First time ACS in patients with on-target lipid levels: Inflammation at admission and re-event rate at follow-up.

BACKGROUND: Dyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first-time presentation of chest pain and on-target LDL-C levels and intermediate FRS/ESC-Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re-event rate up to 6 years follow-up. METHODS: Blind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil-to-Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission. RESULTS: cTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL-6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(-) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL-6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re-event rate at follow-up. CONCLUSIONS: Inflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re-event rate over a follow-up period of up to 6 years.

Evaluation of postoperative results after a presurgical optimisation programme.

BACKGROUND: Presurgical optimisation programmes decrease the risk of postoperative complications, reduce hospital stays and speed up patient recovery. They usually involve a multidisciplinary team addressing physical, nutritional and psychosocial issues. The objective of this study was to assess the results of implementing a presurgical optimisation programme led by a liaison nurse in patients undergoing major surgery in a primary general hospital. METHODS: An observational, retrospective, descriptive, cross-sectional, comparative study based on the revision of patients' health records undergoing major surgery between January 2019 and December 2022. Patients entering the presurgical optimisation programme (intervention group) were compared with patients receiving usual medical care (control group). The presurgical optimisation programme consisted of oral nutritional supplementation, physical exercise, strengthening of lung capacity and psychological and emotional support. Frequency (%) of surgery complications and use of healthcare resources (duration of hospitalisation, time spent in the intensive care unit (ICU), and readmission) at day 30 were recorded. Descriptive statistics were applied. RESULTS: Two hundred eleven patients (58.5% men, mean age: 65.76 years (SD 11.5), 75.2%. non-smokers; mean body mass index (BMI): 28.32 (SD 5.38); mean Nutritional Risk Score (NRS) 3.71 (SD 1.35; oncology diagnosis: 88.6%) were included: 135 in the intervention group, and 76 in the control group. The average duration of the presurgical optimisation programme was 20 days (SD 5). Frequency of postoperative complications was 25% (n = 33) in the intervention group and 52.6% (n = 40) in the control group (p < 0.001) [odds ratio (OR) = 3.4; 95% confidence interval (CI) (1.8; 6.2)]. 14.5% (n = 19) of patients in the intervention group and 34.2% (n = 26) in the control group had remote postoperative complications [OR = 3.1; 95% CI (1.6; 6.2)]. Patients in the intervention group spent fewer days in the hospital [mean 8.34 (SD 6.70) vs 11.63 (SD 10.63)], and there were fewer readmissions at 30 days (7.6% vs 19.7%) compared with the control group. CONCLUSIONS: A presurgical optimisation programme led by a liaison nurse decreases the rate of immediate and late surgical complications and reduces hospital stays and readmissions in patients undergoing major surgery.

Cerebellar output neurons impair non-motor behaviors by altering development of extracerebellar connectivity.

The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the minimum requirement for these neurons is for motor coordination and not learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

Interneuron Diversity: How Form Becomes Function.

A persistent question in neuroscience is how early neuronal subtype identity is established during the development of neuronal circuits. Despite significant progress in the transcriptomic characterization of cortical interneurons, the mechanisms that control the acquisition of such identities as well as how they relate to function are not clearly understood. Accumulating evidence indicates that interneuron identity is achieved through the interplay of intrinsic genetic and activity-dependent programs. In this work, we focus on how progressive interactions between interneurons and pyramidal cells endow maturing interneurons with transient identities fundamental for their function during circuit assembly and how the elimination of transient connectivity triggers the consolidation of adult subtypes.

The chemokine Cxcl14 regulates interneuron differentiation in layer I of the somatosensory cortex.

Spontaneous and sensory-evoked activity sculpts developing circuits. Yet, how these activity patterns intersect with cellular programs regulating the differentiation of neuronal subtypes is not well understood. Through electrophysiological and in vivo longitudinal analyses, we show that C-X-C motif chemokine ligand 14 (Cxcl14), a gene previously characterized for its association with tumor invasion, is expressed by single-bouquet cells (SBCs) in layer I (LI) of the somatosensory cortex during development. Sensory deprivation at neonatal stages markedly decreases Cxcl14 expression. Additionally, we report that loss of function of this gene leads to increased intrinsic excitability of SBCs-but not LI neurogliaform cells-and augments neuronal complexity. Furthermore, Cxcl14 loss impairs sensory map formation and compromises the in vivo recruitment of superficial interneurons by sensory inputs. These results indicate that Cxcl14 is required for LI differentiation and demonstrate the emergent role of chemokines as key players in cortical network development.

Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy.

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10-15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. Notably, drugs that block abnormal functions of these pathways remarkably improve survival in uLMS patients. However, due to chemotherapy resistance, there remains a need for novel drugs that can target these pathways effectively. In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. In addition, we discuss serum markers, artificial intelligence (AI) combined with machine learning, shear wave elastography, current management and medical treatment options, and ongoing clinical trials for patients with uLMS. Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques.

Metabolic dysfunction-associated steatotic liver disease (MASLD) currently represents the predominant cause of chronic liver disease and is closely linked to a significant increase in the risk of hepatocellular carcinoma (HCC), even in the absence of liver cirrhosis. In this retrospective multicenter study, machine learning (ML) methods were employed to investigate the relationship between metabolic profile and prognosis at diagnosis in a total of 219 HCC patients. The eXtreme Gradient Boosting (XGB) method demonstrated superiority in identifying mortality predictors in our patients. Etiology was the most determining prognostic factor followed by Barcelona Clinic Liver Cancer (BCLC) and Eastern Cooperative Oncology Group (ECOG) classifications. Variables related to the development of hepatic steatosis and metabolic syndrome, such as elevated levels of alkaline phosphatase (ALP), uric acid, obesity, alcohol consumption, and high blood pressure (HBP), had a significant impact on mortality prediction. This study underscores the importance of metabolic syndrome as a determining factor in the progression of HCC secondary to MASLD. The use of ML techniques provides an effective tool to improve risk stratification and individualized therapeutic management in these patients.

Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up.

BACKGROUND: Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). AIMS: to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. METHODS: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7-14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. RESULTS: From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. CONCLUSIONS: The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

Precision medicine: "Point of Care Ultrasound" (PoCUS) in the diagnostic approach to the patient with hyponatremia.

Hyponatremia is a multifactorial disorder defined as a decrease in plasma sodium concentration. Its differential diagnosis requires an adequate evaluation of the extracellular volume (ECV). However, ECV determination, simply based on the clinical history, vital signs, physical examination, and laboratory findings can leads to misdiagnosis and inappropriate treatment. The use of Point-of-Care Ultrasound (POCUS), through the combination of Lung Ultrasound (LUS), Venous Excess UltraSound (VExUS) and Focused Cardiac Ultrasound (FoCUS), allows a much more accurate holistic assessment of the patient's ECV status in combination with the other parameters.

Financial toxicity in allogeneic haematopoietic stem cell transplant patients from a social determinants of health perspective.

PURPOSE: Financial toxicity (FT) refers to the subjective perception of financial distress resulting from objective economic strain due to illness, exerting a detrimental influence on health outcomes. This study aimed to describe FT among allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients within a public health framework, employing a social determinants of health approach. METHODS: A multi-centre cross-sectional study involving adult allo-HSCT patients was conducted across three public hospitals in Madrid. FT was assessed using a validated COST scale (range 0-44; lower scores indicating higher FT). Patient-administered paper/online questionnaires were utilized to collect data on sociodemographic, socioeconomic, clinical, and healthcare access variables. Descriptive, non-parametric univariate statistical analysis and multiple linear regression models were performed. RESULTS: Sixty-six patients, with a mean age: 52.5 years (SD: 11.5), 50% women, 28.7% displaced to Madrid for HSCT, and 71.4% lacking financial support were included. The median FT score was 20 points (IQR 12-27.25). Independent factors associated with higher FT included being females (Coef = -3.26; p = 0.079), perceived income loss after HSCT (Coef = -6.81; p < 0.001) and a monthly household income of ≤1000 € compared to 1001-2500€ (Coef = 8.29; p = 0.005) or >2500 € (Coef = 15.75; p < 0.001). CONCLUSIONS: Despite the limited sample size, our findings underscore the presence of financial toxicity among allo-HSCT patients, shaped by social determinants of health. Recognizing and addressing FT within the HSCT process is essential to mitigate social inequalities in health.

