Childhood exposure to outdoor air pollution in different microenvironments and cognitive and fine motor function in children from six European cohorts.

BACKGROUND: Exposure to air pollution during childhood has been linked with adverse effects on cognitive development and motor function. However, limited research has been done on the associations of air pollution exposure in different microenvironments such as home, school, or while commuting with these outcomes. OBJECTIVE: To analyze the association between childhood air pollution exposure in different microenvironments and cognitive and fine motor function from six European birth cohorts. METHODS: We included 1301 children from six European birth cohorts aged 6-11 years from the HELIX project. Average outdoor air pollutants concentrations (NO2, PM2.5) were estimated using land use regression models for different microenvironments (home, school, and commute), for 1-year before the outcome assessment. Attentional function, cognitive flexibility, non-verbal intelligence, and fine motor function were assessed using the Attention Network Test, Trail Making Test A and B, Raven Colored Progressive Matrices test, and the Finger Tapping test, respectively. Adjusted linear regressions models were run to determine the association between each air pollutant from each microenvironment on each outcome. RESULTS: In pooled analysis we observed high correlation (rs = 0.9) between air pollution exposures levels at home and school. However, the cohort-by-cohort analysis revealed correlations ranging from low to moderate. Air pollution exposure levels while commuting were higher than at home or school. Exposure to air pollution in the different microenvironments was not associated with working memory, attentional function, non-verbal intelligence, and fine motor function. Results remained consistently null in random-effects meta-analysis. CONCLUSIONS: No association was observed between outdoor air pollution exposure in different microenvironments (home, school, commute) and cognitive and fine motor function in children from six European birth cohorts. Future research should include a more detailed exposure assessment, considering personal measurements and time spent in different microenvironments.

Prenatal Exposure to Multiple Endocrine-Disrupting Chemicals and Childhood BMI Trajectories in the INMA Cohort Study.

BACKGROUND: Prenatal exposure to endocrine-disrupting chemicals (EDCs) may disrupt normal fetal and postnatal growth. Studies have mainly focused on individual aspects of growth at specific time points using single chemical exposure models. However, humans are exposed to multiple EDCs simultaneously, and growth is a dynamic process. OBJECTIVE: The objective of this study was to evaluate the associations between prenatal exposure to EDCs and children's body mass index (BMI) growth trajectories using single exposure and mixture modeling approaches. METHODS: Using data from the INfancia y Medio Ambiente (INMA) Spanish birth cohort (n=1,911), prenatal exposure to persistent chemicals [hexachlorobenzene (HCB), 4-4'-dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCB-138, -150, and -180), 4 perfluoroalkyl substances (PFAS)] and nonpersistent chemicals (8 phthalate metabolites, 7 phenols) was assessed using blood and spot urine concentrations. BMI growth trajectories were calculated from birth to 9 years of age using latent class growth analysis. Multinomial regression was used to assess associations for single exposures, and Bayesian weighted quantile sum (BWQS) regression was used to evaluate the EDC mixture's association with child growth trajectories. RESULTS: In single exposure models exposure to HCB, DDE, PCBs, and perfluorononanoic acid (PFNA) were associated with increased risk of belonging to a trajectory of lower birth size followed by accelerated BMI gain by 19%-32%, compared with a trajectory of average birth size and subsequent slower BMI gain [e.g., relative risk ratio (RRR) per doubling in DDE concentration=1.19 (95% CI: 1.05, 1.35); RRR for PFNA=1.32 (95% CI: 1.05, 1.66)]. HCB and DDE exposure were also associated with higher probability of belonging to a trajectory of higher birth size and accelerated BMI gain. Results from the BWQS regression showed the mixture was positively associated with increased odds of belonging to a BMI trajectory of lower birth size and accelerated BMI gain (odds ratio per 1-quantile increase of the mixture=1.70; credible interval: 1.03, 2.61), with HCB, DDE, and PCBs contributing the most. DISCUSSION: This study provides evidence that prenatal EDC exposure, particularly persistent EDCs, may lead to BMI trajectories in childhood characterized by accelerated BMI gain. Given that accelerated growth is linked to a higher disease risk in later life, continued research is important. https://doi.org/10.1289/EHP11103.

