NEWS2, S/F-ratio and ROX-index at emergency department for the prediction of adverse outcomes in COVID-19 patients: An external validation study.

BACKGROUND: In the context of the COVID-19 pandemic, the early and accurate identification of patients at risk of deterioration was crucial in overcrowded and resource-limited emergency departments. This study conducts an external validation for the evaluation of the performance of the National Early Warning Score 2 (NEWS2), the S/F ratio, and the ROX index at ED admission in a large cohort of COVID-19 patients from Colombia, South America, assessing the net clinical benefit with decision curve analysis. METHODS: A prospective cohort study was conducted on 6907 adult patients with confirmed COVID-19 admitted to a tertiary care ED in Colombia. The study evaluated the diagnostic performance of NEWS2, S/F ratio, and ROX index scores at ED admission using the area under the receiver operating characteristic curve (AUROC) for discrimination, calibration, and decision curve analysis for the prediction of intensive care unit admission, invasive mechanical ventilation, and in-hospital mortality. RESULTS: We included 6907 patients who presented to the ED with confirmed SARS-CoV-2 infection from March 2020 to November 2021. Mean age was 51 (35-65) years and 50.4% of patients were males. The rate of intensive care unit admission was 28%, and in-hospital death was 9.8%. All three scores have good discriminatory performance for the three outcomes based on the AUROC. S/F ratio showed miscalibration at low predicted probabilities and decision curve analysis indicated that the NEWS2 score provided a greater net benefit compared to other scores across at a 10% threshold to decide ED admission at a high-level of care facility. CONCLUSIONS: The NEWS2, S/F ratio, and ROX index at ED admission have good discriminatory performances in COVID-19 patients for the prediction of adverse outcomes, but the NEWS2 score has a higher net benefit underscoring its clinical utility in optimizing patient management and resource allocation in emergency settings.

Analysis of Genes Involved in Oxidative Stress and Iron Metabolism in Heart Failure: A Step Forward in Risk Stratification.

INTRODUCTION: Heart failure (HF) is a clinical syndrome characterized by cardinal symptoms that may be accompanied by signs. It results from structural and/or functional abnormalities of the heart leading to elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. The prevalence of iron deficiency and anemia justifies the current guidelines recommendation of screening. Genes HP, ACE, MTHFR, HFE, and CYBA are involved in oxidative mechanisms, iron metabolism, and hematologic homeostasis. This study investigates the contribution of variants Hp1/2 (HP), I/D (ACE), C677T (MTHFR), C282Y and H63D (HFE), and C242T (CYBA) to the development of HF, either independently or in epistasis. METHODS: We used a database of 389 individuals, 143 HF patients, and 246 healthy controls. Genotypes were characterized through PAGE electrophoresis, PCR, PCR-RFLP, and multiplex-ARMS. Data analysis was performed with the SPSS® 26.0 software (IBM Corp., Armonk, NY). RESULTS: We observed a significant association between the MTHFR gene and HF predisposition. The presence of allele T and genotype CT constituted risk, while genotype CC granted protection. Epistatic interactions revealed risk between genotype II of the ACE gene and genotypes CC (C282Y) or HH (H63D) of the HFE gene. Risk was also observed for interactions between genotype CC (CYBA)and genotypes 2-2 (HP), CT (MTHFR), or HH (HFE-H63D). CONCLUSION: We concluded that genes HP, ACE, MTHFR, HFE, and CYBA contribute to the susceptibility for HF, individually or in epistasis. This study contributes to the clarification of the role that genes involved in oxidative mechanisms and iron metabolism play in the physiopathology of HF. It is, therefore, a step forward in risk stratification and personalized medicine.

Combining inflammatory miRNA molecules as diagnostic biomarkers for depression: a clinical study.

