David Hervás

RATIONALE: Long-term mortality after hospital discharge in community-acquired pneumonia (CAP) is a neglected issue. A validated, accurate score predicting mortality is needed. OBJECTIVE: To derive and validate the Long-term Pneumonia Mortality Index (L-PMI). METHODS: L-PMI derivation used data from a Spanish multicenter prospective study on CAP with a 1-year follow-up. A logistic regression model for predicting 1-year mortality risk was developed. Performance of the model was assessed by estimating the area under the receiver operating characteristic curve (AUC). The model was externally validated using 2 independent multicenter CAP cohorts from Germany and the United States (USA), and one COVID-19 pneumonia cohort from Spain. We then derived a score from the model to ease its application. MEASUREMENTS AND MAIN RESULTS: The long-term mortality rate after discharge was 6.3%, 4.4%, 17.4%, and 3.6% in the derivation, CAPNETZ (only 6 months of follow-up), USA, and COVID-19 cohorts, respectively. The L-PMI included age, smoking history, nursing home residency, Charlson Comorbidity Index score, CURB-65 score, use of noninvasive or invasive mechanical ventilation, and in-hospital cardiovascular events. The L-PMI showed high discrimination for mortality in the derivation cohort (AUC, 0.82 [95% CI, 0.78-0.85]). In the validation cohorts, the AUC (95% CI) ranged from 0.78 (0.73-0.83) to 0.75 (0.73-0.77) for the CAPNETZ and USA cohorts, respectively, and 0.88 (0.84-0.93) for the COVID-19 cohort. L-PMI allows classification of patients according to their mortality risk into low-, intermediate-, and high-risk groups. CONCLUSIONS: The L-PMI is a novel clinical prediction score that identifies pneumonia patients at risk of mortality up to 1 year after discharge.

ABSTRACT Introduction/Aims To evaluate the usefulness of the Goal Attainment Scale (GAS) light for assessing response to risdiplam in patients with SMA aged ≥15 years. Methods In this population-based, longitudinal, ambispective study, patients were evaluated before and at 12 and 24 months after risdiplam initiation using motor scales (SMA Functional Composite Score Revised [SMA-FCR]), pinch strength (MyoPinch), functional scales (EK2, ALSFRS-R), patient and clinician global impression of change (PGIC and CGIC), and GAS light. Longitudinal changes were assessed using linear mixed-effects models. The minimal detectable change (MDC) and minimal clinically important change (MCIC) of GAS light were calculated. Results Forty-four patients (median age 32 years; 56.8% female) were included: 31.8% non-sitters, 56.8% sitters, and 11.4% walkers. GAS light priorities differed across functional subgroups, with patients prioritising moderately affected domains. After 24 months of risdiplam treatment, motor outcomes showed non-significant improvements in walkers, whereas functional scales improved significantly only in non-sitters. In contrast, GAS light detected significant, increasing improvements across all functional subgroups. The MCIC and MDC for GAS light were 6.5 and 10.65 points, respectively. According to the CGIC, 58% of patients improved slightly, 29% remained stable, and 13% worsened slightly at 24 months. Using the MCIC threshold, 64.5% achieved clinically meaningful goal improvement. Discussion GAS light is a feasible, sensitive, patient-centred tool that may complement standardised outcome measures when evaluating treatment response in adults with SMA. These findings further support risdiplam as a valuable therapeutic option in this population.

Oral squamous cell carcinoma (OSCC) remains a major global health burden, highlighting the need for improved non-invasive tools for early detection and disease monitoring. Because saliva is easily accessible and reflects the oral microenvironment, the salivary microbiome has emerged as a promising source of candidate biomarkers. In this study, we characterized the salivary microbiota of 113 individuals, including 52 patients with OSCC and 61 healthy controls, using 16S rRNA gene sequencing targeting the V3-V4 region. Microbial diversity and composition were analyzed using complementary bioinformatic and statistical approaches, including four differential abundance methods (MaAsLin2, ANCOM-BC2, LinDA, and ALDEx2). OSCC was associated with significant differences in overall microbial community structure, as shown by beta diversity analyses, together with reduced community evenness but no major loss of richness. Differential abundance analyses identified several taxa overrepresented in OSCC, including the genera Tannerella, Solobacterium, Dialister, and Bergeyella, as well as species such as Solobacterium moorei, Tannerella forsythia, and Prevotella nigrescens. In contrast, Leptotrichia was underrepresented in OSCC. These findings support the existence of an OSCC-associated salivary dysbiosis characterized by ecological restructuring rather than global diversity loss. The identified taxa represent exploratory candidate microbial signatures associated with OSCC that require validation in larger, independent, and longitudinal cohorts before any potential clinical application can be considered.

