Aging and cognitive resilience: Molecular mechanisms as new potential therapeutic targets.

As the global population ages, the need to prolong lifespan and healthspan becomes increasingly imperative. Understanding the molecular determinants underlying cognitive resilience, together with changes during aging and the (epi)genetic factors that predispose an individual to decreased cognitive resilience, open avenues for researching novel therapies. This review provides a critical and timely appraisal of the molecular mechanisms underlying cognitive resilience, framed within a critical analysis of emerging therapeutic strategies to mitigate age-related cognitive decline. Significant insights from both animals and human subjects are discussed herein, directed either toward active pharmaceutical ingredients (drug repositioning or macromolecules), or, alternatively, advanced cellular therapies.

Assessing the Risk Stratification of Breast Cancer Polygenic Risk Scores in a Brazilian Cohort.

Polygenic risk scores (PRSs) for breast cancer have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium and differences in variant frequency (allele frequency differences). Thus, locally sourced population-based phenotypic and genomic data sets are essential to assess the validity of PRSs derived from signals detected across populations. Here, we assess the transferability of a breast cancer PRS composed of 313 risk variants (313-PRS) in a Brazilian trihybrid admixed ancestries (European, African, and Native American) whole-genome sequenced cohort, the Rare Genomes Project. We computed 313-PRS in the Rare Genomes Project (n = 853) using the UK Biobank (UKBB; n = 264,307) as reference. We show that although the Brazilian cohorts have a high European ancestry (EA) component, with allele frequency differences and to a lesser extent linkage disequilibrium patterns similar to those found in EA populations, the 313-PRS distribution is inflated when compared with that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. Interestingly, we find that case controls lead to equivalent predictive power when compared with UKBB-EA samples with area under the receiver operating characteristic curve values of 0.66 to 0.62 compared with 0.63 for UKBB.

Preparation Regimens to Improve Capsule Endoscopy visualization and diagnostic yield (PrepRICE); a multicentric randomized trial.

BACKGROUND AND AIMS: Current guidelines recommend bowel preparation before small-bowel capsule endoscopy (SBCE). However, the optimal protocol is yet to be defined. To determine the best timing for preparation in SBCE, we compared small-bowel visualization quality (SBVQ), diagnostic yield (DY), and patient-reported outcomes across four purgative regimens. METHODS: In this prospective, randomized (1:1:1:1), multicentric study, patients with suspected small bowel bleeding were randomized into four arms: G1 (1L of polyethylene-glycol + ascorbic acid [Moviprep®] the night before SBCE), G2 (1L in the morning, up to 2 hours before SBCE), G3 (0.5L up to 2 hours before + 0.5L after the capsule reached the duodenum), and G4 (1L after reaching the duodenum). To assess DY, lesions were categorized as having high (P2) or low (P0 or P1) bleeding potential. Small-bowel visualization quality (SBVQ) was assessed using the Brotz score. Transit times (TT) were measured, and patient tolerability was scored from 0 to 5 with higher scores indicating better tolerability. RESULTS: A total of 387 patients were included; 59% female with a median age of 73 years (IQR 23). The exam completion rate was lower in G1 (90%, p<0.001). Small bowel TT was shorter for patients receiving purgative during SBCE (G3 and G4, p=0.001). SBVQ was better in patients receiving purgative after reaching the SB (p<0.001): median of 7 for G1, 8 for G2, and 9 for G3 and G4. The overall DY of patients receiving intra-procedure purgatives (G3 + G4) was superior (42.7 vs 31.3%, p=0.02); significant differences were found in the second and third terciles. Likewise, G3 and G4 had higher angioectasia detection (p=0.04). Patients' satisfaction was significantly superior for G4 (median 4 points, IQR 1). CONCLUSIONS: The group that received the bowel preparation the night before SBCE had poorer outcomes. Intra-procedure purgative regimens reduced SBTT, enhanced visualization, improved DY, and increased angioectasia detection. G4 was the best-tolerated regimen.