[Clinical practice guideline for the management of acute pancreatitis in the social security of Peru (Essalud)]. / Guía de práctica clínica para el manejo de la pancreatitis aguda en el seguro social del Perú (Essalud).

This article summarizes the clinical practice guideline (CPG) for the management of acute pancreatitis in the Social Security of Peru (EsSalud), to provide evidence-based clinical recommendations for the management of acute pancreatitis in EsSalud. A guideline development group (GEG) was formed that included medical specialists and methodologists. The GEG formulated 7 clinical questions to be answered by this CPG. Systematic searches of systematic reviews and -when considered relevant- primary studies were carried out in PubMed during 2022. The evidence was selected to answer each of the clinical questions posed. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic work meetings, the GEG used the GRADE methodology to review the evidence and formulate the recommendations, the points of good clinical practice, and the corresponding flow charts. Finally, the CPG was approved with Resolution No. 105-IETSI-ESSALUD-2022. This CPG addressed 7 clinical questions on fluid therapy, start of enteral nutrition, analgesia, type of nutrition, antibiotic, and surgical treatment. Based on these questions, 8 recommendations (1 strong and 7 conditional), 13 BPCs, and 1 flowchart were formulated. This article summarizes the methodology and evidence-based conclusions of the CPG for the management of acute pancreatitis in EsSalud.

Prenatal Vitamin D Levels Influence Growth and Body Composition until 11 Years in Boys.

BACKGROUND: Gestational vitamin D levels may influence offspring growth and modulate adipogenesis. Findings from prospective studies are inconsistent, and few have evaluated the persistence of these associations into late childhood. OBJECTIVE: To examine the association between prenatal vitamin D levels and growth and adiposity in late childhood. METHODS: We included 2027 mother-child pairs from the INMA birth cohort. 25-hydroxyvitamin D3 (vitamin D3) levels were measured in serum at 13 weeks of pregnancy. Sex- and age-specific body mass index z-scores were calculated at 7 and 11 years, overweight was defined as z-score ≥ 85th percentile, and body fat mass was measured at 11 years. Z-score body mass index (zBMI) trajectories from birth to 11 years were identified using latent class growth analysis. RESULTS: The prevalence of vitamin D3 deficiency (<20 ng/mL) was 17.5%, and around 40% of the children had overweight at both ages. Associations between vitamin D levels and outcomes differed by sex. In boys, maternal vitamin D3 deficient status was associated with higher zBMI, higher fat mass percentage, higher odds of being overweight, and with an increased risk of belonging to lower birth size followed by accelerated BMI gain trajectory. In girls no associations were observed. CONCLUSION: Our results support a sex-specific programming effect of early pregnancy vitamin D3 levels on offspring body composition into late childhood observed in boys.

Availability, accessibility, and use of green spaces and cognitive development in primary school children.

Green spaces may have beneficial impacts on children's cognition. However, few studies explored the exposure to green spaces beyond residential areas, and their availability, accessibility and uses at the same time. The aim of the present study was to describe patterns of availability, accessibility, and uses of green spaces among primary school children and to explore how these exposure dimensions are associated with cognitive development. Exposures to green space near home, school, commuting route, and other daily activity locations were assessed for 1607 children aged 6-11 years from six birth cohorts across Europe, and included variables related to: availability (NDVI buffers: 100, 300, 500 m), potential accessibility (proximity to a major green space: linear distance; within 300 m), and use (play time in green spaces: hours/year), and the number of visits to green spaces (times/previous week). Cognition measured as fluid intelligence, inattention, and working memory was assessed by computerized tests. We performed multiple linear regression analyses on pooled and imputed data adjusted for individual and area-level confounders. Availability, accessibility, and uses of green spaces showed a social gradient that was unfavorable in more vulnerable socioeconomic groups. NDVI was associated with more playing time in green spaces, but proximity to a major green space was not. Associations between green space exposures and cognitive function outcomes were not statistically significant in our overall study population. Stratification by socioeconomic variables showed that living within 300 m of a major green space was associated with improved working memory only in children in less deprived residential areas (ß = 0.30, CI: 0.09,0.51), and that more time playing in green spaces was associated with better working memory only in children of highly educated mothers (ß per IQR increase in hour/year = 0.10; 95% CI: 0.01, 0.19). However, studying within 300 m of a major green space increased inattention scores in children in more deprived areas (ß = 15.45, 95% CI: 3.50, 27.40).