Background: Inflammation has been implicated in core features of depression pathophysiology and treatment resistance. Therefore, new challenges in the discovery of inflammatory mediators implicated in depression have emerged. MicroRNAs (miRNAs) have been found aberrantly expressed in several pathologies, increasing their potential as biomarkers and therapeutical targets. In this study, the aim was to assess the changes and biomarker potential of inflammation-related miRNAs in depression patients. Methods: Depression diagnosis was performed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 40 healthy controls and 32 depression patients were included in the study. The levels of inflammatory cytokines were measured in plasma, and expression levels of cytokines and inflammation-related miRNAs were evaluated in peripheral blood mononuclear cells (PBMCs). Results: Depression patients were found to have a pro-inflammatory profile in plasma, with significantly higher levels of TNF-α and CCL2 compared with controls. In PBMCs of depression patients, TNF-α and IL-6 expression levels were significantly up and downregulated, respectively. Moreover, miR-342 levels were found upregulated, while miR-146a and miR-155 were significantly downregulated. miR-342 expression levels were positively correlated with TNF-α. Importantly, when analyzed as a diagnostic panel, receiver operating characteristics (ROC) analysis of miR-342, miR-146a, miR-155 in combination, showed to be highly specific and sensitive in distinguishing between depression patients and healthy controls. Conclusion: In summary, these findings suggest that inflammation-related miRNAs are aberrantly expressed in depression patients. Moreover, we show evidences on the potential of the combination of dysregulated miRNAs as a powerful diagnostic tool for depression.

Long non-coding RNA CASC2 regulates osteoblasts matrix mineralization.

Long non-coding RNAs (lncRNAs) are master regulators of gene expression and have recently emerged as potential innovative therapeutic targets. The deregulation of lncRNA expression patterns has been associated with age-related and noncommunicable diseases in the bone tissue, including osteoporosis and tumors. However, the specific role of lncRNAs in physiological or pathological conditions in the bone tissue still needs to be further clarified, for their exploitation as therapeutic tools. In the present study, we evaluate the potential of the lncRNA CASC2 as a regulator of osteogenic differentiation and mineralization. Results show that CASC2 expression is decreased during osteogenic differentiation of human bone marrow-derived Mesenchymal Stem/Stromal cells (hMSCs). CASC2 knockdown, using small interfering RNA against CASC2 (siCASC2), increases the expression of the late osteogenic marker Bone Sialoprotein (BSP), but does not impact ALP staining level nor the expression of early osteogenic transcripts, including RUNX2 and OPG. Although siCASC2 does not impact hMSC proliferation nor apoptosis, it promotes the mineralization of hMSC cultured under osteogenic-inducing conditions, as shown by the increase of calcium deposits. Mass spectrometry-based proteomic analysis revealed that 89 proteins are regulated by CASC2 at late osteogenic stages, including proteins associated with bone diseases or anthropometric and musculoskeletal traits. Specifically, the Cartilage Oligomeric Matrix Protein (COMP) is highly enhanced by CASC2 knockdown at late stages of osteogenic differentiation, at both transcriptional and protein level. On the other hand, inhibition of COMP impairs osteoblasts mineralization as well as the expression of BSP. The results indicate that lncRNA CASC2 regulates late osteogenic differentiation and mineralization in hMSC via COMP and BSP. In conclusion, this study suggests that targeting lncRNA CASC2 could be a potential approach for modulating bone mineralization.

Macrophage-based therapy for intervertebral disc herniation: preclinical proof-of-concept.

Intervertebral disc (IVD) degeneration and herniation is a leading cause of disability globally and a large unmet clinical need. No efficient non-surgical therapy is available, and there is an urgency for minimally invasive therapies capable of restoring tissue function. IVD spontaneous hernia regression following conservative treatment is a clinically relevant phenomenon that has been linked to an inflammatory response. This study establishes the central role of macrophages in IVD spontaneous hernia regression and provides the first preclinical demonstration of a macrophage-based therapy for IVD herniation. A rat model of IVD herniation was used to test complementary experimental setups: (1) macrophage systemic depletion via intravenous administration of clodronate liposomes (Group CLP2w: depletion between 0 and 2 weeks post-lesion; Group CLP6w: depletion between 2 and 6 weeks post-lesion), and (2) administration of bone marrow-derived macrophages into the herniated IVD, 2 weeks post-lesion (Group Mac6w). Herniated animals without treatment were used as controls. The herniated area was quantified by histology in consecutive proteoglycan/collagen IVD sections at 2 and 6 weeks post-lesion. Clodronate-mediated macrophage systemic depletion was confirmed by flow cytometry and resulted in increased hernia sizes. Bone marrow-derived macrophages were successfully administered into rat IVD hernias resulting in a 44% decrease in hernia size. No relevant systemic immune reaction was identified by flow cytometry, cytokine, or proteomic analysis. Furthermore, a possible mechanism for macrophage-induced hernia regression and tissue repair was unveiled through IL4, IL17a, IL18, LIX, and RANTES increase. This study represents the first preclinical proof-of-concept of macrophage-based immunotherapy for IVD herniation.