Miniaturization of hiPSC-derived 3D neural cultures in stirred-tank bioreactors for parallelized preclinical assessment of rAAV.

Introduction: Engineered 3D models employing human induced pluripotent stem cell (hiPSC) derivatives have the potential to recapitulate the cell diversity and structure found in the human central nervous system (CNS). Therefore, these complex cellular systems offer promising human models to address the safety and potency of advanced therapy medicinal products (ATMPs), such as gene therapies. Specifically, recombinant adeno-associated viruses (rAAVs) are currently considered highly attractive for CNS gene therapy due to their broad tropism, low toxicity, and moderate immunogenicity. To accelerate the clinical translation of rAAVs, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. The integration of hiPSC-derived CNS models in rAAV development will require, amongst other factors, robust, small-scale, high-throughput culture platforms that can feed the preclinical trials. Methods: Herein, we pioneer the miniaturization and parallelization of a 200 mL stirred-tank bioreactor-based 3D brain cell culture derived from hiPSCs. We demonstrate the applicability of the automated miniaturized Ambr® 15 Cell Culture system for the maintenance of hiPSC-derived neurospheroids (iNSpheroids), composed of neuronal and glial cells. Critical process parameters were optimized, namely, cell density and agitation mode. Results: Under optimized conditions, stable iNSpheroid cultures were attained in the microbioreactors for at least 15 days, with high cell viability and astrocytic and neuronal phenotype maintenance. This culture setup allowed the parallelization of different rAAVs, in different multiplicity of infections (MOIs), to address rAAV-host interactions at a preclinical scale. The iNSpheroids were exposed to rAAV2- and rAAV9-eGFP in the microbioreactors. Transgene expression was detected 14 days post-transduction, revealing different astrocyte/neuron tropism of the two serotypes. Discussion: We advocate that the iNSpheroid cultures in miniaturized bioreactors are reliable and reproducible screening tools for addressing rAAV transduction and tropism, compatible with preclinical demands.

Digital dual test syphilis/HIV detection based on Fourier Descriptors of Cyclic Voltammetry curves.

BACKGROUND: Effective and timely detection is vital for mitigating the severe impacts of Sexually Transmitted Infections (STI), including syphilis and HIV. Cyclic Voltammetry (CV) sensors have shown promise as diagnostic tools for these STI, offering a pathway towards cost-effective solutions in primary health care settings. OBJECTIVE: This study aims to pioneer the use of Fourier Descriptors (FDs) in analyzing CV curves as 2D closed contours, targeting the simultaneous detection of syphilis and HIV. METHODS: Raw CV signals are filtered, resampled, and transformed into 2D closed contours for FD extraction. Essential shape characteristics are captured through selected coefficients. A complementary geometrical analysis further extracts features like curve areas and principal axes lengths from CV curves. A Mahalanobis Distance Classifier is employed for differentiation between patient and control groups. RESULTS: The evaluation of the proposed method revealed promising results with classification performance metrics such as Accuracy and F1-Score consistently achieving values rounded to 0.95 for syphilis and 0.90 for HIV. These results underscore the potential efficacy of the proposed approach in differentiating between patient and control samples for STI detection. CONCLUSION: By integrating principles from biosensors, signal processing, image processing, machine learning, and medical diagnostics, this study presents a comprehensive approach to enhance the detection of both syphilis and HIV. This setts the stage for advanced and accessible STI diagnostic solutions.

Uncovering the burden of Influenza in children in Portugal, 2008-2018.