Guía de práctica clínica para el manejo de la pancreatitis aguda en el seguro social del Perú (Essalud)

El presente artículo resume la guía de práctica clínica (GPC) para el manejo de la pancreatitis aguda en el Seguro Social del Perú (EsSalud). Su objetivo es proveer recomendaciones clínicas basadas en evidencia para el manejo de la pancreatitis aguda en EsSalud. Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos. El GEG formuló 7 preguntas clínicas a ser respondidas por la presente GPC. Se realizó búsquedas sistemáticas de revisiones sistemáticas y -cuando fue considerado pertinente- estudios primarios en PubMed durante el 2022. Se seleccionó la evidencia para responder cada una de las preguntas clínicas planteadas. La certeza de la evidencia fue evaluada usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones, los puntos de buenas prácticas clínicas y flujogramas correspondientes. Finalmente, la GPC fue aprobada con Resolución N° 105-IETSI-ESSALUD-2022. La presente GPC abordó 7 preguntas clínicas sobre fluidoterapia, momento de inicio de nutrición enteral, analgesia, tipo de nutrición, tratamiento antibiótico y quirúrgico. En base a dichas preguntas se formularon 8 recomendaciones (1 fuerte y 7 condicionales), 13 BPC, y 1 flujograma. El presente artículo resume la metodología y las conclusiones basadas en evidencia de la GPC para el manejo de la pancreatitis aguda en EsSalud.

This article summarizes the clinical practice guideline (CPG) for the management of acute pancreatitis in the Social Security of Peru (EsSalud), to provide evidence-based clinical recommendations for the management of acute pancreatitis in EsSalud. A guideline development group (GEG) was formed that included medical specialists and methodologists. The GEG formulated 7 clinical questions to be answered by this CPG. Systematic searches of systematic reviews and -when considered relevant-primary studies were carried out in PubMed during 2022. The evidence was selected to answer each of the clinical questions posed. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic work meetings, the GEG used the GRADE methodology to review the evidence and formulate the recommendations, the points of good clinical practice, and the corresponding ow charts. Finally, the CPG was approved with Resolution No. 105-IETSI-ESSALUD-2022. This CPG addressed 7 clinical questions on buid therapy, start of enteral nutrition, analgesia, type of nutrition, antibiotic, and surgical treatment. Based on these questions, 8 recommendations (1 strong and 7 conditional), 13 BPCs, and 1 flowchart were formulated. This article summarizes the methodology and evidence-based conclusions of the CPG for the management of acute pancreatitis in EsSalud.

Restoration in mental health after visiting urban green spaces, who is most affected? Comparison between good/poor mental health in four European cities.

Several mechanisms have been proposed to explain the association between green space and health, and one of these is the restoration theory, based on the idea that it is possible to increase mental health and decrease stress visiting a natural environment. The aims of the present study were to understand what activities are most related to restoration and if these are the same for people with poorer and better mental health. A questionnaire was administered in four European cities and data about restoration outcomes, type of activity carried out in green spaces and mental health were collected and analyzed. A cross sectional design was used and total of 3134 respondents participated to the questionnaire. The restoration experience was measured with the restoration outcome score, and the mental health was evaluated with a subscale related to mental health of the Medical Outcome Short Form. Participants were divided in two groups according to mental health score. A multiple regression analysis was performed to investigate the association between mental health, type of activity and restoration. The cities showed a similar trend in the association between restoration and type of activity performed in green environment. People with poorer mental health seem to be more sensitive to the positive effect of visiting the green environment and restoration was more evident in these people than in those with better mental health. At the same time, the type of activity was less evident in people with better mental health, and they seemed to be less influenced by the visiting of green space. Green prescription is important for the entire population: people with poorer mental health could have important restorative effects and people with better mental health could continue to protect their well-being using green space.

Benzophenone-3: Comprehensive review of the toxicological and human evidence with meta-analysis of human biomonitoring studies.

BACKGROUND: Benzophenone-3 (BP-3) and its major metabolite benzophenone-1 (BP-1) are widely used as UV filters in sunscreens and cosmetics to prevent sunburn and skin damage, or as stabilizers to prevent photodegradation in many commercial products. As a result, their presence is ubiquitous in the environment, wildlife and humans. Based on endocrine disruption concerns, international regulatory agencies are performing a closer evaluation. OBJECTIVE AND METHODS: This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative. RESULTS: A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively. DISCUSSION AND CONCLUSIONS: Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.

Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.

Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of this functional decline of HSC and find strategies to counteract it, we established a model in which the Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSC from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the reactive oxygen species pathway and reduced single-cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (bcatenin) elevated, but so was its association with the phosphorylated co-activator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2A-PR72/130 by administration of IQ-1 in OS1Δ/Δ mice. This treatment not only reduced the b-catenin/phosphop300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that the osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of the nuclear b-catenin/phospho-p300 association is a new strategy to restore poor HSC function.

Mid-childhood fat mass and airflow limitation at 15 years: The mediating role of insulin resistance and C-reactive protein.

BACKGROUND: We previously reported an association of high fat mass levels from age 9 to 15 years with lower forced expiratory flow in 1 s (FEV1 )/forced vital capacity (FVC) ratio (i.e., increased risk of airflow limitation) at 15 years. Here, we aimed to assess whether insulin resistance and C-reactive protein (CRP) at 15 years partially mediate this association. METHODS: We included 2263 children from the UK Avon Longitudinal Study of Parents and Children population-based cohort (ALSPAC). Four fat mass index (FMI) trajectories ("low," "medium-low," "medium-high," "high") from 9 to 15 years were previously identified using Group-Based Trajectory Modeling. Data on CRP, glucose, insulin, and post-bronchodilator FEV1 /FVC were available at 15 years. We defined insulin resistance by the homeostasis model assessment-estimated insulin resistance index (HOMA-IR). We used adjusted linear regression models and a causal mediation analysis to assess the mediating role of HOMA-IR and CRP. RESULTS: Compared to children in the "low" FMI trajectory, children in the "medium-high" and "high" FMI trajectories had lower FEV1 /FVC at 15 years. The percentage of the total effect explained by HOMA-IR was 19.8% [-114.1 to 170.0] and 20.4% [1.6 to 69.0] for the "medium-high" and "high" trajectories, respectively. In contrast, there was little evidence for a mediating role of CRP. CONCLUSION: The association between mid-childhood fat mass and FEV1 /FVC ratio at 15 years may be partially mediated by insulin resistance.

The evaluation of the 3-30-300 green space rule and mental health.

BACKGROUND AND AIMS: Urban green space has many health benefits, but it is still unclear how much actually is needed for better health. Recently a new 3-30-300 rule of thumb for urban forestry and urban greening has been proposed, but this rule has not been evaluated for benefits on health. The rule requires that every citizen should be able to see at least three trees from their home, have 30 percent tree canopy cover in their neighbourhood and not live more than 300 m away from the nearest park or green space. The aim of this study was to evaluate the relationship between the 3-30-300 green space rule and its components in relation to mental health. METHODS: We conducted a cross-sectional study based on a population-based sample of 3145 individuals aged 15-97 years from in Barcelona, Spain who participated in the Barcelona Health Survey (2016-2017). We created 3-30-300 green space indicators using questionnaire data, GIS, remote sensing and land cover maps. Mental health status was assessed with the 12-item General Health Questionnaire (GHQ-12) and also the use of tranquilizer/sedatives or antidepressants and psychiatrist or psychologist visits. Analyses were conducted using mixed effects logistic regression models with districts as the random effect, adjusted for relevant covariates. RESULTS: We found that people in Barcelona had relatively little exposure to green space, whether through window view, living in an area with sufficient greenness, or access to a major green space, and only 4.7% met a surrogate 3-30-300 green space rule. Residential surrounding greenness, but not tree window view or access to major green space, was significantly associated with better mental health, less medication use, and fewer psychologist or psychiatrist visits. Meeting the full surrogate 3-30-300 green space rule was associated with better mental health, less medication use, and fewer psychologist or psychiatrist visits, but only for the latter combined the association was statistically significant (Odds ratio = 0.31, 95% CI: 0.11, 0.91). CONCLUSION: Few people achieved the 3-30-300 green space in Barcelona and we used a surrogate measure. We observed health benefits when the full surrogate rule was met.

Urban environment and health behaviours in children from six European countries.

