El corazón de las personas que nacieron con bajo peso podría ser distinto del de los demás

Si durante el embarazo el feto experimenta una falta de nutrientes, intentará ahorrar y engordará menos. Sin embargo, esto puede tener importantes consecuencias en su salud adulta

Transgenerational transmission of small for gestational age

Objective: To evaluate the transgenerational transmission of small for gestational age. Methods: Cohort study including a random sample of 2,043 offspring of deliveries occurring from 1975 to 1993. Of 623 offspring -now adults- that agreed to participate, 152 adults (72 born small-for-gestational age (SGA) and 80 with appropriate intrauterine growth) reported to have at least one child. Multiple regression analysis was used to determine the presence of SGA (defined as a birthweight < 10th percentile) or placental mediated disease (defined as the presence of SGA, preeclampsia or gestational hypertension) in the following generation. Results: Descendants from SGA adults presented lower birthweight percentile (median 26 [interquartile range 7-52] vs. 43 [19-75]; p<0.001) and higher prevalence of SGA (40.3% vs. 16.3%; p=0.001) and placental mediated disease (43.1% vs. 17.5%; p=0.001). After adjustment for confounder variables, parental SGA background was associated with an almost three-fold increased risk of subsequent SGA or any placental mediated disease in the following generation. This association was stronger in SGA mothers as compared to fathers. Conclusions: Our data provides evidence suggesting a transgenerational transmission of SGA highlighting the importance of public health strategies for preventing intrauterine growth impairment

Comparison of 2D versus M-mode echocardiography for assessing fetal myocardial wall thickness

OBJECTIVE: M-mode and 2D have been proposed for evaluating fetal myocardial thickness. However, studies comparing the performance of both modalities are lacking. We aimed to compare 2D versus M-mode reproducibility for assessing myocardial wall thicknesses. METHODS: A prospective study including 45 healthy fetuses from low-risk pregnancies evaluated between 18 and 41 weeks of gestation. Left and right ventricular free-wall and septal myocardial thicknesses were measured at end-diastole (ED) and end-systole (ES) in transverse 4-chamber view using 2D and M-mode. Intra- and interobserver reproducibility was evaluated by the concordance correlation coefficient (CCC). Both techniques were compared by t-test of the CCC. RESULTS: 2D and M-mode demonstrated excellent and similar intraobserver repeatability, with the best concordance in ES septal thickness (M-mode CCC 0.956 versus 2D-mode CCC 0.914). Interobserver reproducibility demonstrated also a high concordance, optimal in ES left ventricular free wall (M-mode 0.925 versus 2 D 0.855). Comparison of both techniques demonstrated a high concordance in all measurements, except for ED septal thickness with better reproducibility using M-mode (CCC 0.954 versus 0.847, p = .017). CONCLUSIONS: 2D and M-mode can be used in a reproducible manner for measuring fetal myocardial thickness, with a slightly better performance of M-mode for assessing ED septal wall thickness

Association of central obesity with unique cardiac remodelling in young adults born small for gestational age

Being born small for gestational age (SGA, 10% of all births) is associated with increased risk of cardiovascular mortality in adulthood together with lower exercise tolerance, but mechanistic pathways are unclear. Central obesity is known to worsen cardiovascular outcomes, but it is uncertain how it affects the heart in adults born SGA. We aimed to assess whether central obesity makes young adults born SGA more susceptible to cardiac remodelling and dysfunction.A perinatal cohort from a tertiary university hospital in Spain of young adults (30-40 years) randomly selected, 80 born SGA (birth weight below 10th centile) and 75 with normal birth weight (controls) was recruited. We studied the associations between SGA and central obesity (measured via the hip-to-waist ratio and used as a continuous variable) and cardiac regional structure and function, assessed by cardiac magnetic resonance using statistical shape analysis. Both SGA and waist-to-hip were highly associated to cardiac shape (F = 3.94, P < 0.001; F = 5.18, P < 0.001 respectively) with a statistically significant interaction (F = 2.29, P = 0.02). While controls tend to increase left ventricular end-diastolic volumes, mass and stroke volume with increasing waist-to-hip ratio, young adults born SGA showed a unique response with inability to increase cardiac dimensions or mass resulting in reduced stroke volume and exercise capacity.SGA young adults show a unique cardiac adaptation to central obesity. These results support considering SGA as a risk factor that may benefit from preventive strategies to reduce cardiometabolic risk.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: [email protected]

Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial

Simple Summary Most patients with glioblastoma, the most frequent primary brain tumor in adults, develop resistance to standard first-line treatment combining temozolomide and radiotherapy. Signaling through the hepatocyte growth factor receptor (c-MET) and the midkine (ALK ligand) promotes gliomagenesis and glioma stem cell maintenance, contributing to the resistance of glioma cells to anticancer therapies. This trial reports for the first time that the addition of crizotinib, an ALK, ROS1, and c-MET inhibitor, to standard RT and TMZ is safe and resulted in a promising efficacy for newly diagnosed patients with glioblastoma. Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade >= 3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation.

Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells. SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1. Consistent with this, SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-alpha. Notably, these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1. Finally, we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter. These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy, heart failure, and diabetic cardiomyopathy, our results point to SIRT3 as a potential target for treating these diseases

FATORES ASSOCIADOS AO ABSENTEÍSMO NO TRABALHO DE PROFISSIONAIS DE ENFERMAGEM

Introdução: O absenteísmo dos profissionais de enfermagem modifica a dinâmica organizacional, compromete a segurança dos pacientes, provoca insatisfação, sobrecarrega os demais membros da equipe, contribui para a ocorrência de infecções, lesões por pressão, elevação dos custos totais e riscos ocupacionais. Então, é imprescindível conhecer os fatores que estão associados ao absenteísmo, para estimular a implementação de políticas públicas e intervenções laborais que visem a promoção da saúde do trabalhador e redução do absenteísmo laboral. Objetivo: Mapear evidências científicas sobre os fatores associados ao absenteísmo no trabalho por profissionais de enfermagem. Métodos: Trata-se de uma revisão de escopo, cuja busca das publicações ocorreu em junho de 2023, na MEDLINE via PubMed, CINAHL, Web of Science, SCOPUS, BDENF e LILACS, sendo incluídos 15 artigos. Resultados: Os fatores associados ao absenteísmo no trabalho por profissionais de enfermagem são diversos: idade, sexo, situação conjugal, escolaridade, condições de saúde autorreferida, doenças osteomusculares, transtornos mentais e comportamentais; esgotamento, relacionamento interpessoal ineficaz, ausência de comunicação efetiva, problemas com os filhos; desorganização do serviço, acidentes de trabalho, falta de infraestrutura e insumos, falta de apoio para aprimoramento, falta de suporte psicossocial, sobrecarga de trabalho, local de trabalho, turno de trabalho e condições do ambiente de trabalho; tipo de vínculo, categoria profissional, horas de trabalho por semana, tempo de trabalho no serviço clínico, duplo vínculo de trabalho e necessidade de planos de carreira e salários. Considerações Finais: Os fatores associados ao absenteísmo possuem causas multifatoriais e complexas, relacionadas aos fatores individuais, interpessoais, ambientais, organizacionais, e ao cargo e função

A 3-biomarker 2-point-based risk stratification strategy in acute heart failure

[Abstract] Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715–0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747–0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality.Instituto de Salud Carlos III; RD06-0003-0000Instituto de Salud Carlos III; RD12/0042/000

A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure

Altres ajuts: ISCIII/RD06-0003-0000Altres ajuts: ISCIII/RD12/0042/0002Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715-0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747-0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere