Ethical regulation of biomedical research in Brazil: a quality improvement initiative.

BACKGROUND: Q-CEP (Qualificação dos Comitês de Ética em Pesquisa que compõem o Sistema CEP/Conep) is a nationwide project resulting from a partnership between the Brazilian National Research Ethics Commission (Conep), the Ministry of Health and Hospital Moinhos de Vento (HMV). It was developed to consolidate policy for ethical review of research with human beings in all members of the CEP/Conep System, Brazil's national system of institutional review boards. The aim of this study was therefore to report on the experience and results of the Q-CEP project. METHODS: An observational, retrospective study includes data from the Q-CEP, obtained from visits to all the institutional research ethics committees (RECs) in the country. The actions implemented by Q-CEP were part of a two-step process: (i) training visits to each REC; (ii) development of distance learning modules on strategic topics pertaining to research ethics evaluation. The data presented herein cover step one (training visits), defined by Q-CEP as the diagnostic stage of the project. For a country with social and economics inequalities such as Brazil, this is a particularly important stage; an accurate picture of reality is needed to inform planning of quality improvement strategies. RESULTS: In 2019-2021, Q-CEP visited 832 RECs and trained 11,197 people. This sample covered almost all active RECs in the country; only 4 (0.5%) were not evaluated. Of the 94 items evaluated, 62% did not reach the target of at least 80% compliance and around 1/4 (26%) were below 50% compliance. The diagnostic stage of the process revealed inadequacies on the part of the RECs in their ethical reviews. The analysis of informed consent forms showed compliance in only 131 RECs (15.74%). The description of pending issues made by RECs in their reports was compliant in 19.33% (n = 161). Administrative and operational aspects were also considered inadequate by more than half of the RECs. CONCLUSIONS: Overall, Brazilian RECs showed poor compliance in several aspects of their operation, both in ethics evaluation and in other processes, which justifies additional training. The Q-CEP project is part of a quality improvement policy promoted by the Brazilian Ministry of Health. The data obtained in the diagnostic step of the project have contributed to the qualification and consolidation of one of the world's largest research ethics evaluation systems.

Tumor-Infiltrating T Cells in Skin Basal Cell Carcinomas and Squamous Cell Carcinomas: Global Th1 Preponderance with Th17 Enrichment-A Cross-Sectional Study.

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs.

Disposable electrochemical sensor: Highly sensitive determination of nitrofurazone antibiotic in environmental samples and pharmaceutical formulations.

The study presents the successful development of a new electrochemical sensor with low cost and disposability for application in nitrofurazone detection in environmental and pharmaceutical samples. The sensors were fabricated using materials obtained from local storage and conductive carbon ink. The modification of the screen-printed electrodes with the hybrid nanomaterial based on silver nanoparticles, carbon quantum dots, and carbon nanotubes showed synergistic contributions in the nitrofurazone electrooxidation, as observed in the wide linear range (0.008 at 15.051 µM), with a sensitivity of 0.650 µA/µM. The limit of detection obtained was 4.6 nM. Differential pulse voltammetry, cyclic voltammetry, X-ray photoelectron spectroscopy, X-ray diffraction analysis, and high-resolution transmission electron microscopy were used to evaluate the electrochemical and structural characteristics. Studies of possible interferences were considered with nitrofurazone in the presence of the ions and organic molecules. The results were satisfactory, with a variation of 93.3% ± 4.39% at 100% ± 2.40%. The low volume used in the analyses (50 µL), disposability, high sensibility, selectivity, and low limit of detection are advantages that make the proposed sensor an electrochemical tool of high viability for the NFZ detection in environmental matrices and pharmaceutical formulations.

The Effect of Coping on the Relationship between Work-Family Conflict and Stress, Anxiety, and Depression.

The challenges experienced in the context of the pandemic have required a significant reconciliation between work and family domains due to confinement and the need to spend more time at home, which may have increased the levels of stress, anxiety, and depression, making it necessary to use resilient coping strategies to overcome the difficulties felt. This study examined the effect of resilient coping on the relationship between work-family conflict and stress, anxiety, and depression in this context. Data were collected using a self-report protocol from a sample of Portuguese workers (N = 476). The results indicated that work-family conflict was positively associated with stress, anxiety, and depression. Resilient coping established a negative relationship with stress, anxiety, and depression. The moderation effect was not corroborated; it was found that in the presence of the moderating variable (resilient coping), the relationship between the variables of work-family conflict and stress, anxiety, and depression was strengthened. This study reinforces the importance of appropriate interventions in resilient coping in the work-family context, which helps control stress, anxiety, and resilience levels.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSEs score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

MASLD and MASH at the crossroads of hepatology trials and cardiorenal metabolic trials.