BACKGROUND: Urban environmental design is increasingly considered influential for health and wellbeing, but evidence is mostly based on adults and single exposure studies. We evaluated the association between a wide range of urban environment characteristics and health behaviours in childhood. METHODS: We estimated exposure to 32 urban environment characteristics (related to the built environment, traffic, and natural spaces) for home and school addresses of 1,581 children aged 6-11 years from six European cohorts. We collected information on health behaviours including total amount of overall moderate-to-vigorous physical activity, physical activity outside school hours, active transport, sedentary behaviours and sleep duration, and developed patterns of behaviours with principal component analysis. We used an exposure-wide association study to screen all exposure-outcome associations, and the deletion-substitution-addition algorithm to build a final multi-exposure model. RESULTS: In multi-exposure models, green spaces (Normalized Difference Vegetation Index, NDVI) were positively associated with active transport, and inversely associated with sedentary time (22.71 min/day less (95 %CI -39.90, -5.51) per interquartile range increase in NDVI). Residence in densely built areas was associated with more physical activity and less sedentary time, and densely populated areas with less physical activity outside school hours and more sedentary time. Presence of a major road was associated with lower sleep duration (-4.80 min/day (95 %CI -9.11, -0.48); compared with no major road). Results for the behavioural patterns were similar. CONCLUSIONS: This multicohort study suggests that areas with more vegetation, more building density, less population density and without major roads are associated with improved health behaviours in childhood.

Aberrant Salience and Disorganized Symptoms as Mediators of Psychosis.

Introduction: Ideas of reference (IR) are frequent in psychopathology, mainly in psychotic disorders. The frequency of IR and preoccupation about them are related to the psychotic dimension, and to a lesser extent, to negative or emotional disorganized dimensions. Aberrant salience (AS), has been proposed as an indicator of the onset of psychosis, particularly of schizophrenia. This study analyzed the mediating role of AS, disorganized symptoms and preoccupation about IR in the relationship between IR and the psychotic dimension. Method: The sample consisted of 330 participants (116 university students and 214 clinically active patients), 62.4% of whom were women aged 18-79. The Referential Thinking Scale, the Aberrant Salience Inventory, and the Brief Psychiatric Rating Scale were administered. Results: Evidence of a partial mediation model showed that the relationships between IR and the psychotic dimension were mediated jointly by AS and the disorganized dimension, and preoccupation about IR no longer had a role. This relationship was significantly influenced by participant age. The variables in the model explained 54.16% of the variance. Conclusion: The model proposed enabled a set of vulnerabilities (unusual thought content) to be predicted that could lead to a high-risk general pathological state and proneness to psychosis in particular. These findings are discussed with regard to early detection and prevention of psychosis.

Use of the Natural Outdoor Environment in Different Populations in Europe in Relation to Access: Implications for Policy.

This cross-cultural study explores the relationship of natural outdoor environment (NOE) use with NOE access. Most urban planning recommendations suggest optimal accessibility to be 300 m-500 m straight distance to spaces with vegetation of at least 1 hectare. Exploring this recommendation, we used data (n = 3947) from four European cities collected in the framework of the PHENOTYPE study: Barcelona (Spain), Doetinchem (The Netherlands), Kaunas (Lithuania) and Stoke-on-Trent (United Kingdom) to obtain residential access to NOE (straight or network distances, using 300 m and 150 m buffers, to NOE larger than 1 hectare or 0.5 hectare) and use of NOE (i.e., self-reported time spent in NOE). Poisson regression models were used to examine the associations between residential access and use of NOE. The models with the strongest association with time spent in NOE in the combined sample were for those living within 300 m straight line distance to either 0.5 ha or 1 ha NOE. Noting that the only indicator that was consistent across all individual cities was living with 150 m network buffer of NOE (of at least 1 ha), this warrants further exploration in reducing recommendations of 300 m straight-line distance to 150 m network distance to 1 ha of NOE for a general indicator for cities within Europe.

Early-childhood BMI trajectories in relation to preclinical cardiovascular measurements in adolescence.