Abstract Fraud in the insurance sector represents a significant challenge for companies and society, leading to substantial economic losses for insurers and impacting pricing policies, ultimately affecting the users of these insurance services. This study highlights the urgent need to develop effective methods for fraud detection, especially in contexts where data is imbalanced and fraudulent cases are much less frequent than non-fraudulent ones. The primary objective of this study is to design and validate a fraud detection model for the insurance sector, with a specific focus on automobile insurance claims. The methodology used to implement the Random Forest Quantile Classifier is detailed, emphasizing its ability to optimize classification thresholds, achieving the best possible specificity and sensitivity. This model also allows for adjusting these thresholds to meet the specific needs of the insurance company. A case study was conducted using actual data provided by an insurance company to evaluate the performance of the proposed model. The performance of the Random Forest Quantile Classifier was compared with other machine learning methods. The results indicated that the proposed model outperformed the others in fraud detection, achieving an optimal balance between true positive and true negative rates. Additionally, the model includes the ability to interpret the effects of variables on predictions, preventing it from functioning as a black box. This research contributes to advancing and improving fraud detection techniques, providing valuable tools for professionals and researchers dedicated to financial data analysis.

Extract Community-acquired pneumonia (CAP) is an acute infectious disease that may be accompanied by organ dysfunction. During the acute episode, the respiratory, renal, cardiovascular/haemodynamic, and neurological systems are most frequently affected. The extent of organ dysfunction correlates closely with prognosis in CAP [1]. Early and accurate assessment of the degree of organ involvement is therefore essential to predict outcomes and identify patients at risk of complications. The Sequential Organ Failure Assessment (SOFA) score, developed in 1996, was originally intended to support the management of critically ill patients in the intensive care unit (ICU) [2]. Since then, it has been widely adopted. In 2016, the Sepsis-3 consensus defined sepsis as life-threatening organ dysfunction resulting from a dysregulated host response to infection [3], and incorporated the SOFA score into its operational criteria. These criteria have subsequently been validated in patients with CAP [4, 5]. More recently, the SOFA score has been updated to SOFA-2, which incorporates contemporary organ-support modalities and revised scoring thresholds [6]. However, as acknowledged by its developers, SOFA-2 was derived and validated exclusively in ICU cohorts, and its applicability to patients managed outside the ICU remains uncertain. The aim of the present study, therefore, is to evaluate the performance of the SOFA-2 score in patients admitted to hospital with CAP.

Raúl Méndez, Paula González-Jiménez, David Hervás, Rosario Menéndez, on behalf of all authors of ‘The Long-term Pneumonia Mortality Index. An International

Children born after threatened preterm labor (TPL) are at increased risk for executive function (EF) difficulties, even when born at term. However, EF development in this population remains understudied, particularly regarding the role of gestational age and early psychosocial adversity. Prenatal stress (e.g., maternal anxiety at TPL diagnosis and trauma history) and postnatal environmental factors may contribute to variability in EF outcomes. In this prospective cohort study with a 6-year follow-up, EF was assessed at ages 2 and 6 using the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). The sample included 180 mother-child dyads: 120 children born after TPL (full-term n = 27, late-preterm n = 56, very-preterm n = 37) and 60 full-term controls. Bayesian mixed-effects models were used to examine associations between EF outcomes and gestational age group, time, and relevant prenatal and postnatal factors, including child sex, parental education, maternal trauma history, and maternal anxiety. The models showed a group × time interaction for global EF scores. At age 2, all TPL groups showed higher EF difficulty scores compared with controls, with the largest differences observed in the very-preterm group. Between ages 2 and 6, EF scores decreased in TPL groups relative to controls, indicating a greater reduction in EF difficulties over time, although patterns varied across EF domains. Higher maternal anxiety (prenatal and postnatal), greater maternal trauma exposure, and lower parental education were associated with higher EF difficulty scores, whereas female sex was associated with lower scores. Children born after TPL show early EF vulnerabilities across gestational ages, including those born at term. EF outcomes change across early childhood and are associated with both biological and environmental factors. These findings support the importance of early monitoring of children exposed to prenatal complications and highlight the role of perinatal maternal mental health and family context in early executive function development.

