibrous structures to deliver and release drugs for the treatment of cancer in a specific area.

Metabolically healthy overweight in young adulthood: is it a matter of duration and degree of overweight?

BACKGROUND AND AIM: Given the controversy regarding metabolically healthy obesity, we studied the association between duration and degree of body mass index (BMI) from adolescence to early adulthood and metabolic status of both overweight/obese and under/normal weight subjects. METHODS AND RESULTS: Participants of the EPITeen cohort were evaluated at 13, 17, 21 and 24 years (n = 1040). Duration and degree of BMI in the 11-year period was summarized through the area under the curve of BMI (BMIAUC). Metabolic health at 24 y was defined as optimal levels of lipids, blood pressure and glucose. The association between BMIAUC per year and metabolic health was estimated through binary logistic regression models, adjusted for confounders and stratified by BMI. The proportion of metabolically healthy overweight/obesity at 24 y was 13.4%. After adjustment for sociodemographic and behavioural factors, the increase of one kg/m2 in BMI on average per year during the period between 13 and 24 y was associated with 14% lower odds of being metabolically healthy among under/normal weight participants (OR = 0.86, 95% CI 0.78-0.94); and 8% lower odds of metabolic health among obese/overweight participants (OR = 0.92, 95% CI 0.85-1.00). After additional adjustment for waist circumference, the association was attenuated, especially in the obese/overweight group (OR = 1.03, 95% CI 0.93-1.14). About 20% of the metabolically healthy obese/overweight at 13 y transitioned to metabolically unhealthy obesity/overweight at 24 y. CONCLUSION: The results support the hypothesis that the healthy obesity phenotype could be explained by a lower exposure to adiposity, either by shorter time or lower quantity, and a more favourable body fat distribution.

Rapid Ethnonutrition Assessment Method Is Useful to Prototype Dietary Assessments with a Focus on Local Biodiverse Food Plants.

Ethnonutrition is the study of diets in the context of food systems of different peoples and cultures. Its scope comprises native or local categories used to classify food, and also includes biodiverse food availability, local culinary techniques, seasonality, and cultural perceptions related to diet with nutritional implications. Here, we describe a method useful for gathering ethnonutrition data to design dietary interventions or assessments, the Rapid Ethnonutrition Assessment (REA). REA is a tool that offers food and nutrition research a broad biocultural view of diets, considering food system-level, by prototyping dietary assessments with high efficiency. This method permits us to prevent misinterpretations that lead to wrong conclusions in nutritional research.

Association between insulin resistance and haematological parameters: A cohort study from adolescence to adulthood.

BACKGROUND: The aim of this study was to quantify the relationship between insulin resistance and haematological parameters from adolescence to adulthood. METHODS: Participants from the EPITeen cohort were evaluated at 13, 17, and 21 years, through standardized procedures. A fasting blood sample was obtained, and insulin resistance was evaluated by the homeostatic model assessment (HOMA-IR). The cross-sectional association between HOMA-IR and haematological parameters at 21 years was quantified in 1671 participants by multivariate linear regression coefficients (ß) and 95% confidence intervals (95%CI). For the longitudinal analysis (n = 496), trajectories of insulin and glucose were estimated using model-based clustering, and haematological parameters were compared according to trajectories using ANOVA. RESULTS: At 21 years, after adjustment for BMI, positive associations (ß [95%CI]) were found between HOMA-IR and red blood count (0.05 [0.03;0.07] in females; 0.02 [0.00;0.04] in males); and haematocrit (0.29 [0.12;0.46] in females; 0.21 [0.04,0.38] in males). In females, HOMA-IR was inversely associated with packed cell volume (PCV) (-0.35 [-0.66;-0.05]) and iron levels (-3.98 [-6.94,-1.03]) but positively associated with white blood cells (0.31 [0.19;0.43]) and platelets (7.66 [3.93;11.39]). In males, a higher HOMA-IR was significantly associated with higher haemoglobin (0.09 [0.03;0.16]). Regarding the longitudinal analysis, similar trends were found, but statistical significance was not reached. CONCLUSIONS: Both longitudinal and cross-sectional analyses support the hypothesis that insulin resistance is associated with increased red blood cells count and haematocrit in young adults, even within normal ranges of insulin and glucose.

The use of weight adjusted for height rather than body mass index to assess growth trajectory: Results from a population-based cohort.