Application of Machine Learning Techniques to Assess Alpha-Fetoprotein at Diagnosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is associated with high mortality rates. Approximately 80% of cases occur in cirrhotic livers, posing a significant challenge for appropriate therapeutic management. Adequate screening programs in high-risk groups are essential for early-stage detection. The extent of extrahepatic tumor spread and hepatic functional reserve are recognized as two of the most influential prognostic factors. In this retrospective multicenter study, we utilized machine learning (ML) methods to analyze predictors of mortality at the time of diagnosis in a total of 208 patients. The eXtreme gradient boosting (XGB) method achieved the highest values in identifying key prognostic factors for HCC at diagnosis. The etiology of HCC was found to be the variable most strongly associated with a poorer prognosis. The widely used Barcelona Clinic Liver Cancer (BCLC) classification in our setting demonstrated superiority over the TNM classification. Although alpha-fetoprotein (AFP) remains the most commonly used biological marker, elevated levels did not correlate with reduced survival. Our findings suggest the need to explore new prognostic biomarkers for individualized management of these patients.

Prognostic Factors for Mortality in Hepatocellular Carcinoma at Diagnosis: Development of a Predictive Model Using Artificial Intelligence.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for 75% of primary liver tumors. Controlling risk factors associated with its development and implementing screenings in risk populations does not seem sufficient to improve the prognosis of these patients at diagnosis. The development of a predictive prognostic model for mortality at the diagnosis of HCC is proposed. METHODS: In this retrospective multicenter study, the analysis of data from 191 HCC patients was conducted using machine learning (ML) techniques to analyze the prognostic factors of mortality that are significant at the time of diagnosis. Clinical and analytical data of interest in patients with HCC were gathered. RESULTS: Meeting Milan criteria, Barcelona Clinic Liver Cancer (BCLC) classification and albumin levels were the variables with the greatest impact on the prognosis of HCC patients. The ML algorithm that achieved the best results was random forest (RF). CONCLUSIONS: The development of a predictive prognostic model at the diagnosis is a valuable tool for patients with HCC and for application in clinical practice. RF is useful and reliable in the analysis of prognostic factors in the diagnosis of HCC. The search for new prognostic factors is still necessary in patients with HCC.

[Tixagevimab-cilgavimab as pre-exposure prophylactic treatment against SARS-CoV-2 in kidney transplantation patients]. / Tixagevimab-cilgavimab como tratamiento profiláctico preexposición frente a SARS-CoV-2 en pacientes trasplantados renales.

INTRODUCTION: It has been reported that after vaccination with RNAm or viral vectors from SARS-CoV-2 a significant number of solid organ transplant recipients do not develop an effective immune response. In this scenario, the use of tixagevimab-cilgavimab was approved by the European Medicines Agency for COVID-19 prophylaxis in immunocompromised patients in March 2022. We present our experience with a group of kidney transplant recipients who received prophylactic treatment with tixagevimab-cilgavimab. MATERIAL AND METHODS: Prospective study from a cohort of kidney transplant recipients who had been previously vaccinated with 4 doses and did not achieve a satisfactory immune response to vaccination, presenting antibody titers lower than 260 BAU/mL when measured by ELISA. A total of 55 patients who received a single dose of 150mg of tixagevimab and 150mg of cilgavimab between May and September of 2022 were included in this study. RESULTS: No immediate or severe adverse reactions, including worsening of kidney function, were observed after administering the drug or during follow up. All patients who had received the drug 3 months prior presented positive antibody titers (>260 BAU/mL). Seven patients were diagnosed with COVID, and one of those patients had to be admitted to the hospital and died 5 days later from infectious complications and a suspected diagnosis of bacterial coinfection. CONCLUSIONS: In our experience, all kidney transplant recipients reached antibody titers higher than 260 BAU/mL 3 months after receiving prophylactic treatment with tixagevimab-cilgavimab with no severe or irreversible adverse reactions.

T4 Bacteriophage and E. coli Interaction in the Murine Intestine: A Prototypical Model for Studying Host-Bacteriophage Dynamics In Vivo.

Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.

Survivin-Sodium Iodide Symporter Reporter as a Non-Invasive Diagnostic Marker to Differentiate Uterine Leiomyosarcoma from Leiomyoma.