ABSTRACT Introduction/Aims To evaluate the usefulness of the Goal Attainment Scale (GAS) light for assessing response to risdiplam in patients with SMA aged ≥15 years. Methods In this population-based, longitudinal, ambispective study, patients were evaluated before and at 12 and 24 months after risdiplam initiation using motor scales (SMA Functional Composite Score Revised [SMA-FCR]), pinch strength (MyoPinch), functional scales (EK2, ALSFRS-R), patient and clinician global impression of change (PGIC and CGIC), and GAS light. Longitudinal changes were assessed using linear mixed-effects models. The minimal detectable change (MDC) and minimal clinically important change (MCIC) of GAS light were calculated. Results Forty-four patients (median age 32 years; 56.8% female) were included: 31.8% non-sitters, 56.8% sitters, and 11.4% walkers. GAS light priorities differed across functional subgroups, with patients prioritising moderately affected domains. After 24 months of risdiplam treatment, motor outcomes showed non-significant improvements in walkers, whereas functional scales improved significantly only in non-sitters. In contrast, GAS light detected significant, increasing improvements across all functional subgroups. The MCIC and MDC for GAS light were 6.5 and 10.65 points, respectively. According to the CGIC, 58% of patients improved slightly, 29% remained stable, and 13% worsened slightly at 24 months. Using the MCIC threshold, 64.5% achieved clinically meaningful goal improvement. Discussion GAS light is a feasible, sensitive, patient-centred tool that may complement standardised outcome measures when evaluating treatment response in adults with SMA. These findings further support risdiplam as a valuable therapeutic option in this population.

Abstract Fraud in the insurance sector represents a significant challenge for companies and society, leading to substantial economic losses for insurers and impacting pricing policies, ultimately affecting the users of these insurance services. This study highlights the urgent need to develop effective methods for fraud detection, especially in contexts where data is imbalanced and fraudulent cases are much less frequent than non-fraudulent ones. The primary objective of this study is to design and validate a fraud detection model for the insurance sector, with a specific focus on automobile insurance claims. The methodology used to implement the Random Forest Quantile Classifier is detailed, emphasizing its ability to optimize classification thresholds, achieving the best possible specificity and sensitivity. This model also allows for adjusting these thresholds to meet the specific needs of the insurance company. A case study was conducted using actual data provided by an insurance company to evaluate the performance of the proposed model. The performance of the Random Forest Quantile Classifier was compared with other machine learning methods. The results indicated that the proposed model outperformed the others in fraud detection, achieving an optimal balance between true positive and true negative rates. Additionally, the model includes the ability to interpret the effects of variables on predictions, preventing it from functioning as a black box. This research contributes to advancing and improving fraud detection techniques, providing valuable tools for professionals and researchers dedicated to financial data analysis.

Oral squamous cell carcinoma (OSCC) remains a major global health burden, highlighting the need for improved non-invasive tools for early detection and disease monitoring. Because saliva is easily accessible and reflects the oral microenvironment, the salivary microbiome has emerged as a promising source of candidate biomarkers. In this study, we characterized the salivary microbiota of 113 individuals, including 52 patients with OSCC and 61 healthy controls, using 16S rRNA gene sequencing targeting the V3-V4 region. Microbial diversity and composition were analyzed using complementary bioinformatic and statistical approaches, including four differential abundance methods (MaAsLin2, ANCOM-BC2, LinDA, and ALDEx2). OSCC was associated with significant differences in overall microbial community structure, as shown by beta diversity analyses, together with reduced community evenness but no major loss of richness. Differential abundance analyses identified several taxa overrepresented in OSCC, including the genera Tannerella, Solobacterium, Dialister, and Bergeyella, as well as species such as Solobacterium moorei, Tannerella forsythia, and Prevotella nigrescens. In contrast, Leptotrichia was underrepresented in OSCC. These findings support the existence of an OSCC-associated salivary dysbiosis characterized by ecological restructuring rather than global diversity loss. The identified taxa represent exploratory candidate microbial signatures associated with OSCC that require validation in larger, independent, and longitudinal cohorts before any potential clinical application can be considered.

Extract Community-acquired pneumonia (CAP) is an acute infectious disease that may be accompanied by organ dysfunction. During the acute episode, the respiratory, renal, cardiovascular/haemodynamic, and neurological systems are most frequently affected. The extent of organ dysfunction correlates closely with prognosis in CAP [1]. Early and accurate assessment of the degree of organ involvement is therefore essential to predict outcomes and identify patients at risk of complications. The Sequential Organ Failure Assessment (SOFA) score, developed in 1996, was originally intended to support the management of critically ill patients in the intensive care unit (ICU) [2]. Since then, it has been widely adopted. In 2016, the Sepsis-3 consensus defined sepsis as life-threatening organ dysfunction resulting from a dysregulated host response to infection [3], and incorporated the SOFA score into its operational criteria. These criteria have subsequently been validated in patients with CAP [4, 5]. More recently, the SOFA score has been updated to SOFA-2, which incorporates contemporary organ-support modalities and revised scoring thresholds [6]. However, as acknowledged by its developers, SOFA-2 was derived and validated exclusively in ICU cohorts, and its applicability to patients managed outside the ICU remains uncertain. The aim of the present study, therefore, is to evaluate the performance of the SOFA-2 score in patients admitted to hospital with CAP.

