ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility.

ERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility per se, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high KSR1 expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.

The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis.

The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the RHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1- and sterol regulatory element-binding factor (SREBF)-dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome-wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR-regulated gene signature predicts long-term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy-resistant breast cancer patients. These results reveal a hitherto unknown, VAV-catalysis-dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate-pathway-dependent processes that contribute to the malignant features of breast cancer cells.

Circum-Mediterranean influence in the Y-chromosome lineages associated with prostate cancer in Mexican men: A Converso heritage founder effect?

Prostate cancer is the second most common neoplasia amongst men worldwide. Hereditary susceptibility and ancestral heritage are well-established risk factors that explain the disparity trends across different ethnicities, populations, and regions even within the same country. The Y-chromosome has been considered a prototype biomarker for male health. African, European, Middle Eastern, and Hispanic ancestries exhibit the highest incidences of such neoplasia; Asians have the lowest rates. Nonetheless, the contribution of ancestry patterns has been scarcely explored among Latino males. The Mexican population has an extremely diverse genetic architecture where all the aforementioned ancestral backgrounds converge. Trans-ethnic research could illuminate the aetiology of prostate cancer, involving the migratory patterns, founder effects, and the ethnic contributions to its disparate incidence rates. The contribution of the ancestral heritage to prostate cancer risk were explored through a case-control study (152 cases and 372 controls) study in Mexican Mestizo males. Seventeen microsatellites were used to trace back the ancestral heritage using two Bayesian predictor methods. The lineage R1a seems to contribute to prostate cancer (ORadjusted:8.04, 95%CI:1.41-45.80) development, whereas E1b1a/E1b1b and GHIJ contributed to well-differentiated (Gleason ≤ 7), and late-onset prostate cancer. Meta-analyses reinforced our findings. The mentioned lineages exhibited a connection with the Middle Eastern and North African populations that enriched the patrilineal diversity to the southeast region of the Iberian Peninsula. This ancestral legacy arrived at the New World with the Spanish and Sephardim migrations. Our findings reinforced the contribution of family history and ethnic background to prostate cancer risk, although should be confirmed using a large sample size. Nonetheless, given its complex aetiology, in addition to the genetic component, the lifestyle and xenobiotic exposition could also influence the obtained results.

The Organotypic Culture of Mouse Seminiferous Tubules as a Reliable Methodology for the Study of Meiosis In Vitro.

Male mouse meiosis has been traditionally studied using descriptive methods like histological sections and spreading or squashing techniques, which allow the observation of fixed meiocytes in either wildtype or genetically modified mice. For these studies, the sacrifice of the males and the extraction of the testicles are required to obtain the material of study. Other functional in vivo studies include the administration of intravenous or intraperitoneal drugs, or the exposure to mutagenic agents or generators of DNA damage, in order to study their impact on meiosis progression. However, in these studies, the exposure times or drug concentration are important limitations to consider when acknowledging animal welfare. Recently, several approaches have been proposed to offer alternative methodologies that allow the in vitro study of spermatocytes with a considerable reduction in the use of animals. Here we revisit and validate an optimal technique of organotypic culture of fragments of seminiferous tubules for meiotic studies. This technique is a trustable methodology to develop functional studies that preserve the histological configuration of the seminiferous tubule, aim homogeneity of the procedures (the use of the same animal for different study conditions), and allow procedures that would compromise the animal welfare. Therefore, this methodology is highly recommendable for the study of meiosis and spermatogenesis, while it supports the principle of 3R's for animal research.

Spermatocytes have the capacity to segregate chromosomes despite centriole duplication failure.

Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility.

Variation and plasticity in life-history traits and fitness of wild Arabidopsis thaliana populations are not related to their genotypic and ecological diversity.