BACKGROUND: Despite their higher risk of developing severe disease, little is known about the burden of influenza in Portugal in children aged < 5 years old. This study aims to cover this gap by estimating the clinical and economic burden of severe influenza in children, in Portugal, during ten consecutive influenza seasons (2008/09-2017/18). METHODS: We reviewed hospitalizations in children aged < 5 years old using anonymized administrative data covering all public hospitals discharges in mainland Portugal. The burden of hospitalization and in-hospital mortality directly coded as due to influenza was supplemented by the indirect burden calculated from excess hospitalization and mortality (influenza-associated), estimated for four groups of diagnoses (pneumonia or influenza, respiratory, respiratory or cardiovascular, and all-cause), through cyclic regression models integrating the incidence of influenza. Means were reported excluding the H1N1pdm09 pandemic (2009/10). RESULTS: The mean annual number of hospitalizations coded as due to influenza was 189 (41.3 cases per 100,000 children aged < 5 years old). Hospitalization rates decreased with increasing age. Nine-in-ten children were previously healthy, but the presence of comorbidities increased with age. Children stayed, on average, 6.1 days at the hospital. Invasive mechanical ventilation was used in 2.4% of hospitalizations and non-invasive in 3.1%. Influenza-associated excess hospitalizations between 2008 and 2018 were estimated at 1,850 in pneumonia or influenza, 1,760 in respiratory, 1,787 in respiratory or cardiovascular, and 1,879 in all-cause models. A total of 95 influenza-associated excess deaths were estimated in all-cause, 14 in respiratory or cardiovascular, and 9 in respiratory models. Over ten years, influenza hospitalizations were estimated to have cost the National Health Service at least €2.9 million, of which 66.5% from healthy children. CONCLUSIONS: Influenza viruses led to a high number of hospitalizations in children. Most were previously healthy. Results should lead to a reflection on the adequate preventive measures to protect this age group.

Amiodarone-Induced Electrical Storm: A Nightmare in the Emergency Room.

Drug-induced long QT syndrome (LQTS) is defined as prolonged corrected QT interval (QTc ≥460 ms) plus polymorphic ventricular arrhythmia fitting the description of torsades de pointes temporally associated with the administration of a drug or combination of drugs. Amiodarone therapy is a known uncommon cause of acquired QT interval prolongation that should not be underestimated. We present a case of an iatrogenic electrical storm with atrial fibrillation (AF) in which amiodarone was administered to attempt chemical cardioversion, resulting in an unnoticed prolongation of the QT interval, with subsequent repeated polymorphic ventricular tachycardia, managed with isoproterenol. Concomitant drugs and slight electrolyte disturbances potentiated this phenomenon. Given the widespread use of this drug in the emergency department, our case highlights a pertinent matter for all medical emergency practitioners. Additionally, it stresses the significance of potential precipitating factors, such as electrolyte imbalances, which are clinical conditions very frequent in the emergency context, along with the importance of recognizing drug interactions. Finally, this case also emphasizes the vital importance of closely monitoring the patient's receiving amiodarone.

Participation in clinical trials increases the detection of pre-malignant lesions during colonoscopy

Background: colorectal adenoma detection has been associated with the effectiveness of cancer prevention. Clinical trials have been designed to determine the role of several interventions to increase the detection of pre-malignant lesions. We hypothesized that colonoscopy in the setting of clinical trials has a higher pre-malignant lesion detection rate.Methods: a cross-sectional study was performed that compared the detection of pre-malignant lesions in 147 randomly sampled non-research colonoscopies and 294 from the control group of two prospective trials. Outpatients aged 40-79 years, with no personal history of colorectal cancer (CRC) were included.Results: baseline characteristics were similar between the two groups. The pre-malignant lesion detection rate in the trial vs control group was 65.6 % vs 44.2 % (OR 2.411; 95 % CI: 1.608-3.614; p < 0.001), the polyp detection rate was 73.8 % vs 59.9 % (OR 1.889; 95 % CI: 1.242-2.876; p = 0.003), the adenoma detection rate was 62.6 % vs 44.2 % (OR 2.110; 95 % CI: 1.411-3.155; p < 0.001) and the sessile serrated lesion detection rate was 17 % vs 4.1 % (OR 4.816; 95 % CI: 2.014-11.515; p < 0.001). The mean number of pre-malignant and sessile serrated lesions was 1.70 vs 1.06 (p = 0.002) and 0.32 vs 0.06 (p = 0.001) lesions per colonoscopy, respectively. There was no significant change in any of the study outcomes according to the multivariate analysis with each single potential confounder.Conclusions: patients involved in colonoscopy trials may benefit from higher quality examinations, as shown by the higher detection rates. Institutions should consider supporting clinical research in colonoscopy as a simple means to improve colonoscopy quality and colorectal cancer prevention. (AU)