Outcomes of endoscopic treatment for early correction of craniosynostosis in children: a 26-year single-center experience.

OBJECTIVE: Surgery is the cornerstone of craniosynostosis treatment. In this study, two widely accepted techniques are described: endoscope-assisted surgery (EAS) and open surgery (OS). The authors compared the perioperative and reconstructive outcomes of EAS and OS in children ≤ 6 months of age treated at the Napoleón Franco Pareja Children's Hospital (Cartagena, Colombia). METHODS: According to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement, patients with defined criteria who underwent surgery to correct craniosynostosis between June 1996 and June 2022 were retrospectively enrolled. Demographic data, perioperative outcomes, and follow-up were obtained from their medical records. Student t-tests were used for significance. Cronbach's α was used to assess agreement between estimated blood loss (EBL). Spearman's correlation coefficient and the coefficient of determination were used to establish associations between the results of interest, and the odds ratio was used to calculate the risk ratio of blood product transfusion. RESULTS: A total of 74 patients met the inclusion criteria; 24 (32.4%) belonged to the OS group and 50 (67.6%) to the EAS group. There was a high interobserver agreement quantifying the EBL. The EBL, transfusion of blood products, surgical time, and hospital stay were shorter in the EAS group. Surgical time was positively correlated with EBL. There were no differences between the two groups in the percentage of cranial index correction at 12 months of follow-up. CONCLUSIONS: Surgical correction of craniosynostosis in children aged ≤ 6 months by EAS was associated with a significant decrease in EBL, transfusion requirements, surgical time, and hospital stay compared with OS. The results of cranial deformity correction in patients with scaphocephaly and acrocephaly were equivalent in both study groups.

The Paramount Importance of Renal Dysfunction in Heart Failure Prognosis - Results from the REFERENCE study / La importancia primordial de la disfunción renal en el pronóstico de la insuficiencia cardíaca - Resultados del estudio REFERENCE

Aims: In heart failure patients renal dysfunction represents impaired tissue perfusion. We investigated the association of customarily used renal function parameters with short-term prognosis in patients admitted with acute decompensated heart failure in class III or IV of New York Heart Association. Material and Methods: Univariate Cox proportional hazard model was used to assess the relationship between variables and outcomes. Survival curves were designed using the Kaplan-Meier method. Results: We followed 65 patients for a median of 13.7 (Q1-Q3 6.7-18.9) months. Variables associated with an increased risk for short-term rehospitalization were baseline urea (HR: 1.098, 95% CI: 1.022-1.179, P-value=0.01), admission urea (HR: 1.048, 95% CI: 1.013-1.084, P-value=0.006), baseline creatinine (HR: 1.111, 95% CI: 1.004-1.229, P-value=0.041), admission creatinine (HR: 1.047, 95% CI: 1.005-1.092, P-value=0.027) and admission glomerular filtration rate <30 mL/min (HR: 3.535, 95% CI: 1.467-8.518, P-value=0.005). Increased risk for short-term mortality was associated with baseline urea (HR: 1.145, 95% CI: 1.032-1.270, P-value=0.010), admission urea (HR: 1.076, 95% CI: 1.021-1.135, P-value=0.006), baseline creatinine (HR: 1.157, 95% CI: 1.009-1.328, P value=0.037), admission creatinine (HR: 1.127, 95% CI: 1.055-1.204, P-value<0.001) and admission glomerular filtration rate <30 mL/min (HR: 9.791, 95% CI: 2.855-33.580, P-value<0.001). Variables associated with an increased risk for end of follow-up mortality were admission urea (HR: 1.056, 95% CI: 1.019-1.094, P-value=0.003), admission creatinine (HR: 1.104, 95% CI: 1.054-1.156, P- value<0.001) and admission glomerular filtration rate <30 mL/min (HR: 3.906, 95% CI: 1.7208.871, P- value=0.001). Conclusion: Renal dysfunction was a reliable predictor of worse prognosis as several parameters correlated with short-term prognosis. (AU)