BACKGROUND: Despite its implications for population dynamics and evolution, the relationship between genetic and phenotypic variation in wild populations remains unclear. Here, we estimated variation and plasticity in life-history traits and fitness of the annual plant Arabidopsis thaliana in two common garden experiments that differed in environmental conditions. We used up to 306 maternal inbred lines from six Iberian populations characterized by low and high genotypic (based on whole-genome sequences) and ecological (vegetation type) diversity. RESULTS: Low and high genotypic and ecological diversity was found in edge and core Iberian environments, respectively. Given that selection is expected to be stronger in edge environments and that ecological diversity may enhance both phenotypic variation and plasticity, we expected genotypic diversity to be positively associated with phenotypic variation and plasticity. However, maternal lines, irrespective of the genotypic and ecological diversity of their population of origin, exhibited a substantial amount of phenotypic variation and plasticity for all traits. Furthermore, all populations harbored maternal lines with canalization (robustness) or sensitivity in response to harsher environmental conditions in one of the two experiments. CONCLUSIONS: Overall, we conclude that the environmental attributes of each population probably determine their genotypic diversity, but all populations maintain substantial phenotypic variation and plasticity for all traits, which represents an asset to endure in changing environments.

Prediction of the antigenic regions in eight RhD variants identified by computational biology.

BACKGROUND AND OBJECTIVES: Changes in RHD generate variations in protein structure that lead to antigenic variants. The classical model divides them into quantitative (weak and Del) and qualitative (partial D). There are two types of protein antigens: linear and conformational. Computational biology analyses the theoretical assembly of tertiary protein structures and allows us to identify the 'topological' differences between isoforms. Our aim was to determine the theoretical antigenic differences between weak RhD variants compared with normal RhD based on structural analysis using bioinformatic techniques. MATERIALS AND METHODS: We analysed the variations in secondary structures and hydrophobicity of RHD*01, RHD*01W.1, W2, W3, RHD*09.03.01, RHD*09.04, RHD*11, RHD*15 and RHD*21. We then modelled the tertiary structure and calculated their probable antigenic regions, intra-protein interactions, displacement and membrane width and compared them with Rhce. RESULTS: The 10 proteins are similar in their secondary structure and hydrophobicity, with the main differences observed in the exofacial coils. We identified six potential antigenic regions: one that is unique to RhD (R3), one that is common to all D (R6), three that are highly variable among RhD isoforms (R1, R2 and R4), one that they share with Rhce (R5) and two that are unique to Rhce (Ra and Rbc). CONCLUSION: The alloimmunization capacity of these subjects could be explained by the variability of the antigen pattern, which is not necessarily recognized or recognized with lower intensity by the commercially available antibodies, and not because they have a lower protein concentration in the membrane.

Prenatal Stress as a Risk Factor for Maternal-Foetal Morbidity: A Longitudinal Study.

Pregnancy is one of the most complex periods in a woman's life, not only because of the biological changes involved but also because of the psychological aspects. Stress during pregnancy refers to the concerns and distress that arise during pregnancy and that can be assessed by means of psychological and physiological scales. The aim of this study was to analyse prenatal stress and to evaluate its consequences on the health of both the mother and the foetus. A descriptive longitudinal study was carried out on a sample of 398 pregnant women being followed up during their entire pregnancy, who gave birth at the Punta de Europa University Hospital in Algeciras (Spain) between September 2021 and August 2023. The Prenatal Distress Questionnaire (PDQ) was used, as well as serum cortisol levels in each trimester of pregnancy and birth experience using the Childbirth Experience Questionnaire in its validated Spanish version, CEQ-E. Demographic and obstetric variables were included. One of the main findings was that experiencing more stress in late pregnancy had a negative impact on obstetric outcomes. Women who had higher levels of prenatal distress had higher blood cortisol levels and increased risk of having a caesarean section at delivery. A significant negative correlation was also found between stress and Apgar test values in the first minute of life. It is concluded that interventions promoted by the health system that provide comprehensive prenatal care contribute to decreased stress as perceived by these pregnant women, thus reducing the risk of maternal and foetal morbidity.