We compared different growth models parameterizations regarding (i) adjustment of weight-for-height, as denoted by body mass index (BMI); (ii) adjustment for different covariates, ie, age or height; and (iii) the use of different smoothing methods, ie, polynomial, fractional polynomial, or linear splines. A total of 11 459 measurements of weight and height from 719 participants were used, obtained from the EPITeen cohort at 13, 17, and 21 years, and extracted from child health books. The individual growth curves were modeled using mixed-effects polynomial, fractional polynomial, and linear splines, and each model parameterization included as covariate age or height. The goodness-of-fit of the model parametrizations was compared using the relative squared error (RSE) and the relative absolute error (RAE). The adjustment of weight-for-height as denoted by BMI was found to be biased, especially for extreme values of height and presented the worst fit indexes from all model parameterizations tested (RSE = 12.46%; RAE = 22.63%). Regardless of the smoothing method, the weight-for-height retrieved the best fit indexes in comparison to the adjustment for age. With regard to the smoothing methods and comparing weight-for-height model parameterizations, the fractional polynomial model performed better (RSE = 0.75%; RAE = 5.70%), followed by linear splines (RSE = 0.77%; RAE = 5.82%), and conventional polynomial (RSE = 0.91%; RAE = 6.82%). Therefore, growth modeling in pediatric age should be based on the modeling of weight-for-height because the use of BMI leaves residual confounding for height. Regarding the smoothing methods, although differences were relatively small, the fractional polynomials performed better in comparison to conventional polynomials and linear splines.

Decreases in adiposity reduce the risk of hypertension: Results from a prospective cohort of adolescents.

This study aimed to evaluate the effect of age-related changes in body mass index and waist circumference during adolescence on blood pressure levels and incidence of hypertension. Among the 2159 adolescents recruited at 13 years in Porto, Portugal, we evaluated those free of hypertension at baseline and followed-up at 17 years (n = 1377) - EPITeen cohort, 2003-2008. Changes in BMI percentage (BMI%) and waist circumference percentage (WC%) were evaluated continuously as the difference between 13 and 17 years, then categorized in sex-specific quartiles. Hypertension was defined as systolic and/or diastolic blood pressure ≥ 95th sex- age- and height-specific reference percentile. The association between changes in adiposity and incidence of hypertension was computed through generalized linear models with log link function and Poisson distribution [incidence rate ratios (IRR), 95% confidence intervals (95%CI)], adjusting for baseline adiposity, sex, and family history of hypertension. Overall incidence rate of hypertension was 23.8 (95%CI 19.6-28.8) per 1000 person-years. Participants presenting the highest decrease in BMI% from 13 to 17 years (1st quartile) presented lower SBP at 17y, while for those with increasing BMI% (4th quartile) SBP increased. In comparison to stable BMI% (3rd quartile), decreases in BMI% (1st quartile) were associated with 44% lower risk of hypertension at 17y (IRR = 0.56, 95%CI 0.32-0.97). Increases in BMI% (4th quartile) were associated with increased incidence, although without statistical significance (IRR = 1.11, 95%CI 0.66-1.85). Results were similar when considering changes in WC%. Decreases in BMI and WC throughout adolescence in the whole spectrum of adiposity levels presented potential benefit for blood pressure.

Association between the exposure to phthalates and adiposity: A meta-analysis in children and adults.

BACKGROUND: Exposure to environmental chemicals has become one of the major concerns in the past decades. Phthalates are a family of synthetic organic chemicals used in the manufacture of plastics, solvents, and personal care products. These compounds are considered as endocrine-disrupting compounds (EDCs) since they may interfere with the endocrine system and disrupt its physiologic function. AIM: The purpose of this work is to synthesize results from published literature on the association between the exposure to phthalates and adiposity in adults and children. METHODS: We searched PubMed from inception up to 01 August 2019, to retrieve original papers reporting data on the association between EDCs and adiposity, using the following search expression: (("Endocrine disruptor" OR Endocrine disruptor[mh] OR phthalate) AND (Obesity OR Overweight OR BMI OR "Body fat" OR Adipose tissue[mh] OR Body size[mh] OR "body size" OR "body weight" OR Anthropometry OR "anthropometric measures")) AND (humans[mh]). The study variables and characteristics were collected during data extraction, namely the study design, sample, exposure, outcome, descriptive and association measures. Study quality was assessed using the STROBE template for observational studies. Although studies examined several adiposity measures, Body Mass Index (BMI) and Waist Circumference (WC) were the most commonly used, therefore, we used the beta coefficients regarding BMI and WC, and odds ratios when BMI outcome was categorical to perform the meta-analysis. Data from the studies were combined using fixed effects meta-analyses to compute summary regression coefficients or odds ratios and corresponding 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the I2 statistic. RESULTS: In the systematic review we found 29 publications addressing the association between phthalate compounds and adiposity. The vast majority of the included studies reported associations that were not statistically significant. For most of the phthalate compounds there were few studies providing compatible measures and therefore it was not possible to combine the results in a meta-analysis. Both for BMI and WC, the meta-analysis for MiBP, MCPP and MbzP showed negative associations and null association for MBP in children, although none of them was significant. For MEP, positive but not significant associations were found both in children and adults. Conversely, for MEHP a negative association was found also in children and adults although it did not reach statistical significance. Only for MECPP a significant association was found for obesity in adults (OR = 1.67 (95% CI 1.30; 2.16). CONCLUSION: In general, a positive association between phthalates and adiposity measures was found, especially in adults. However, most of the results did not reach statistical significance and the inconsistencies found between studies did not allow to reach a definitive conclusion. Additionally, we cannot exclude a possible effect of publication bias.