Cardiovascular diseases are the leading causes of morbidity and mortality. Overweight, obesity, and accelerated growth during early childhood have been associated with adverse cardiovascular outcomes in later life. Few studies have assessed whether trajectories of accelerated growth in early childhood are associated with preclinical cardiovascular measurements. We aimed to evaluate the associations between childhood body mass index (BMI) growth trajectories and measures of macro- and microvascular function in early adolescence. Measurements of macrovascular function (systolic and diastolic blood pressure (SBP and DBP), pulse wave velocity (PWV), and microvascular function (central retinal arteriolar/veinular equivalent) were assessed at 11 years old in a Spanish birth cohort study (n = 489). BMI trajectories from birth to 9 years were identified using latent class growth analysis. Multiple linear regression assessed the associations between the BMI trajectories and macro- and microvascular function. Compared to children with average birth size and slower BMI gain (reference), children with a lower birth size and accelerated BMI gain had increased SBP [ß = 6.57; (95% CI 4.00, 9.15)], DBP [ß = 3.65; (95% CI 1.45, 5.86)], and PWV [ß = 0.14; (95% CI 0.01, 0.27)]. Children with higher birth size and accelerated BMI gain had increased SBP [ß = 4.75; (95% CI 1.79, 7.71) compared to the reference. No significant associations between BMI trajectories and the microvascular measurements were observed. In conclusion, we found that childhood BMI trajectories characterized by accelerated growth are associated with preclinical macrovascular measurements in young adolescents.

Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress.

The cellular mechanisms required to ensure homeostasis of the hematopoietic niche and the ability of this niche to support hematopoiesis upon stress remain elusive. We here identify Wnt5a in Osterix+ mesenchymal progenitor and stem cells (MSPCs) as a critical factor for niche-dependent hematopoiesis. Mice lacking Wnt5a in MSPCs suffer from stress-related bone marrow (BM) failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small GTPase CDC42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. In MSPCs from patients from BM failure states which share features of peripheral cytopenia and hypocellular BM, we find similar defects in actin stress fiber orientation, reduced and incorrect colocalization of autophagosomes and lysosomes, and CDC42 activation. Strikingly, a short pharmacological intervention to attenuate elevated CDC42 activation in vivo in mice prevents defective actin-anchored autophagy in MSPCs, salvages hematopoiesis and protects against lethal cytopenia upon stress. In summary, our study identifies Wnt5a as a restriction factor for niche homeostasis by affecting CDC42-regulated actin stress-fiber orientation and autophagy upon stress. Our data further imply a critical role for autophagy in MSPCs for adequate support of hematopoiesis by the niche upon stress and in human diseases characterized by peripheral cytopenias and hypocellular BM.

Guía de práctica clínica para el tratamiento farmacológico inicial de nefritis lúpica en el Seguro Social del Perú (EsSalud) / Clinical practice guideline for the initial pharmacological treatment of lupus nephritis in the Peruvian Social Security (EsSalud)

Introducción: El presente artículo resume la guía de práctica clínica (GPC) para el tratamiento farmacológico inicial nefritis lúpica en el Seguro Social del Perú (EsSalud). Objetivo: Proveer recomendaciones clínicas basadas en evidencia para tratamiento farmacológico inicial de adultos con nefritis lúpica clase I a V no refractarios en EsSalud. Material y Métodos: Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos, el cual formuló preguntas clínicas. Se realizaron búsquedas sistemáticas de revisiones sistemáticas y ­cuando fue considerado pertinente­ estudios primarios en PubMed durante el 2021. Se seleccionó la evidencia para responder cada una de las preguntas clínicas planteadas. Se evaluó la certeza de evidencia usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones. La GPC fue revisada por expertos externos antes de su aprobación. Resultados: La GPC abordó 6 preguntas clínicas, divididas en 2 temas: tratamiento inicial de la fase de inducción y mantenimiento. En base a dichas preguntas se formularon 11 recomendaciones (todas condicionales), 22 puntos de buena práctica clínica, y 2 flujogramas. Conclusión: Se emitieron recomendaciones basadas en evidencia para el manejo de pacientes con esta patología.