The role of physical activity in the association between disability and mortality among US older adults: a nationwide prospective cohort study.

To examine whether physical activity can mitigate the mortality risk associated with disability in activities of daily living and instrumental activities in daily living among older adults. This analysis comprised 177,360 US participants (104,556 women), aged ≥ 60 years, with valid data from the 1997 through 2018 waves of the US National Health Interview Survey. Participants reported the frequency and duration of leisure-time PA, and their disabilities in activities of daily living and instrumental activities in daily living. Mortality data were obtained from the National Death Index. Over a mean (SD) follow-up of 8.02 (5.43) years, 66,694 deaths occurred from all-cause, 22,673 from cardiovascular disease, and 13,845 from cancer. Among people with disability in activities in daily living, those reaching physical activity recommendations had 25%, 24% and 33% lower risk of all-cause mortality, cardiovascular diseases, and cancer death, respectively, compared with those who do not meet physical activity recommendations. Values were 23%, 22% and 24% for those with disability in instrumental activities in daily living. Risk reductions associated with reaching the recommended physical activity ranged 16% to 29% for people without disability. Combining disability type and compliance with physical activity, individuals with disability in activities of daily living or instrumental activities in daily living who meet the recommended physical activity had moderately higher mortality than those without disability who did not achieve the recommended physical activity. Compliance with physical activity recommendations can partially mitigate excess mortality resulting from disability in activities in daily living or instrumental activities in daily living in older adults.

Time measurement validity and reliability of the 4 × 10-m shuttle run test in adult population: The ADULT-FIT project.

OBJECTIVES: The purpose of this study was to analyze the time measurement validity and reliability (between raters and test-retest) of the 4 × 10-m shuttle run test to assess motor fitness in adults, according to gender, age, and physical activity levels. DESIGN: Cross-sectional. A total of 230 adults (86 women) aged 18-64 years participated in the study. METHODS: The time taken to complete the 4 × 10-m shuttle run test was recorded simultaneously by a trained and an untrained rater (inter-rater reliability) and by photoelectric cells (time measurement validity). 48-72 h later, the test was repeated under the same conditions (test-retest reliability). RESULTS: The systematic error for trained rater vs. photocell was close to zero (0.0125, p < 0.01), with an effect size of 0.006; and for both, untrained rater vs. photocell and trained rater vs. untrained rater was ∼0.2 s (p < 0.001) with an effect size of 0.09. For the test-retest reliability, the systematic error was 0.05 s (p < 0.001), with an effect size of 0.26, the intraclass correlation coefficient was 0.998 and the coefficient of variation reported a variability of 0.73 %. Results were not influenced by gender and age, while these improved for active vs. non-active participants. CONCLUSIONS: Findings indicate that measurements with trained raters are a valid and reliable method for assessing the 4 × 10-m shuttle run test in adults. It is highly recommended that raters be trained to minimize the measurement error.

Use of computational biology to compare the theoretical tertiary structures of the most common forms of RhCE and RhD.

BACKGROUND AND OBJECTIVES: Computational biology analyses the theoretical tertiary structure of proteins and identifies the 'topological' differences between RhD and RhCE. Our aim was to identify the theoretical structural differences between the four isoforms of RhCE and RhD using computational biological tools. MATERIALS AND METHODS: Physicochemical profile was determined by hydrophobicity and electrostatic potential analysis. Secondary and tertiary structures were generated using computational biology tools. The structures were evaluated and validated using Ramachandran algorithm, which calculates the single score, p-value and root mean square deviation (RMSD). Structures were overlaid on local refinement of 'RhAG-RhCE-ANK' (PBDID 7uzq) and RhAG to compare their spatial distribution within the membrane. RESULTS: All proteins differed in surface area and electrostatic distance due to variations in hydrophobicity and electrostatic potential. The RMSD between RhD and RhCE was 0.46 ± 0.04 Å, and the comparison within RhCE was 0.57 ± 0.08 Å. The percentage of amino acids in the hydrophobic thickness was 50.24% for RhD while for RhCE it ranged between 73.08% and 76.68%. The RHAG hydrophobic thickness was 34.2 Å, and RhCE's hydrophobic thickness was 33.83 Å. We suggest that the C/c antigens differ exofacially at loops L1 and L2. For the E/e antigens, the difference lies in L6. By contrast, L4 is the same for all proteins except Rhce. CONCLUSION: The physicochemical properties of Rh proteins made them different, although their genes are homologous. Using computational biology, we model structures with sufficient precision, similar to those obtained experimentally. An amino acid variation alters the folding of the tertiary structure and the interactions with other proteins, modifying the electrostatic environment, the spatial conformations and therefore the antigenic recognition.