Evaluation of a new composite score combining SPICE and protrusion angle scores to distinguish submucosal lesions from innocent bulges

Introduction and aim: in capsule endoscopy (CE), small bowel subepithelial lesions (SBSL) are difficult to distinguish from innocent mucosal protrusions. The SPICE score (smooth, protruding lesions index on CE) and a score that assesses the SBSL protrusion angle were developed. The aim of the study was to determine if a composite score is superior to the proposed models.Methods: all CE between 01/2010 and 12/2020 were included in the study if a smooth, round protruding lesion was identified. Both scores and a composite score (SPICE > 2 and angle < 90°) were calculated after video review. Mucosal protrusions were defined as SBSL if they had a histological/imaging diagnosis and innocent protrusions if otherwise. All patients without at least one appointment and an additional diagnostic exam after CE were excluded.Results: a total of 34 CE were included; 64.7 % were males, aged 65.4 ± 14.7 years. The most common indication for CE was anemia (52.9 %). SBSL was identified in 17 cases, with lipomas (14.7 %) being the most frequent diagnosis. Both the SPICE (AUROC 0.90, p < 0.001) and protrusion angle scores (AUROC 0.74, p = 0.019) accurately distinguished SBSL from innocent protrusions. Applying a 90° cut-off, the protrusion angle had a sensitivity of 52.9 % and specificity of 88.2 %. Applying a cut-off of > 2 points, the SPICE score has a sensitivity of 64.7 % and specificity of 94.2 %. The composite score had a sensitivity, specificity, positive and negative predictive value of 47.0 %, 100 %, 100 % and 65.4 %.Conclusion: we propose that additional follow-up investigation should always be undertaken in cases where both a SPICE > 2 and angle of < 90° are obtained, as the likelihood of SBSL is high. (AU)

The rebleeding rate in patients evaluated for obscure gastrointestinal bleeding after negative small bowel findings by device assisted enteroscopy

BACKGROUND: data on the long-term outcome of patients with obscure gastrointestinal bleeding (OGIB) with positive small bowel findings in capsule endoscopy but negative small bowel findings in device-assisted enteroscopy are scarce. OBJECTIVE: this study aimed to evaluate the rebleeding rate and time to rebleed in patients with no small bowel findings in enteroscopy, after a positive capsule endoscopy in the setting of OGIB. Baseline predictors for rebleeding were assessed. METHODS: a retrospective double-center study was performed, including patients with OGIB with positive findings by capsule endoscopy and negative small bowel findings by enteroscopy. RESULTS: thirty-five patients were included. Rebleeding occurred in 40 % of patients during a median follow-up of 27 months. Further evaluation in patients with a rebleed was performed in 85.7 %, leading to a final diagnosis in 78.6 %. The rebleeding rate increased progressively over time, from 17.2 % at one month to 54.4 % at four years. Overt bleeding at the time of the first episode was a predictor of rebleeding (p = 0.03) according to the multivariate analysis. This was 50 % at one year compared with 21.8 % in patients with occult bleeding on admission. CONCLUSIONS: in obscure gastrointestinal bleeding, long-term follow-up and further evaluation may be considered after a positive capsule endoscopy. Even if there are no small bowel findings by device-assisted enteroscopy. The rebleeding rate in our study was 40 %, mainly in the presence of an overt bleeding on admission