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

Corkscrew Technique for Extraction of Premolars and Molars in Standing Sedated Horses: Cadaveric Study and Clinical Cases.

Several tooth extraction techniques are described in equine literature, and oral extraction techniques in standing sedated horses are popular among equine practitioners. The objectives of this study were to develop the corkscrew technique for cheek tooth extraction (CSET) in equine cadaver heads and evaluate this technique in clinical cases. We hypothesized that the CSET could be performed safely to extract cheek teeth in standing sedated horses. First, the CSET was attempted and developed in eight equine cadaver heads. Second, the CSET was performed in clinical cases between 2016 and 2020, and the following information was recorded: diagnosis, affected tooth, procedure duration, intraoperative difficulties, tooth size, postoperative complications, medication, hospitalization time, and 1-year follow-up. Sixteen CSET procedures were performed in eight equine skulls with a 75% success rate. In 24 clinical cases, 25 CSET procedures were attempted to extract 22 superior and 3 inferior cheek teeth. CSET was successful in 76% of procedures. Fractures of the tooth and stripping of screw threads were the major complications that led to the failure of CSET. CSET is a viable and safe technique to extract cheek teeth in standing sedated horses. Longitudinal drilling is a must for this technique to be successful.

Deep Learning and High-Resolution Anoscopy: Development of an Interoperable Algorithm for the Detection and Differentiation of Anal Squamous Cell Carcinoma Precursors-A Multicentric Study.

High-resolution anoscopy (HRA) plays a central role in the detection and treatment of precursors of anal squamous cell carcinoma (ASCC). Artificial intelligence (AI) algorithms have shown high levels of efficiency in detecting and differentiating HSIL from low-grade squamous intraepithelial lesions (LSIL) in HRA images. Our aim was to develop a deep learning system for the automatic detection and differentiation of HSIL versus LSIL using HRA images from both conventional and digital proctoscopes. A convolutional neural network (CNN) was developed based on 151 HRA exams performed at two volume centers using conventional and digital HRA systems. A total of 57,822 images were included, 28,874 images containing HSIL and 28,948 LSIL. Partial subanalyses were performed to evaluate the performance of the CNN in the subset of images acetic acid and lugol iodine staining and after treatment of the anal canal. The overall accuracy of the CNN in distinguishing HSIL from LSIL during the testing stage was 94.6%. The algorithm had an overall sensitivity and specificity of 93.6% and 95.7%, respectively (AUC 0.97). For staining with acetic acid, HSIL was differentiated from LSIL with an overall accuracy of 96.4%, while for lugol and after therapeutic manipulation, these values were 96.6% and 99.3%, respectively. The introduction of AI algorithms to HRA may enhance the early diagnosis of ASCC precursors, and this system was shown to perform adequately across conventional and digital HRA interfaces.

Artificial Intelligence and Colposcopy: Automatic Identification of Cervical Squamous Cell Carcinoma Precursors.

Background/Objectives: Proficient colposcopy is crucial for the adequate management of cervical cancer precursor lesions; nonetheless its limitations may impact its cost-effectiveness. The development of artificial intelligence models is experiencing an exponential growth, particularly in image-based specialties. The aim of this study is to develop and validate a Convolutional Neural Network (CNN) for the automatic differentiation of high-grade (HSIL) from low-grade dysplasia (LSIL) in colposcopy. Methods: A unicentric retrospective study was conducted based on 70 colposcopy exams, comprising a total of 22,693 frames. Among these, 8729 were categorized as HSIL based on histopathology. The total dataset was divided into a training (90%, n = 20,423) and a testing set (10%, n = 2270), the latter being used to evaluate the model's performance. The main outcome measures included sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiving operating curve (AUC-ROC). Results: The sensitivity was 99.7% and the specificity was 98.6%. The PPV and NPV were 97.8% and 99.8%, respectively. The overall accuracy was 99.0%. The AUC-ROC was 0.98. The CNN processed 112 frames per second. Conclusions: We developed a CNN capable of differentiating cervical cancer precursors in colposcopy frames. The high levels of accuracy for the differentiation of HSIL from LSIL may improve the diagnostic yield of this exam.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Deep learning and minimally invasive inflammatory activity assessment: a proof-of-concept study for development and score correlation of a panendoscopy convolutional network.