Introducción: En la insuficiencia cardíaca, la disfunción renal representa hipoperfusión tisular. Investigamos la asociación entre parámetros utilizados cotidianamente y el pronóstico precoz de enfermos ingresados por insuficiencia cardíaca descompensada en clase III o IV de la New York Heart Association. Material y métodos: Aplicamos el modelo de riesgo proporcional de Univariante Cox y curvas de supervivencia de Kaplan-Meier. Resultados: La mediana de seguimiento de los 65 enfermos fue de 13.7 (Q1-Q3 6.7-18.9) meses. Se correlacionaron con el reingreso precoz la urea basal (HR: 1.098, 95% CI: 1.022-1.179, P-value=0.01), la urea al ingreso (HR: 1.048, 95% CI: 1.013-1.084, P-value=0.006), la creatinina basal (HR: 1.111, 95% CI: 1.004-1.229, P-value=0.041), creatinina al ingreso (HR: 1.047, 95% CI: 1.005-1.092, P-value=0.027) y la tasa de filtración glomerular <30 mL/min al ingreso <30 mL/min (HR: 3.535, 95% CI: 1.467-8.518, P-value=0.005). El riesgo de mortalidad precoz se correlacionó con la urea basal (HR: 1.145, 95% CI: 1.032-1.270, P-value=0.010), la urea al ingreso (HR: 1.076, 95% CI: 1.021-1.135, P-value=0.006), la creatinina basal (HR: 1.157, 95% CI: 1.009-1.328, P value=0.037), creatinina al ingreso (HR: 1.127, 95% CI: 1.055-1.204, P-value<0.001) y la tasa de filtración glomerular <30 mL/min al ingreso <30 mL/min (HR: 9.791, 95% CI: 2.855-33.580, P-value<0.001). Se correlacionarón con la mortalidad al final del seguimiento la urea al ingreso (HR: 1.056, 95% CI: 1.019-1.094, P-value=0.003), la creatinina al ingreso (HR: 1.104, 95% CI: 1.054-1.156, P- value<0.001) y la tasa de filtración glomerular <30 mL/min al ingreso (HR: 3.906, 95% CI: 1.7208.871, P- value=0.001). Conclusiones: La disfunción renal fue un predictor de peor pronóstico precoz. (AU)

Alterations of bovine nucleus pulposus cells with aging.

Aging is one of the major etiological factors driving intervertebral disc (IVD) degeneration, the main cause of low back pain. The nucleus pulposus (NP) includes a heterogeneous cell population, which is still poorly characterized. Here, we aimed to uncover main alterations in NP cells with aging. For that, bovine coccygeal discs from young (12 months) and old (10-16 years old) animals were dissected and primary NP cells were isolated. Gene expression and proteomics of fresh NP cells were performed. NP cells were labelled with propidium iodide and analysed by flow cytometry for the expression of CD29, CD44, CD45, CD146, GD2, Tie2, CD34 and Stro-1. Morphological cell features were also dissected by imaging flow cytometry. Elder NP cells (up-regulated bIL-6 and bMMP1 gene expression) presented lower percentages of CD29+, CD44+, CD45+ and Tie2+ cells compared with young NP cells (upregulated bIL-8, bCOL2A1 and bACAN gene expression), while GD2, CD146, Stro-1 and CD34 expression were maintained with age. NP cellulome showed an upregulation of proteins related to endoplasmic reticulum (ER) and melanosome independently of age, whereas proteins upregulated in elder NP cells were also associated with glycosylation and disulfide bonds. Flow cytometry analysis of NP cells disclosed the existence of 4 subpopulations with distinct auto-fluorescence and size with different dynamics along aging. Regarding cell morphology, aging increases NP cell area, diameter and vesicles. These results contribute to a better understanding of NP cells aging and highlighting potential anti-aging targets that can help to mitigate age-related disc disease.

Chitosan 3D scaffolds with resolvin D1 for vertebral arthrodesis: a pilot study.