RATIONALE: Long-term mortality after hospital discharge in community-acquired pneumonia (CAP) is a neglected issue. A validated, accurate score predicting mortality is needed. OBJECTIVE: To derive and validate the Long-term Pneumonia Mortality Index (L-PMI). METHODS: L-PMI derivation used data from a Spanish multicenter prospective study on CAP with a 1-year follow-up. A logistic regression model for predicting 1-year mortality risk was developed. Performance of the model was assessed by estimating the area under the receiver operating characteristic curve (AUC). The model was externally validated using 2 independent multicenter CAP cohorts from Germany and the United States (USA), and one COVID-19 pneumonia cohort from Spain. We then derived a score from the model to ease its application. MEASUREMENTS AND MAIN RESULTS: The long-term mortality rate after discharge was 6.3%, 4.4%, 17.4%, and 3.6% in the derivation, CAPNETZ (only 6 months of follow-up), USA, and COVID-19 cohorts, respectively. The L-PMI included age, smoking history, nursing home residency, Charlson Comorbidity Index score, CURB-65 score, use of noninvasive or invasive mechanical ventilation, and in-hospital cardiovascular events. The L-PMI showed high discrimination for mortality in the derivation cohort (AUC, 0.82 [95% CI, 0.78-0.85]). In the validation cohorts, the AUC (95% CI) ranged from 0.78 (0.73-0.83) to 0.75 (0.73-0.77) for the CAPNETZ and USA cohorts, respectively, and 0.88 (0.84-0.93) for the COVID-19 cohort. L-PMI allows classification of patients according to their mortality risk into low-, intermediate-, and high-risk groups. CONCLUSIONS: The L-PMI is a novel clinical prediction score that identifies pneumonia patients at risk of mortality up to 1 year after discharge.

BACKGROUND AND OBJECTIVE: Nusinersen was the first disease-modifying treatment approved for spinal muscular atrophy (SMA). However, long-term results of broad unselected populations-particularly adolescents and adults-remain limited. We aimed to evaluate nusinersen long-term persistence and effectiveness in a population-based cohort. METHODS: We conducted a population-based, ambispective observational study of all SMA patients in the Valencian community (Spain) between 2017 and 2022, with follow-up until December 2025 or censoring (due to death, clinical trial, or treatment switch). Demographic, clinical, and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. Nusinersen discontinuation risks and motor trajectories were evaluated using Bayesian linear and mixed linear models. RESULTS: Of 72 patients included, 18 were < 12 years old (all treated with nusinersen) and 54 were ≥ 12 years (28 treated; 26 untreated) at the baseline visit. After a median follow-up of 4.6 years until censoring, all children were found responders, compared with 68% of those ≥ 12 years. Discontinuation rates were 11% in children compared to 75% in the older cohort. In patients ≥ 12 years, reasons for discontinuation included: treatment burden (71%), and loss (53%) or lack of benefit (43%). Lower baseline SMA-FCR (expEstimate = 0.84 [0.718,0.93],prob:1) and older age (expEstimate = 1.028 [1.011,1.055],prob:1) independently predicted higher discontinuation risk. Sustained treatment was associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration. DISCUSSION: Nusinersen persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy although a 25% of adolescents and younger adults with higher baseline function experienced sustained benefit.

BACKGROUND AND OBJECTIVE: Nusinersen was the first disease-modifying treatment approved for spinal muscular atrophy (SMA). However, long-term results of broad unselected populations-particularly adolescents and adults-remain limited. We aimed to evaluate nusinersen long-term persistence and effectiveness in a population-based cohort. METHODS: We conducted a population-based, ambispective observational study of all SMA patients in the Valencian community (Spain) between 2017 and 2022, with follow-up until December 2025 or censoring (due to death, clinical trial, or treatment switch). Demographic, clinical, and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. Nusinersen discontinuation risks and motor trajectories were evaluated using Bayesian linear and mixed linear models. RESULTS: Of 72 patients included, 18 were < 12 years old (all treated with nusinersen) and 54 were ≥ 12 years (28 treated; 26 untreated) at the baseline visit. After a median follow-up of 4.6 years until censoring, all children were found responders, compared with 68% of those ≥ 12 years. Discontinuation rates were 11% in children compared to 75% in the older cohort. In patients ≥ 12 years, reasons for discontinuation included: treatment burden (71%), and loss (53%) or lack of benefit (43%). Lower baseline SMA-FCR (expEstimate = 0.84 [0.718,0.93],prob:1) and older age (expEstimate = 1.028 [1.011,1.055],prob:1) independently predicted higher discontinuation risk. Sustained treatment was associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration. DISCUSSION: Nusinersen persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy although a 25% of adolescents and younger adults with higher baseline function experienced sustained benefit.

Children born after threatened preterm labor (TPL) are at increased risk for executive function (EF) difficulties, even when born at term. However, EF development in this population remains understudied, particularly regarding the role of gestational age and early psychosocial adversity. Prenatal stress (e.g., maternal anxiety at TPL diagnosis and trauma history) and postnatal environmental factors may contribute to variability in EF outcomes. In this prospective cohort study with a 6-year follow-up, EF was assessed at ages 2 and 6 using the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). The sample included 180 mother-child dyads: 120 children born after TPL (full-term n = 27, late-preterm n = 56, very-preterm n = 37) and 60 full-term controls. Bayesian mixed-effects models were used to examine associations between EF outcomes and gestational age group, time, and relevant prenatal and postnatal factors, including child sex, parental education, maternal trauma history, and maternal anxiety. The models showed a group × time interaction for global EF scores. At age 2, all TPL groups showed higher EF difficulty scores compared with controls, with the largest differences observed in the very-preterm group. Between ages 2 and 6, EF scores decreased in TPL groups relative to controls, indicating a greater reduction in EF difficulties over time, although patterns varied across EF domains. Higher maternal anxiety (prenatal and postnatal), greater maternal trauma exposure, and lower parental education were associated with higher EF difficulty scores, whereas female sex was associated with lower scores. Children born after TPL show early EF vulnerabilities across gestational ages, including those born at term. EF outcomes change across early childhood and are associated with both biological and environmental factors. These findings support the importance of early monitoring of children exposed to prenatal complications and highlight the role of perinatal maternal mental health and family context in early executive function development.

Raúl Méndez, Paula González-Jiménez, David Hervás, Rosario Menéndez, on behalf of all authors of ‘The Long-term Pneumonia Mortality Index. An International

Introduction Functional analysis of microbiome with microbial-derived metabolites (MDMs) has emerged as key for several inflammatory and cardiovascular diseases. However, the data on the relationship of pulmonary embolism (PE) to microbiome are scarce. This study aimed to compare MDM levels between acute PE patients and healthy controls, and to investigate their associations with predisposing factors ( i.e. unprovoked, provoked and cancer-associated thrombosis). Methods We collected serum samples from a multicentric cohort, including 96 patients with acute PE at hospital admission and 30 healthy controls. Serum concentrations of MDMs and inflammation/coagulation-related markers were quantified by liquid chromatography–mass spectrometry and flow cytometry, respectively. Results Compared with healthy controls, patients with acute PE showed significantly higher serum levels of trimethylamine N-oxide (TMAO) (11.5 μM versus 6.7 μM; p=0.02) and acetate (48.3 μM versus 33.0 μM; p=0.04); and lower levels of propionate (3.8 μM versus 5.3 μM; p=0.007), butyrate (4.03 µM versus 7.68 µM; p=0.009), isobutyrate (5.0 μM versus 7.32 μM; p=0.002) and valerate (0.4 μM versus 0.63 μM; p<0.001). Valerate showed the best discrimination between PE and controls (area under the receiver operating characteristic curve 0.758, 95% CI 0.66–0.86). In the multinomial analysis, higher values of TMAO and acetate were associated with a higher probability of unprovoked PE. MDM levels exhibited different correlation with inflammation-related markers highlighting TGF-β1, CCL2 and CXCL10. Conclusion These findings reveal imbalances in the serological concentrations of MDMs in patients with acute PE and highlight the potential role of the microbiome and its functional metabolites as novel predisposing risk factors for PE.