Background: Capsule endoscopy (CE) is a valuable tool for assessing inflammation in patients with Crohn's disease (CD). The current standard for evaluating inflammation are validated scores (and clinical laboratory values) like Lewis score (LS), Capsule Endoscopy Crohn's Disease Activity Index (CECDAI), and ELIAKIM. Recent advances in artificial intelligence (AI) have made it possible to automatically select the most relevant frames in CE. Objectives: In this proof-of-concept study, our objective was to develop an automated scoring system using CE images to objectively grade inflammation. Design: Pan-enteric CE videos (PillCam Crohn's) performed in CD patients between 09/2020 and 01/2023 were retrospectively reviewed and LS, CECDAI, and ELIAKIM scores were calculated. Methods: We developed a convolutional neural network-based automated score consisting of the percentage of positive frames selected by the algorithm (for small bowel and colon separately). We correlated clinical data and the validated scores with the artificial intelligence-generated score (AIS). Results: A total of 61 patients were included. The median LS was 225 (0-6006), CECDAI was 6 (0-33), ELIAKIM was 4 (0-38), and SB_AIS was 0.5659 (0-29.45). We found a strong correlation between SB_AIS and LS, CECDAI, and ELIAKIM scores (Spearman's r = 0.751, r = 0.707, r = 0.655, p = 0.001). We found a strong correlation between LS and ELIAKIM (r = 0.768, p = 0.001) and a very strong correlation between CECDAI and LS (r = 0.854, p = 0.001) and CECDAI and ELIAKIM scores (r = 0.827, p = 0.001). Conclusion: Our study showed that the AI-generated score had a strong correlation with validated scores indicating that it could serve as an objective and efficient method for evaluating inflammation in CD patients. As a preliminary study, our findings provide a promising basis for future refining of a CE score that may accurately correlate with prognostic factors and aid in the management and treatment of CD patients.

Artificial intelligence in Crohn's disease: the development of an automated score for disease activity evaluation This study introduces an innovative AI-based approach to evaluate Crohn's Disease. The AI system automatically analyzes images from capsule endoscopy, focusing on finding ulcers and erosions to measure disease activity. The research reveals a robust correlation between the AI-generated score assessing inflammation in the small bowel and traditional clinical scores. This suggests that the AI solution could be a quicker and more consistent way to evaluate Crohn's Disease, speeding up the evaluation process and reducing manual scoring variability. While promising, the study acknowledges limitations and emphasizes the need for further validation with larger groups of patients. Overall, it represents a crucial step toward integrating AI into gastroenterology, offering a glimpse into a future of more objective and personalized Crohn's Disease evaluation.

Bioprinting salivary gland models and their regenerative applications.

OBJECTIVE: Salivary gland (SG) hypofunction is a common clinical condition arising from radiotherapy to suppress head and neck cancers. The radiation often destroys the SG secretory acini, and glands are left with limited regenerative potential. Due to the complex architecture of SG acini and ducts, three-dimensional (3D) bioprinting platforms have emerged to spatially define these in vitro epithelial units and develop mini-organs or organoids for regeneration. Due to the limited body of evidence, this comprehensive review highlights the advantages and challenges of bioprinting platforms for SG regeneration. METHODS: SG microtissue engineering strategies such as magnetic 3D bioassembly of cells and microfluidic coaxial 3D bioprinting of cell-laden microfibers and microtubes have been proposed to replace the damaged acinar units, avoid the use of xenogeneic matrices (like Matrigel), and restore salivary flow. RESULTS: Replacing the SG damaged organ is challenging due to its complex architecture, which combines a ductal network with acinar epithelial units to facilitate a unidirectional flow of saliva. Our research group was the first to develop 3D bioassembly SG epithelial functional organoids with innervation to respond to both cholinergic and adrenergic stimulation. More recently, microtissue engineering using coaxial 3D bioprinting of hydrogel microfibers and microtubes could also supported the formation of viable epithelial units. Both bioprinting approaches could overcome the need for Matrigel by facilitating the assembly of adult stem cells, such as human dental pulp stem cells, and primary SG cells into micro-sized 3D constructs able to produce their own matrix and self-organize into micro-modular tissue clusters with lumenized areas. Furthermore, extracellular vesicle (EV) therapies from organoid-derived secretome were also designed and validated ex vivo for SG regeneration after radiation damage. CONCLUSION: Magnetic 3D bioassembly and microfluidic coaxial bioprinting platforms have the potential to create SG mini-organs for regenerative applications via organoid transplantation or organoid-derived EV therapies.

Advances in the application of iron oxide nanoparticles (IONs and SPIONs) in three-dimensional cell culture systems.