PURPOSE: Over the last years, the number of vertebral arthrodesis has been steadily increasing. The use of iliac crest bone autograft remains the "gold standard" for bone graft substitute in these procedures. However, this solution has some side effects, such as the problem of donor site morbidity indicating that there is a real need for adequate alternatives. This pilot study aimed to evaluate the usefulness of chitosan (Ch) porous 3D scaffolds incorporated with resolvin D1 (RvD1) as an alternative implant to iliac bone autograft. METHODS: We have performed bilateral posterolateral lumbar vertebral arthrodesis in a rat animal model. Three experimental groups were used: (i) non-operated animals; (ii) animals implanted with Ch scaffolds incorporated with RvD1 and (iii) animals implanted with iliac bone autograft. RESULTS: The collagenous fibrous capsule formed around the Ch scaffolds with RvD1 is less dense when compared with the iliac bone autograft, suggesting an important anti-inflammatory effect of RvD1. Additionally, new bone formation was observed in the Ch scaffolds with RvD1. CONCLUSION: These results demonstrate the potential of these scaffolds for bone tissue repair applications.

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices.

BACKGROUND: The vast and promising class of long non-coding RNAs (lncRNAs) has been under investigation for distinct therapeutic applications. Nevertheless, their role as molecular drivers of bone regeneration remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 on the extracellular matrix (ECM) components is still largely unknown. This research study was designed to decode the H19-mediated ECM regulatory network, and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodeling processes are disrupted, such as osteoporosis. METHODS: Mass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. Moreover, qRT-PCR, immunofluorescence and proliferation, differentiation and apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis. RESULTS: Our study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone marrow-isolated MSC from patients with osteoporosis, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and have a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, whose expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but does not influence ALP staining or mineralization, revealing that H19 silencing and miR-29c mimics have complementary but not overlapping functions. CONCLUSION: Our data suggest H19 as a therapeutic target to engineer the bone ECM and to control cell behavior.

The impact of matrix age on intervertebral disc regeneration.

With the lack of effective treatments for low back pain, the use of extracellular matrix (ECM)-based biomaterials have emerged with undeniable promise for IVD regeneration. Decellularized scaffolds can recreate an ideal microenvironment inducing tissue remodeling and repair. In particular, fetal tissues have a superior regenerative capacity given their ECM composition. In line with this, we unraveled age-associated alterations of the nucleus pulposus (NP) matrisome. Thus, the aim of the present work was to evaluate the impact of ECM donor age on IVD de/regeneration. Accordingly, we optimized an SDS (0.1 %, 1 h)-based decellularization protocol that preserves ECM cues in bovine NPs from different ages. After repopulation with adult NP cells, younger matrices showed the highest repopulation efficiency. Most importantly, cells seeded on younger scaffolds produced healthy ECM proteins suggesting an increased capacity to restore a functional IVD microenvironment. In vivo, only fetal matrices decreased neovessel formation, showing an anti-angiogenic potential. Our findings demonstrate that ECM donor age has a strong influence on angiogenesis and ECM de novo synthesis, opening new avenues for novel therapeutic strategies for the IVD. Additionally, more appropriate 3D models to study age-associated IVD pathology were unveiled.

Immunomodulatory biomaterial-based wound dressings advance the healing of chronic wounds via regulating macrophage behavior.

Successful wound healing is a process that has three overlying phases: inflammatory, proliferative and remodeling. Chronic wounds are characterized by a perpetuated inflammation that inhibits the proliferative and remodeling phases and impairs the wound healing. Macrophages are key modulators of the wound healing process. Initially, they are responsible for the wound cleaning and for the phagocytosis of pathogens and afterwards they lead to the resolution of the inflammatory response and they express growth factors important for angiogenesis and cytokines and growth factors needed for cell proliferation and deposition of extracellular matrix. The phenotype of the macrophage changes gradually throughout the healing process from the initial M1 pro-inflammatory phenotype characteristic of the acute response to the M2 pro-regenerative phenotype that allows an accurate tissue repair. In chronic wounds, M1 pro-inflammatory macrophages persist and impair tissue repair. As such, immunomodulatory biomaterials arise as promising solutions to accelerate the wound healing process. In this review, we discuss the importance of macrophages and their polarization throughout the different phases of wound healing; macrophage dysfunction in chronic wounds and the use of immunomodulatory biomaterials to overcome the critical problem of chronic wounds-the continued inflammatory phase that impairs healing.