Chiral Derivatives of Xanthones with Antimicrobial Activity.

According to the World Health Organization, the exacerbated use of antibiotics worldwide is increasing multi-resistant infections, especially in the last decade. Xanthones are a class of compounds receiving great interest in drug discovery and development that can be found as natural products or obtained by synthesis. Many derivatives of xanthones are chiral and associated with relevant biological activities, including antimicrobial. The aim of this review is to compile information about chiral derivatives of xanthones from natural sources and their synthesized examples with antimicrobial activity.

Synthetic Chiral Derivatives of Xanthones: Biological Activities and Enantioselectivity Studies.

Many naturally occurring xanthones are chiral and present a wide range of biological and pharmacological activities. Some of them have been exhaustively studied and subsequently, obtained by synthesis. In order to obtain libraries of compounds for structure activity relationship (SAR) studies as well as to improve the biological activity, new bioactive analogues and derivatives inspired in natural prototypes were synthetized. Bioactive natural xanthones compromise a large structural multiplicity of compounds, including a diversity of chiral derivatives. Thus, recently an exponential interest in synthetic chiral derivatives of xanthones (CDXs) has been witnessed. The synthetic methodologies can afford structures that otherwise could not be reached within the natural products for biological activity and SAR studies. Another reason that justifies this trend is that both enantiomers can be obtained by using appropriate synthetic pathways, allowing the possibility to perform enantioselectivity studies. In this work, a literature review of synthetic CDXs is presented. The structures, the approaches used for their synthesis and the biological activities are described, emphasizing the enantioselectivity studies.

WAGNER syndrome: anatomic, functional and genetic characterization of a Portuguese family.

PURPOSE: To report the clinical (anatomic and functional) and genetic findings of Wagner Syndrome (WS) in a Portuguese family. METHODS: Nine members of the family agreed to be examined. All had complete clinical eye examinations. The proband and selected patients underwent color fundus photography, spectral domain optical coherence tomography (SD-OCT), automatic static white-on-white computerized perimetry, and electrophysiology assessment (flash ERG, multifocal(mf) ERG and dark adaptometry). A pedigree was constructed based on interviews with known affected subjects. Genomic DNA samples derived from venous blood were collected from all affected family members examined. RESULTS: Twenty-eight family members are affected. This family has the typical features of Wagner Syndrome, namely an empty vitreous cavity with veils, mild myopia and cataract. Four examined patients underwent vitreoretinal surgery due to abnormal peripheral vitreoretinal adhesions with peripheral retinal traction (n = 3). Retinal detachment was observed in 5 of the examined subjects. Four of them occurred between the ages of 5 and 15 years. Chorioretinal atrophy is also a frequent finding which results in moderate to severe visual field and advanced rod-cone dystrophy from younger ages, also confirmed by absence of scotopic function on dark adaptation. The macular dysfunction on mfERG was profound and of early onset. A heterozygous mutation in intron 7 of the VCAN gene (c.4004-1G > A) was found. CONCLUSIONS: We described a rare autosomal dominant vitreoretinopathy with near complete penetrance in a Portuguese family. Abnormal peripheral vitreoretinal adhesions, retinal detachment and chorioretinal atrophy are present in most of the examined individuals at young ages. Early onset of advanced visual field and electrophysiologic abnormalities were observed in this family. We also added relevant information to the literature by reporting our experience in surgical management of Wagner Syndrome patients with, and at risk of, retinal detachment.

Relationship between dietary vitamin D and serum 25-hydroxyvitamin D levels in Portuguese adolescents.

OBJECTIVE: To understand the relationship between vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels in a sample of Portuguese adolescents. DESIGN: Cross-sectional evaluation carried out in the 2003/2004 school year. Vitamin D intake was assessed by an FFQ and 25(OH)D was measured in a fasting blood sample. SETTING: Public and private schools in Porto, Portugal. SUBJECTS: Adolescents aged 13 years (n 521) enrolled at school (EPITeen cohort). RESULTS: Both mean (sd) intake and serum 25(OH)D level were far below the recommended, 4·47 (2·49) µg/d and 16·5 (5·7) ng/ml, respectively. A significant difference in serum level was found according to season, with lower values in winter than summer (14·8 (4·6) v. 17·3 (5·9) ng/ml, P<0·001). Vitamin D intake was weakly correlated with serum 25(OH)D (r=0·056, P=0·203). CONCLUSIONS: Dietary vitamin D and serum 25(OH)D levels were positively but weakly correlated and the error was higher among those with higher serum 25(OH)D concentration. Our results support the need for strategies that promote increase of the most important food sources of vitamin D to reduce the high prevalence of low vitamin D status.