BACKGROUND: The field of tissue engineering has remarkably progressed through the integration of nanotechnology and the widespread use of magnetic nanoparticles. These nanoparticles have resulted in innovative methods for three-dimensional (3D) cell culture platforms, including the generation of spheroids, organoids, and tissue-mimetic cultures, where they play a pivotal role. Notably, iron oxide nanoparticles and superparamagnetic iron oxide nanoparticles have emerged as indispensable tools for non-contact manipulation of cells within these 3D environments. The variety and modification of the physical and chemical properties of magnetic nanoparticles have profound impacts on cellular mechanisms, metabolic processes, and overall biological function. This review article focuses on the applications of magnetic nanoparticles, elucidating their advantages and potential pitfalls when integrated into 3D cell culture systems. This review aims to shed light on the transformative potential of magnetic nanoparticles in terms of tissue engineering and their capacity to improve the cultivation and manipulation of cells in 3D environments.

Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

AIMS: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. METHODS AND RESULTS: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). CONCLUSIONS: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

Insulin-like growth factor binding protein-7 concentrations in chronic heart failure: Results from the EMPEROR programme.

AIMS: Insulin-like growth factor binding protein-7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio-renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio-renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. METHODS AND RESULTS: IGFBP7 was measured in 1125 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher-risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28-3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61-13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 (p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. CONCLUSION: Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence-associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio-renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time.

The significance of the two cytosolic glutamine synthetase enzymes, GLN1;3 and GLN1;5, in the context of seed development and germination in Arabidopsis thaliana.

Glutamine synthetase (GS), an initial enzyme in nitrogen (N) plant metabolism, exists as a group of isoenzymes found in both cytosolic (GS1) and plastids (GS2) and has gathered significant attention for enhancing N use efficiency and crop yield. This work focuses on the A. thaliana GLN1;3 and GLN1;5 genes, the two predicted most expressed genes in seeds, among the five isogenes encoding GS1 in this species. The expression patterns were studied using transgenic marker line plants and qPCR during seed development and germination. The observed patterns highlight distinct functions for the two genes and confirm GLN1;5 as the most highly expressed GS1 gene in seeds. The GLN1;5, expression, oriented towards hypocotyl and cotyledons, suggests a role in protein turnover during germination, while the radicle-oriented expression of GLN1;3 supports a function in early external N uptake. While the single mutants exhibited a normal phenotype, except for a decrease in seed parameters, the double gln1;3/gln1;5 mutant displayed a germination delay, substantial impairment in growth, nitrogen metabolism, and number and quality of the seeds, as well as a diminishing in flowering. Although seed and pollen-specific, GLN1;5 expression is upregulated in the meristems of the gln1;3 mutants, filling the lack of GLN1;3 and ensuring the normal functioning of the gln1;3 mutants. These findings validate earlier in silico data on the expression patterns of GLN1;3 and GL1;5 genes in seeds, explore their different functions, and underscore their essential role in plant growth, seed production, germination, and early stages of plant development.

Pulmonary Rehabilitation Associated with Noninvasive Ventilation on Physical Capacity and Quality of Life in Post-COVID-19: A Randomized Controlled Double-Blinded Clinical Trial Protocol.

Background: The coronavirus disease-2019 (COVID-19) pulmonary rehabilitation (PR) seems to be a better choice to improve physical and functional capacity after acute infection. However, there is a lack of evidence regarding the effects of different strategies to optimize post-acute phase rehabilitation and reduce long COVID-19 physical deteriorations. Objective: To compare the use of a noninvasive ventilation (NIV) plus aerobic exercise strategy during PR program with to a standard PR (without NIV) on physical capacity and quality of life outcomes in post-COVID-19. Methods: Double-blinded randomized controlled clinical trial. A total of 100 individuals discharged from hospital in a post-acute phase of severe COVID-19 will be randomized into two groups: PR + NIV (Group 1) and PR (Group 2). Inclusion criteria include participants who present symptomatic dyspnea II and III by the modified Medical Research Council, aged 18 years or older. Both groups will receive aerobic and resistance exercise, and inspiratory muscle training. However, group 1 will perform aerobic training with bilevel NIV. Cardiopulmonary exercise test will assess the O2 peak uptake, 6-minute walk test will assess the walking distance and short-form 36 will assess the quality of life before and after 8 weeks (after 24 PR sessions). Moreover, patients will be contacted by telephone every 3 months for one year to record possible adverse events, hospitalizations, and death. All data will be registered in RedCap, and analyses will be performed in the STATA v13 software. Clinical Trial Registration: RBR-3t9pkzt.