Parámetros hematológicos descuidados en el pronóstico dela insuficiencia cardíaca-Evidencia del estudio REFERENCE / Neglected hematological parameters in heart failure prognosis – Disclosures from the REFERENCE study

Aims: In heart failure patients, anemia and iron deficiency are predictors of poor outcome. We studied the association of anemia, iron deficiency and relatedhematological parameters with short-term rehospitalization, short-term all-cause mortality and end of follow-up all-cause mortality in heart failure patients.Material and Methods: Anemia, iron deficiency, red cell distribution width and erythropoietin were assessed in patients hospitalized with acute decompensated heart failure.Univariate Cox proportional hazard model was used to assess the relationship between variables and outcomes.Results: 65 patients were followed for a median of 13.7 (Q1-Q3 6.7-18.9) months. Mean age was 79.2 (SD 10.8) years. The mean left ventricular ejectionfraction was 50.38 ± 19.07 %. Variables associated with an increased risk for short-term rehospitalization were red cell distribution width (HR 1.35; 95% CI 1.16-1.58), anemia (HR 3.81; 95% CI 1.29-11.28) and anemia with iron deficiency (HR 3.50; 95% CI 1.30-9.38). Increased risk for short-term mortality was associatedwith red cell distribution width (HR 1.83; 95% CI 1.29-2.59), erythropoietin (HR 1.38; 95% CI 1.04-1.82), absolute iron deficiency (HR 7.22; 95% CI 1.50-34.81)and anemia with iron deficiency (HR 4.48; 95% CI 1.26-15.88). Variables associated with increased risk for end of follow-up mortality were red cell distributionwidth (HR 1.31; 95% CI 1.12-1.54) and erythropoietin (HR 1.29; 95% CI 1.11-1.49).Conclusions: Conclusions: Anemia and red cell distribution width correlated with higher risk for short-term rehospitalization. Absolute iron deficiency, red celldistribution width and erythropoietin were associated with higher risk for short-term mortality. Red cell distribution width and erythropoietin were associatedwith higher risk for end of follow-up mortality. (AU)

Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood.

Neuroinflammation is increasingly recognized as playing a critical role in depression. Early-life stress exposure and constitutive differences in glucocorticoid responsiveness to stressors are two key risk factors for depression, but their impacts on the inflammatory status of the brain is still uncertain. Moreover, there is a need to identify specific molecules involved in these processes with the potential to be used as alternative therapeutic targets in inflammation-related depression. Here, we studied how peripubertal stress (PPS) combined with differential corticosterone (CORT)-stress responsiveness (CSR) influences depressive-like behaviors and brain inflammatory markers in male rats in adulthood, and how these alterations relate to microglia activation and miR-342 expression. We found that high-CORT stress-responsive (H-CSR) male rats that underwent PPS exhibited increased anhedonia and passive coping responses in adulthood. Also, animals exposed to PPS showed increased hippocampal TNF-α expression, which positively correlated with passive coping responses. In addition, PPS caused long-term effects on hippocampal microglia, particularly in H-CSR rats, with increased hippocampal IBA-1 expression and morphological alterations compatible with a higher degree of activation. H-CSR animals also showed upregulation of hippocampal miR-342, a mediator of TNF-α-driven microglial activation, and its expression was positively correlated with TNF-α expression, microglial activation and passive coping responses. Our findings indicate that individuals with constitutive H-CSR are particularly sensitive to developing protracted depression-like behaviors following PPS exposure. In addition, they show neuro-immunological alterations in adulthood, such as increased hippocampal TNF-α expression, microglial activation and miR-342 expression. Our work highlights miR-342 as a potential therapeutic target in inflammation-related depression.