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How complexity leadership and cohesion influence team effectiveness / Como a liderança de complexidade e a coesão influenciam a eficácia das equipes / Como el liderazgo de complexidad y la cohesión influyen en la eficacia de los equipos

This research tested the hypothesis that enabling leadership behaviors are positively related to the objective and subjective dimensions of teamwork effectiveness. Hypotheses testing was done during a laboratory task in which 40 teams of 5 people each (N = 200) engaged in a simulation task using the pc game SimCity4. The results suggest that enabling leadership and task cohesion are not related to team performance, R2 = .08, MSE = 1.02, F(4, 35) = .79, p = .54; and that enabling leadership is positively related to team viability, mediated by task cohesion, R2 = .71, MSE = 0.31, F(4, 35) = 21.87, p < .001. These findings also suggest that engaging in enabling leadership behaviors promotes team member commitment to a shared goal, which in turn enhances the shared perception that the team has the necessary conditions to keep working together on future assignments.

Esta investigação testou a hipótese de que os comportamentos de facilitação estão positivamente relacionados com as dimensões objetiva e subjetiva da eficácia das equipas de trabalho. Participaram neste estudo 40 equipas de 5 elementos (N = 200), onde se utilizou o jogo de computador SimCity4. A análise dos efeitos diretos e indiretos sugere que os comportamentos de facilitação e a coesão de tarefa não se relacionam com o desempenho, R2 = .08, M.S.E = 1.02, F(4, 35) = .79, p = .54; e que a coesão de tarefa medeia a relação entre comportamentos de facilitação e a viabilidade, R2 = .71, MSE = 0.31, F(4, 35) = 21.87, p < .001. Estes resultados sugerem que a prática de comportamentos de facilitação promove a união dos membros da equipa, o que por sua vez é importante para a crença partilhada de que a equipa tem condições para continuar unida no futuro.

La presente investigación probó la hipótesis de que los comportamientos de facilitación están positivamente relacionados con las dimensiones objetiva y subjetiva de la eficacia de los equipos de trabajo. En este estudio participaron 40 equipos de 5 elementos (N = 200), donde se utilizó el juego de ordenador SimCity4. El análisis de los efectos directos e indirectos sugiere que el comportamiento de facilitación y la cohesión de tareas no están relacionados con el rendimiento, R2 = .08, MSE = 1.02, F(4, 35) = .79, p = .54; y que la cohesión de tarea media la relación entre comportamientos de facilitación y la viabilidad, R2 = .71, MSE = 0.31, F(4, 35) = 21.87, p < .001. Estos resultados sugieren que la práctica de comportamiento de facilitación promueve la unión de los miembros del equipo, así como la creencia compartida de que el equipo tiene condiciones para continuar unido en el futuro.

Portuguese validation of the consideration of future consequences scale

The Consideration of Future Consequences Scale (CFC-S) is a measure of the extent to which individuals reflect and are influenced by the immediate as well as by the distant outcomes of current behavior. It´s composed by 12 items, grouped into two subscales (future and immediate). This study aims to explore the factor structure, psychometric properties and construct validity of the Portuguese version of the CFC-S in 5 samples, composed by 527 participants with ages between 13 and 71. A 2 factor structure has been found through Confirmatory Factor Analysis among several tested models. Item 5 has been eliminated in order to achieve better fit indices (χ2df = 3.88, CFI = .90, GFI = .95, RMSEA = .07) and improve internal consistency. Both CFC subscales presented strong correlations with several psychological phenomena (Sensation Seeking, Self-Esteem, Temporal Extension and Time Perspective) and main effects among groups of age and criminal record (for CFC-I, p < .001, for CFC-F, p < .001). These results allow us to support CFC as an efficient psychological evaluation instrument and as an important metric for individual differences in the study of temporal orientation (AU)

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