Background/Objectives: Tracheal replacement remains an unmet necessity in airway pathology treatment. We describe a decellularization and cryopreservation tracheal replacement protocol tested in vivo. Methods: A prospective experimental cohort study is conducted in which tracheas from white New Zealand rabbits (n = 32) are decellularized and cryopreserved, sterilized with gamma radiation, and tutorized with a stent. Bilateral, pedicled fasciomuscular flaps are harvested, implanting one cryopreserved and one non-cryopreserved in each of 16 rabbits, dividing them into four groups (remaining tracheas implanted at 2, 4, 8, and 12 weeks, respectively). After removal, the tracheas are both histologically and biomechanically evaluated. Results: Decellularization is effective, with minimal effects on the biomechanical characteristics of the trachea. Implantation results in a well-vascularized organ, with no inflammatory or tissular rejection cellular response. Organs achieve all basal histological and biomechanical characteristics within 8 weeks of implantation, with no differences observed between cryopreserved and non-cryopreserved scaffolds. Conclusions: The present decellularization and cryopreservation protocol yields biocompatible, well-tolerated by the host tracheas with analogous histological and biomechanical characteristics to native ones.

Background/Objectives: Proliferative verrucous leukoplakia (PVL) is an oral disorder with the greatest degree of malignant transformation. However, it is relatively rare. This study compared the clinical characteristics of patients with oral squamous cell carcinoma (OSCC) who had and had not been previously diagnosed with PVL. Methods: This case control study compared the clinical characteristics of patients classified as early (T1 and T2) or advanced (T3 and T4) OSCC according to the T size of the Tumor, Node, Metastasis (TNM) classification, including age, gender, location, and clinical type of oral squamous cell carcinoma. The analysis involved 140 patients. Group 1: 50 OSCC patients with PVL (OSCC-PVL) and Group 2: 90 OSCC patients without PVL (OSCC-noPVL). Results: The patients with OSCC-PVL were younger than those with OSCC-noPVL, but this did not reach statistical significance. Regarding patient gender, those with OSCC-PVL were much more frequently female (70%), while OSCC-noPVL was more prevalent in men (65.5%) (p < 0.01). There were also significant differences in the oral locations between the two groups: the gingiva was most prevalent in OSCC-PVL and the tongue in OSCC-noPVL. Erythroleukoplastic forms were significantly more common in OSCC-PVL (30% vs. 7.7%), while ulcerated forms were more frequent in OSCC-noPVL (63.3% vs. 42%). Finally, early T stages were much more prevalent in our patients with OSCC-PVL. Conclusions: We found that OSCC preceded by PVL was much more frequent in women, had less aggressive clinical forms, and had significantly more frequent early T stages than in OSCC-noPVL.

We aimed to identify a profile of urine microRNAs (miRNAs) with diagnostic and stratification potential in the whole range of bladder cancer (BC) categories, to avoid current invasive, harmful and expensive procedures. We collected a first morning urine sample from the screening (35 BC patients and 15 age- and gender-matched controls) and validation cohorts (172 BC and 94 controls). In the screening stage we analyzed the expression level of 179 miRNAs by real-time reverse transcription quantitative PCR in urine supernatants. miRNA levels in each sample were normalized by the levels of the previously identified and stably expressed miR-29c-3p. We performed an ordinal regression for each miRNA with False Discovery Rate (FDR) adjustment to identify dysregulated miRNAs, and an ordinal elastic net logistic regression model to identify a miRNA profile for BC diagnosis and stratification with the software R (v3.5.1). Next, we validated the most dysregulated miRNAs, and empirically identified the real miRNA targets in BC cells by miR-eCLIP immunoprecipitation and sequencing. We identified 70 dysregulated miRNAs in BC patients (p < 0.05 FDR-adjusted). With the expression level of 7 miRNAs in urine (miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p, miR-21-5p) we could stratify BC patients and control subjects. To enable the global use of our model, we developed the free BladdermiRaCan online tool. Furthermore, we identified miR-21-5p, miR-425-5p and miR-99a-5p as follow-up markers for BC relapse, and miR-21-5p and miR-221-3p as markers for metastasis. These miRNAs were also dysregulated in BC tissue sections from a subgroup of patients from which urine samples were studied. In conclusion, we have validated and patented a 7-miRNAs urine profile able to diagnose and stratify BC patients; BladdermiRaCan will enable the global use of our model. The experimentally verified target proteins identified for these miRNAs may unravel novel therapeutic targets.