Insuficiencia Cardíaca: una Enfermedad Maligna Conclusiones del Estudio REFERENCE / Heart Failure a Malignant Disease- Insights from the REFERENCE Study

Aims: Heart failure (HF) short-term prognosis persists poor. We studied the rate of short-term readmission due to HF, short-term all-cause mortality and end of follow-up all-cause mortality. Material and Methods: We assessed patients admitted with acuteHF in class III or IV of NYHA. Univariate Cox proportional hazard model was performed. Survival curves were plotted using the Kaplan-Meier method and compared with the log-rank test for readmission days post-discharge. Results: We followed 65 patients for a median of 13.7 (Q1-Q3 6.7-18.9) months. The 30-day post-discharge readmission rate was 13.8%, the 90-day post-discharge readmission percentage was 33.8% and year readmission rate 61.5%. The 30-day mortality rate was 10.8% and 90- day mortality was 18.5%. Year mortality rate was 36.9% and 40% of the patients were deceased by the end of the follow-up. Length of stay (LOS) correlated with short-term readmission in the general population (HR: 1.022, 95% CI: 1.009-1.036, P value<0.001) and in Heart Failure with Reduced Ejection Fraction patients (HFrEF) (HR: 1.029, 95% CI: 1.008-1.050, Pvalue=0.006). The number of hospitalizations correlated with short-term readmission in the general population (HR: 1.543, 95% CI: 1.224-1.945, P- value<0.001) and in the Heart Failure with Mid-Range Ejection Fraction subgroup (HFmrEF) (HR: 2.814, 95% CI: 1.075-7.365, P- value=0.035). In the Heart Failure with Preserved Ejection Fraction (HFpEF) subgroup both the LOS per specific admission (HR: 1.063, 95% CI: 1.006-1.123, P value=0.030) and the accumulated LOS for all admissions (HR: 1.051, 95% CI: 1.008-1.095, P value=0.019) were associated with end of followup mortality... (AU)

Introducción: La insuficiencia cardíaca (IC) tiene un mal pronóstico a corto plazo. Estudiamos las tasas de reingreso precoz por IC, mortalidad global precoz y mortalidad global al final del seguimiento. Material y métodos: Evaluamos a enfermos ingresados por IC descompensada en clase III o IV de la NYHA. Se utilizó el modelo de riesgo proporcional de Univariante Cox. Se aplicó el método de Kaplan-Meier para obtener curvas de supervivencia para dias de reingreso pós-alta e se comparó al log-rank test. Resultados: La mediana de seguimiento de los 65 enfermos fue de 13.7 (Q1-Q3 6.7-18.9) meses. La tasa de reingreso a los 30 días del alta fue del 13.8%, a los 90 días del alta fue del 33.8% y la tasa anual fue del 61.5%. La mortalidad a los 30 días del alta fue del 10.8% y del 18.5% a los 90 días. La mortalidad anual fue del 36.9% y al final del seguimiento del 40%. La duración del ingreso se correlacionó con el reingreso precoz en la población general (HR: 1.022, 95% CI: 1.009-1.036, P-value<0.001) y en el subgrupo con fracción de eyección reducida (HR: 1.029, 95% CI: 1.008-1050, P-value=0.006). El número de ingresos fue un marcador de mal pronóstico para el reingreso precoz en la población general (HR: 1.543, 95% CI: 1.224-1.945, P-value<0.001) y en el subgrupo con fracción de eyección intermedia (HR: 2.814, 95% CI: 1,075-7,365, P-value=0.035). En el subgrupo con fracción de eyección preservadala duración de ingreso por hospitalización... (AU)

Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions.

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, ß2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

Gal-3 y ST2 como biomarcadores: un paso al frente en el pronóstico de la Insuficiencia Cardíaca / Gal-3 and ST2 Biomarkers - A Step Forward in Heart Failure Prognostication