Bisphenol A increases the size of primary mammary tumors and promotes metastasis in a murine model of breast cancer.

Triple negative breast cancer (TNBC) is a subtype of breast tumor characterized for the absence of estrogen and progesterone receptors expression and low HER2/neu expression. Bisphenol A (BPA) is an endocrine disrupting chemical with estrogenic activity that has been associated with increasing rates of breast cancer. Moreover, BPA is a solid organic synthetic chemical employed in the manufacture of many consumer products, epoxy resins and polycarbonate plastics including baby bottles, containers for food and beverages, and the lining of beverage cans. The G-protein-coupled estrogen receptor (GPER) is activated by endogenous hormones and synthetic ligands, such as BPA. GPER is expressed in TNBC cells and its expression is associated with larger tumor size, metastasis and worse survival prognosis. In breast cancer cells, BPA induces activation of signal transduction pathways that mediates migration and invasion via GPER in human TNBC MDA-MB-231 cells. In this study, we demonstrate that BPA induces an increase of GPER expression and its translocation from cytosol to cytoplasmic membrane, metalloproteinase (MMP)-2 and MMP-9 secretion, migration and invasion in murine TNBC 4T1 cells. In a murine TNBC model "in vivo" using 4T1 cells, BPA induces the formation of mammary tumors with more weight and volume, and an increase in the number of mice with metastasis to lung and nodules in lung compared with tumors and metastasis to lung of untreated Balb/cJ mice. In conclusion, our findings demonstrate that BPA mediates the growth of mammary primary tumors and metastasis to lung in a murine model of breast cancer.

Divergent patterns of meiotic double strand breaks and synapsis initiation dynamics suggest an evolutionary shift in the meiosis program between American and Australian marsupials.

In eutherian mammals, hundreds of programmed DNA double-strand breaks (DSBs) are generated at the onset of meiosis. The DNA damage response is then triggered. Although the dynamics of this response is well studied in eutherian mammals, recent findings have revealed different patterns of DNA damage signaling and repair in marsupial mammals. To better characterize these differences, here we analyzed synapsis and the chromosomal distribution of meiotic DSBs markers in three different marsupial species (Thylamys elegans, Dromiciops gliorides, and Macropus eugenii) that represent South American and Australian Orders. Our results revealed inter-specific differences in the chromosomal distribution of DNA damage and repair proteins, which were associated with differing synapsis patterns. In the American species T. elegans and D. gliroides, chromosomal ends were conspicuously polarized in a bouquet configuration and synapsis progressed exclusively from the telomeres towards interstitial regions. This was accompanied by sparse H2AX phosphorylation, mainly accumulating at chromosomal ends. Accordingly, RAD51 and RPA were mainly localized at chromosomal ends throughout prophase I in both American marsupials, likely resulting in reduced recombination rates at interstitial positions. In sharp contrast, synapsis initiated at both interstitial and distal chromosomal regions in the Australian representative M. eugenii, the bouquet polarization was incomplete and ephemeral, γH2AX had a broad nuclear distribution, and RAD51 and RPA foci displayed an even chromosomal distribution. Given the basal evolutionary position of T. elegans, it is likely that the meiotic features reported in this species represent an ancestral pattern in marsupials and that a shift in the meiotic program occurred after the split of D. gliroides and the Australian marsupial clade. Our results open intriguing questions about the regulation and homeostasis of meiotic DSBs in marsupials. The low recombination rates observed at the interstitial chromosomal regions in American marsupials can result in the formation of large linkage groups, thus having an impact in the evolution of their genomes.

NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review.

Arylamine N-acetyltransferase 2 has been related to drug side effects and cancer susceptibility; its protein structure and acetylation capacity results from the polymorphism's arrays on the NAT2 gene. Absorption, distribution, metabolism, and excretion, cornerstones of the pharmacological effects, have shown diversity patterns across populations, ethnic groups, and even interethnic variation. Although the 1000 Genomes Project database has portrayed the global diversity of the NAT2 polymorphisms, several populations and ethnicities remain underrepresented, limiting the comprehensive picture of its variation. The NAT2 clinical entails require a detailed landscape of its striking diversity. This systematic review spans the genetic and acetylation patterns from 164 articles from October 1992 to October 2020. Descriptive studies and controls from observational studies expanded the NAT2 diversity landscape. Our study included 243 different populations and 101 ethnic minorities, and, for the first time, we presented the global patterns in the Middle Eastern populations. Europeans, including its derived populations, and East Asians have been the most studied genetic backgrounds. Contrary to the popular perception, Africans, Latinos and Native Americans have been significantly represented in recent years. NAT2*4, *5B, and *6A were the most frequent haplotypes globally. Nonetheless, the distribution of *5B and *7B were less and more frequent in Asians, respectively. Regarding the acetylator status, East Asians and Native Americans harboured the highest frequencies of the fast phenotype, followed by South Europeans. Central Asia, the Middle East, and West European populations were the major carriers of the slow acetylator status. The detailed panorama presented herein, expands the knowledge about the diversity patterns to genetic and acetylation levels. These data could help clarify the controversial findings between acetylator states and the susceptibility to diseases and reinforce the utility of NAT2 in precision medicine.

Results From Spain's 2022 Para Report Cards on Physical Activity of Children and Adolescents With Disabilities.

This report aims to provide a better understanding of physical activity (PA) and related factors among Spanish children and adolescents living with disabilities. The 10 indicators used for the Global Matrix on Para Report Cards of children and adolescents living with disabilities were evaluated based on the best available data in Spain. An analysis of strengths, weaknesses, opportunities, and threats based on data provision was drafted by three experts and critically reviewed by the authorship team to provide a national perspective for each evaluated indicator. Government was the indicator with the highest grade (C+), followed by Sedentary Behaviors (C-), School (D), Overall PA (D-), and Community & Environment (F). The remaining indicators received an incomplete grade. There were low levels of PA in Spanish children and adolescents living with disabilities. Yet, opportunities to improve the current surveillance of PA among this population exist.

Antenatal Fear of Childbirth as a Risk Factor for a Bad Childbirth Experience.

Giving birth is one of the most impressive experiences in life. However, many pregnant women suffer from fear of childbirth (FOC) and experience labour in very different ways, depending on their personality, previous life experiences, pregnancy, and birth circumstances. The aim of this study was to analyse how fear of childbirth affects the childbirth experience and to assess the related consequences. For this, a descriptive cross-sectional study was carried out in a sample of 414 women between 1 July 2021 and 30 June 2022. The Birth Anticipation Scale (BAS) was used to measure fear of childbirth and the Childbirth Experience Questionnaire (CEQ-E) was applied to measure satisfaction with the childbirth experience. Fear of childbirth negatively and significantly predicted the childbirth experience. In addition, women who were more fearful of childbirth were found to have worse obstetric outcomes and a higher likelihood of having a caesarean delivery (p = 0.008 C. I 95%). Fear behaved as a risk factor for the birth experience, so the greater the fear, the higher the risk of having a worse birth experience (OR 1.1). Encouraging active listening and support strategies may increase pregnant women's confidence, thus decreasing their fear of the process and improving their childbirth experience.

Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species.

RAS-ERK (extracellular signal-regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named "trans-phosphorylation." We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein-aimed therapeutics.

Fitness, body composition, and metabolic risk scores in children and adolescents: the UP&DOWN study.

We aimed to analyse the longitudinal association between physical fitness (PF) and body composition (BC) with a metabolic risk score (Met4) in children and adolescents and to elucidate whether the association between PF and Met4 differs when using relativized or absolute fitness variables. A total of 188 children (86 females) and 195 adolescents (97 females) were included. Cardiorespiratory fitness (CRF) was determined by the 20-m shuttle run test, and muscular fitness (MF) was determined by hand grip and standing long jump tests. Height and weight were measured, and the body mass index (Kg/m2) was calculated. Triceps and subscapular skinfolds were assessed to compute body fat percentage. Met4 was computed from systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose levels. Relative CRF was longitudinally and negatively associated with Met4 in female children (ß = -0.031, p = 0.025), while absolute CRF was positively associated with Met4 in male children and adolescents (ß = 0.000, p < 0.05). Relative upper and lower-body MF were longitudinally and negatively associated with Met4 in female adolescents (ß = -1.347, ß = -0.005, p < 0.05), while absolute lower-body MF was positively associated with Met4 in male children (ß = 0.000, p = 0.019). BC was longitudinally and positively associated with Met4 in male children (ß-ranging from 0.011 to 0.055, all p < 0.05) and male adolescents (ß-ranging from 0.011 to 0.046, all p < 0.05).  Conclusion: BC is more strongly associated with Met4 than PF in children and adolescents. An optimal body weight status should be considered the main objective of health-promoting programs at childhood and adolescence. Furthermore, the way of expressing the fitness variables determines the direction of the association with Met4. What is Known: • Physical fitness is an important health indicator in children and adolescents, with great amount of previous evidence supporting the preventive role of maintaining optimal levels of both cardiorespiratory and muscular fitness for future cardiometabolic issues. What is New: • The way of reporting physical fitness variables can affect the associations between physical fitness features and cardiometabolic outcomes. Since body composition variables have a great impact on both physical fitness and cardiometabolic health, relativizing physical fitness performance by body composition could lead to erroneous conclusions.

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study.

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness.

Health literacy and prognosis of heart failure: a prospective propensity-matched study in the community.

AIMS: Health literacy (HL), the ability to obtain and understand health information, is critical to self-care in chronic disorders. A low HL is common among these patients and has been associated with a worse prognosis. Nevertheless, the relationship between HL and the prognosis of heart failure (HF) with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction remains unsettled. To analyse the relationship between HL and the prognosis of patients with incident HFrEF and HFpEF. METHODS AND RESULTS: Prospective study over 10 years (2010-19) on 6444 patients diagnosed with incident HF. The main outcomes were mortality, hospitalizations, and visits to emergency services. The independent relationship between HL and the prognosis, stratifying patients for cardiovascular comorbidity after propensity score-matching was analysed.After matching 5355 HF patients, 1785 with low HL (874 with HFrEF and 911 with HFpEF) vs. 3570 with adequate HL (1748 with HFrEF and 1822 with HFpEF), during a median follow-up of 5.41 years, 3874 patients died (72.3%) and 3699 patients were hospitalized (69.1%). After adjustment for potential confounders, an adequate HL was associated with a lower all-cause and cardiovascular mortality, less hospitalizations, and less 30-day readmissions [relative risk (RR) for HF <0.72 (0.66-0.86), RR for HFrEF <0.69 (0.63-0.95), and RR for HFpEF <0.62 (0.55-0.88), P < 0.001 in all cases], both for patients with HFrEF and HFpEF. Analyses of recurrent hospitalizations gave larger HL effects than time-to-first-event analyses. CONCLUSIONS: In this propensity-matched study, a low HL is associated with a worse prognosis of patients with incident HFrEF and HFpEF.