Objective: This study evaluates the prevalence of Obstructive Sleep Apnea (OSA) in patients with Pulmonary Embolism (PE) and its association with persistent perfusion defects. Additionally, it explores differentially expressed miRNAs in OSA patients. Methods: A prospective observational study was conducted across 10 hospitals (July 2022–October 2024), including acute PE patients. At three months, respiratory polygraphy and perfusion scintigraphy assessed OSA diagnosis and residual perfusion defects respectively. Blood samples were analyzed for miRNA expression. Statistical analyses were performed using SPSS 28.0 and R 4.3.2. Elastic-Net Generalized Linear Models identified relevant miRNAs. KEGG and mirWalk databases determined target genes while Cytoscape enabled interactome analysis. Results: 202 patients (55.9% male, mean age 63.3 ± 14.5 years) were included. OSA prevalence was 61.1%. Residual perfusion defects were independently associated with CT90 >15 [OR =1.015, 95%CI (1-1.029), p=0.044], while segmental PE location was protective [OR=0.345, 95%CI (0.136-0.876), p=0.025]. A 16-miRNA panel differentiated OSA patients with 9 showing the highest impact (coefficient >0.4): mir_32_5p, mir_328_3p, mir_128_3p, mir_132_3p, mir_136_5p, mir_1260a, mir_99b_5p, mir_335_5p, and mir_136_3p. Pathway and gene interaction analyses identified affected signaling pathways. Conclusion: OSA is highly prevalent in PE patients and may contribute to residual perfusion defects via prolonged nocturnal hypoxia, potentially leading to incomplete PE resolution and chronic complications. A 16-miRNA panel could serve as biomarker in this patients, though further validation is needed

OBJECTIVES: Bilateral endoscopic thoracic sympathectomy is an effective treatment for primary hyperhidrosis, yet the causes of its main side effect, compensatory sweating, remain unclear. This study aimed to identify risk factors for compensatory sweating in a long-term follow-up cohort. METHODS: Patients who underwent bilateral endoscopic thoracic sympathectomy for primary hyperhidrosis between 2010 and 2023 (n = 98) were interviewed, and preoperative data were collected. Compensatory sweating was classified as mild, moderate, or severe according to the Society of Thoracic Surgeons guidelines. Quality of life (QOL) was assessed using the Hyperhidrosis Disease Severity Scale from the International Hyperhidrosis Society. Logistic and ordinal Bayesian regression models were applied to analyse associations between predictors, compensatory sweating outcomes, and QOL. RESULTS: The procedure achieved an overall effectiveness of 94.38%, with 34.69% of patients reporting compensatory sweating, predominantly mild (26.53%). Nearly all patients (97.95%) experienced a ≥ 50% reduction in sweating, and 94.89% achieved ≥80% reduction. Higher haemoglobin levels and marijuana protected against compensatory sweating incidence and severity. Conversely, smoking and hyperhidrosis involving both hands and axillae increased compensatory sweating risk. Better QOL outcomes were correlated with higher haemoglobin levels and female sex, while worse outcomes were associated with older age, higher body mass index, and axillary involvement. CONCLUSIONS: Long-term follow-up highlights key predictors for compensatory sweating, emphasizing the importance of tailored preoperative counseling. Identifying at-risk patients, such as smokers and those with low haemoglobin levels, is essential for improving outcomes and managing expectations in the treatment of primary hyperhidrosis.

BACKGROUND: Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. Its poor prognosis is largely attributed to late-stage diagnosis, highlighting the need for sensitive, minimally invasive biomarkers for early detection. In this study, we aimed to identify circulating cell-free DNA (cfDNA) methylation-based biomarkers for LC through genome-wide profiling of plasma-derived cfDNA from patients with LC (stages I-IV) using the Infinium DNA MethylationEPIC array (> 850,000 CpGs). A relaxed elastic net penalized logistic regression model was applied to identify differentially methylated CpGs between LC patients and non-neoplastic controls, and selected candidates were validated in an independent cohort. RESULTS: A 21-CpG episignature was identified, predominantly hypomethylated in LC, which distinguished cases (n = 25) from controls (n = 8) with a cross-validated area under the curve (AUC) of 0.70. Two CpGs with the largest effect sizes (associated with EMP2 and IKZF2) were selected for validation. Digital droplet PCR (ddPCR) analysis in an independent cohort of 47 individuals (23 LC patients and 24 controls) confirmed significant hypomethylation at the EMP2 locus (median % methylation: 73.60% in tumors vs. 86.83% in controls; p = 0.0034), achieving an AUC of 0.75. CONCLUSIONS: Our findings support the utility of methylome-wide cfDNA profiling for LC biomarker discovery. EMP2 promoter methylation represents a promising candidate for the minimally invasive detection of LC across heterogeneous clinical presentations.