Leiomyosarcoma (LMS) has been challenging to diagnose because of limitations in clinical and radiographic predictors, as well as the lack of reliable serum or urinary biomarkers. Most uterine masses consist of benign leiomyoma (LM). However, it is currently a significant challenge in gynecology practice to differentiate LMS from LM. This inability poses grave consequences for patients, leading to a high number of unnecessary hysterectomies, infertility, and other major morbidities and possible mortalities. This study aimed to evaluate the use of Survivin-Sodium iodide symporter (Ad-Sur-NIS) as a reporter gene biomarker to differentiate malignant LMS from benign LM by using an F18-NaBF4 PET/CT scan. The PET/CT scan images showed a significantly increased radiotracer uptake and a decreased radiotracer decay attributable to the higher abundance of Ad-Sur-NIS in the LMS tumors compared to LM (p < 0.05). An excellent safety profile was observed, with no pathological or metabolic differences detected in Ad-Sur-NIS-treated animal versus the vehicle control. Ad-Sur-NIS as a PET scan reporter is a promising imaging biomarker that can differentiate uterine LMS from LM using F18-NaBF4 as a radiotracer. As a new diagnostic method, the F18 NaBF4 PET/CT scan can provide a much-needed tool in clinical practices to effectively triage women with suspicious uterine masses and avoid unnecessary invasive interventions.

Polycythemia Vera: Barriers to and Strategies for Optimal Management.

Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth knowledge of this condition, it necessitates a multifaceted management approach to mitigate symptoms and prevent thrombotic and hemorrhagic events, ensuring prolonged survival. The therapeutic landscape has been revolutionized in recent years, where venesection and hydroxycarbamide associated with antiplatelet therapy have a central role and are now accompanied by other drugs, such as interferon and Janus kinase inhibitors. Ongoing research and advancements in targeted therapies hold promise for further enhancing the therapeutic choice for PV management.

Vascular and Platelet Effects of Tomato Soffritto Intake in Overweight and Obese Subjects.

Tomatoes are known for their numerous health benefits, including antioxidants, anti-cancer, antimicrobial, anti-inflammatory, anti-neurodegenerative, antiplatelet, and cardio-protective properties. However, their potential health benefits in the Mediterranean diet's popular soffritto remain largely unexplored in scientific research. The objective was to evaluate the effects of soffritto intake on platelet activity, vascular endothelial function, weight, lipid profile, and blood parameters. In a prospective, controlled, randomized two-arm longitudinal cross-over trial, 40 overweight and obese individuals received 100 g/day of soffritto, or a control, for 42 days. The primary outcome was the effect on vascular endothelial function and platelet activity. As exploratory secondary outcomes, anthropometric measures, serum lipid profile, and hemogram profile were measured before and after a 6-week intervention with or without soffritto supplementation. Compared with the control group, soffritto supplementation for six weeks improved collagen-induced (-5.10 ± 3.06%) platelet aggregation (p < 0.05). In addition, after six weeks, a reduction in ADP-induced aggregation (-3.67 ± 1.68%) was also only observed in the soffritto group (p < 0.05). No significant effects of the soffritto intake were observed on vascular endothelial function, anthropometric measures, serum lipid profile, or blood parameters (p > 0.05). In conclusion, as a basic culinary technique, soffritto may have a role in the primary prevention of cardiovascular disease by reducing platelet activation, which could contribute to a reduction in thrombotic events.

Terapia de REGEN COV como base de terapia inmunomoduladora mixta en pacientes hospitalizados por neumonía por SARS-CoV-2: Serie de casos / REGEN COV Therapy as the Basis of Mixed Immunomodulatory Therapy in Patients Hospitalized for SARS- CoV-2 Pneumonia: Case Series

Los países en desarrollo con sistema de salud de baja inversión encuentran un reto en priorizar el tratamiento de COVID-19 según su eficacia y sus costos. Materiales y métodos: se explora la utilidad hospitalaria de una intervención segura con eficacia ambulatoria comprobada. Se describe la administración de un tratamiento inmunomodulador combinado a base de imdevimab y casirivimab (REGEN COV). Resultados: los resultados individualizados apuntan a resultados prometedores en pacientes de alto riesgo a progresión y mortalidad. Conclusión: se ha demostrado que REGEN COV es eficiente para tratar dicha enfermedad. Sin embargo, se necesitan ensayos clínicos aleatorizados para comprobar su eficacia en combinación. (AU)

Developing countries with low-investment health systems find it challenging to prioritize COVID-19 treatment according to its efficacy and affordability. Materials and methods: therefore, the in-hospital utility of a safe intervention with outpatient efficacy is explored. We describe the administration of immunomodulatory combination therapy based on imdevimab and casirivimab (REGEN COV). Results: individualized results point to promising outcomes in patients at high risk of progression and mortality. Conclusion: REGEN COV has been shown to be efficient in treating said disease. However, randomized clinical trials are needed to verify their efficacy in combination. (AU)