Aims: The American College of Cardiology (ACA)/ American Heart Association (AHA) granted Galectin-3 (Gal-3) and Suppression of Tumorigenicity 2 (ST2) evaluation a class II recommendation for HF prognosis, as an adjunctive to conventional clinical risk factors and natriuretic peptides dosing in 2013. However, in Europe this endorsement is not valid. The purpose of this study was to study the association of Gal-3 and ST2 collected at-admission with early (defined as the period of 90 days post-discharge) rehospitalization and overall mortality, and end of follow-up overall mortality in HF patients. Additionally, aminoterminal B-type natriuretic peptide (NT-proBNP) at admission was considered to test if a multi-marker strategy could yield supplementary information. Material and Methods: Gal-3, ST2 and NT-proBNP were assessed in patients hospitalized with acute decompensated HF in class III or IV of New York Heart Association (NYHA). Univariate Cox proportional hazard model was used to assess the relationship between variables and outcomes. Since there are no standardized cut-offs for Gal-3 and ST2, the multiclass Area Under the Curve Receiver-Operator Characteristic (AUCROC) as defined by Hand and Till was used to evaluate the overall performance of each biomarker as a predictor of the outcomes. Results: We followed 65 patients for a median of 13.7 (Q1-Q3 6.7-18.9) months. Gal-3 correlated with short-term rehospitalization (HR: 9.886, 95% CI: 2.027-48.214, P-value=0.005), short-term mortality (HR: 13.731, 95% CI: 1.650-114.276, P value=0.015) and end of follow-up mortality (HR: 4.492, 95% CI: 1.594-12.656, P-value=0.004). The association of elevated NT-proBNP determinations increased the risk of short-term rehospitalization (HR: 11.985, 95% CI: 1.962-73.218, P value=0.007) and end of follow-up mortality (HR: 78.025, 95% CI: 7.592-801.926, P-value<0.001). ST2 correlated with end of follow-up mortality (HR: 4.846, 95% CI: 1.396-16.825, P-value=0.013)... (AU)

Immunomodulatory potential of chitosan-based materials for cancer therapy: a systematic review of in vitro, in vivo and clinical studies.

Chitosan (Ch) has recently been used in different studies as a vaccine adjuvant with an ability to modulate the tumor microenvironment (TME). This systematic review aims to elucidate the added value of using Ch-based therapies for immunotherapeutic strategies in cancer treatment, through the exploration of different Ch-based formulations, their capacity to modulate immune cells in vitro and in vivo, and their translational potential for clinical settings. A systematic review was conducted on PubMed, following both inclusion and exclusion steps. Original articles which focused on the immunomodulatory role of Ch-based formulations in the TME were included, as well as its usage as a delivery vehicle for other immunomodulatory molecules. This review illustrates the added value of Ch-based systems to reshape the TME, through the modulation of immune cells using different Ch formulations, namely solutions, films, gels, microneedles and nanoparticles. Generally, Ch-based formulations increase the recruitment and proliferation of cells associated with pro-inflammatory abilities and decrease cells which exert anti-inflammatory activities. These effects correlated with a decreased tumor weight, reduced metastases, reversion of the immunosuppressive TME and increased survival in vivo. Overall, Ch-based formulations present the potential for immunotherapy in cancer. Nevertheless, clinical translation remains challenging, since the majority of the studies use Ch in formulations with other components, implicating that some of the observed effects could result from the combination of the individual effects. More studies on the use of different Ch-based formulations, complementary to standardization and disclosure of the Ch properties used are required to improve the immunomodulatory effects of Ch-based formulations in cancer.

Antiviral therapies: advances and perspectives.

Viral infections cause high morbidity and mortality, threaten public health, and impose a socioeconomic burden. We have seen the recent emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), the causative agent of COVID-19 that has already infected more than 29 million people, with more than 900 000 deaths since its identification in December 2019. Considering the significant impact of viral infections, research and development of new antivirals and control strategies are essential. In this paper, we summarize 96 antivirals approved by the Food and Drug Administration between 1987 and 2019. Of these, 49 (51%) are used in treatments against human immunodeficiency virus (HIV), four against human papillomavirus, six against cytomegalovirus, eight against hepatitis B virus, five against influenza, six against herpes simplex virus, 17 against hepatitis C virus and one against respiratory syncytial virus. This review also describes future perspectives for new antiviral therapies such as nanotechnologies, monoclonal antibodies and the CRISPR-Cas system. These strategies are suggested as inhibitors of viral replication by various means, such as direct binding to the viral particle, blocking the infection, changes in intracellular mechanisms or viral genes, preventing replication and virion formation. We also observed that a large number of viral agents have no therapy available and the majority of those approved in the last 32 years are restricted to some groups, especially anti-HIV. Additionally, the emergence of new viruses and strains resistant to available antivirals has necessitated the formulation of new antivirals.