Introduction: This article summarizes the clinical practice guideline (CPG) for initial pharmacological treatment of lupus nephritis in the Peruvian Social Security (EsSalud). Objective: To provide evidence-based clinical recommendations for initial pharmacological treatment of adults with non-refractory class I to V lupus nephritis in EsSalud. Material and Methods: A guideline development group (GDG) was formed that included medical specialists and methodologists, which formulated clinical questions. Systematic searches of systematic reviews and -when considered pertinent- primary studies were performed in PubMed during 2021. Evidence was selected to answer each of the clinical questions posed. The certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic working meetings, the GEG used the GRADE methodology to review the evidence and formulate recommendations. The CPG was reviewed by external experts before approval. Results: The CPG addressed 6 clinical questions, divided into 2 topics: initial treatment of the induction phase and maintenance. Based on these questions, 11 recommendations (all conditional), 22 points of good clinical practice, and 2 flowcharts were formulated. Conclusion: Evidence-based recommendations were issued for the management of patients with this pathology.

Urban environment and obesity and weight-related behaviours in primary school children.

BACKGROUND: Urban environments are characterised by many factors that may influence children's lifestyle and increase the risk of childhood obesity, but multiple urban exposures have scarcely been studied. OBJECTIVE: We evaluated the association between multiple urban exposures and childhood obesity outcomes and weight-related behaviours. METHODS: We conducted a cross-sectional study including 2213 children aged 9-12 years in Sabadell, Spain. We estimated ambient air pollution, green spaces, built and food environment, road traffic and road traffic noise at residential addresses through a total of 28 exposure variables in various buffers. Childhood obesity outcomes included body mass index (BMI), waist circumference and body fat. Weight-related behaviours included diet (fast food and sugar-sweetened beverage consumption), physical activity, sedentary behaviour, sleep duration and well-being. Associations between exposures (urban environment) and outcomes (obesity and behaviours) were estimated in single and multiple-exposure regression models and in a hierarchical clustering on principal components (HCPC) analysis. RESULTS: Forty percent of children were overweight or obese. In single exposure models, very few associations were observed between the urban exposures and obesity outcomes or weight-related behaviours after correction for multiple testing. In multiple exposure models, PMcoarse, denser unhealthy food environment and land use mix were statistically significant associated with childhood obesity outcomes (e.g 17.7 facilities/km2 increase of unhealthy food environment (OR overweight/obesity status) = 1.20 [95% CI: 1.01; 1.44]). Cluster analysis identified 5 clusters of urban exposures. Compared to the most neutral cluster, the cluster with high air pollution, road traffic, and road noise levels was associated with a higher BMI and higher odds of overweight and obesity (ß (zBMI) = 0.17, [95% CI: 0.01, 0.17]; OR (overweight/obesity) = 1.36, [95% CI: 0.99, 1.85]); the clusters were not associated with the weight-related behaviours. CONCLUSIONS: This systematic study of many exposures in the urban environment suggests that an exposure pattern characterised by higher levels of ambient air pollution, road traffic and road traffic noise is associated with increased childhood obesity risk and that PMcoarse, land use mix and food environment are separately associated with obesity risk. These findings require follow-up in longitudinal studies and different settings.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.

Secreted factors from mouse embryonic fibroblasts maintain repopulating function of single cultured hematopoietic stem cells.

Hematopoietic stem cell self-renewal, proliferation, and differentiation are independently regulated by intrinsic as well as extrinsic mechanisms. We previously demonstrated that murine proliferation of hematopoietic stem cells is supported in serum-free medium supplemented with two growth factors, stem cell factor and interleukin 11. The survival of hematopoietic stem cells is additionally improved by supplementing this medium with two more growth factors, neural growth factor and collagen 1 (four growth factors) or serum-free medium conditioned by the hematopoietic stem cell-supportive stromal UG26-1B6 cells1. Here, we describe a robust and versatile alternative source of conditioned medium from mouse embryonic fibroblasts. We found that this conditioned medium supports survival and phenotypical identity of hematopoietic stem cells, as well as cell cycle entry in single cell cultures of CD34- CD48- CD150+ Lineage- SCA1+ KIT+ cells supplemented with two growth factors. Strikingly, in comparison with cultures in serum-free medium with four growth factors, conditioned medium from mouse embryonic fibroblasts increases the numbers of proliferating clones and the number of Lineage- SCA1+ KIT+ cells, both with two and four growth factors. In addition, conditioned medium from mouse embryonic fibroblasts supports self-renewal in culture of cells with short- and long-term hematopoiesis-repopulating ability in vivo. These findings identify conditioned medium from mouse embryonic fibroblasts as a robust alternative serumfree source of factors to maintain self-renewal of in vivo-repopulating hematopoetic stem cells in culture.