Background: Malnutrition in amyotrophic lateral sclerosis (ALS) is associated with disease severity, and epigenetic regulation may be involved. The aim of this study was to assess the methylation levels of specific DNA sequences from the nuclear and mitochondrial genomes in a population with ALS to elucidate their relationship with nutritional status and the evolution of the disease. Methods: Patients with ALS were evaluated between 2013 and 2021 (n = 66). They were categorized according to their nutritional status, using the Global Leadership Initiative on Malnutrition (GLIM) criteria, and disease progression, using the ALS Functional Rating (ALSFRS-R) Scale. DNA samples were extracted from leukocytes at the time of diagnosis for analysis of DNA methylation levels of markers of oxidative stress, mitochondrial function and global methylation (D-loop, GSTP1, and LINE-1). Results: According to the GLIM criteria, 29 (43.9%) patients had malnutrition (22.7%—moderate; 21.2%—severe), which was positively correlated with ALS disease progression (r = 0.414; p < 0.01) and death (r = 0.687; p < 0.01). Mortality occurred in 43.9% of the patients (median time to death, 18.7 (1.7–82.7) months). A significant association was observed between DNA methylation levels of the D-loop, GSTP1, and the CpG1 site of LINE-1 and malnutrition, disease progression at diagnosis, and death. The D-loop was the best predictor of malnutrition (AUC, 0.79; p < 0.01), disease progression (AUC, 0.70; p < 0.01), and mortality (AUC, 0.71; p < 0.01). Conclusions: This study revealed, for the first time, the early detection of D-loop methylation levels as a potential biomarker of nutritional status in patients with ALS, which may be useful for personalized nutritional management aimed at counteracting disease progression.

Introduction Functional analysis of microbiome with microbial-derived metabolites (MDMs) has emerged as key for several inflammatory and cardiovascular diseases. However, the data on the relationship of pulmonary embolism (PE) to microbiome are scarce. This study aimed to compare MDM levels between acute PE patients and healthy controls, and to investigate their associations with predisposing factors ( i.e. unprovoked, provoked and cancer-associated thrombosis). Methods We collected serum samples from a multicentric cohort, including 96 patients with acute PE at hospital admission and 30 healthy controls. Serum concentrations of MDMs and inflammation/coagulation-related markers were quantified by liquid chromatography–mass spectrometry and flow cytometry, respectively. Results Compared with healthy controls, patients with acute PE showed significantly higher serum levels of trimethylamine N-oxide (TMAO) (11.5 μM versus 6.7 μM; p=0.02) and acetate (48.3 μM versus 33.0 μM; p=0.04); and lower levels of propionate (3.8 μM versus 5.3 μM; p=0.007), butyrate (4.03 µM versus 7.68 µM; p=0.009), isobutyrate (5.0 μM versus 7.32 μM; p=0.002) and valerate (0.4 μM versus 0.63 μM; p<0.001). Valerate showed the best discrimination between PE and controls (area under the receiver operating characteristic curve 0.758, 95% CI 0.66–0.86). In the multinomial analysis, higher values of TMAO and acetate were associated with a higher probability of unprovoked PE. MDM levels exhibited different correlation with inflammation-related markers highlighting TGF-β1, CCL2 and CXCL10. Conclusion These findings reveal imbalances in the serological concentrations of MDMs in patients with acute PE and highlight the potential role of the microbiome and its functional metabolites as novel predisposing risk factors for PE.

We aimed to identify a profile of urine microRNAs (miRNAs) with diagnostic and stratification potential in the whole range of bladder cancer (BC) categories, to avoid current invasive, harmful and expensive procedures. We collected a first morning urine sample from the screening (35 BC patients and 15 age- and gender-matched controls) and validation cohorts (172 BC and 94 controls). In the screening stage we analyzed the expression level of 179 miRNAs by real-time reverse transcription quantitative PCR in urine supernatants. miRNA levels in each sample were normalized by the levels of the previously identified and stably expressed miR-29c-3p. We performed an ordinal regression for each miRNA with False Discovery Rate (FDR) adjustment to identify dysregulated miRNAs, and an ordinal elastic net logistic regression model to identify a miRNA profile for BC diagnosis and stratification with the software R (v3.5.1). Next, we validated the most dysregulated miRNAs, and empirically identified the real miRNA targets in BC cells by miR-eCLIP immunoprecipitation and sequencing. We identified 70 dysregulated miRNAs in BC patients (p < 0.05 FDR-adjusted). With the expression level of 7 miRNAs in urine (miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p, miR-21-5p) we could stratify BC patients and control subjects. To enable the global use of our model, we developed the free BladdermiRaCan online tool. Furthermore, we identified miR-21-5p, miR-425-5p and miR-99a-5p as follow-up markers for BC relapse, and miR-21-5p and miR-221-3p as markers for metastasis. These miRNAs were also dysregulated in BC tissue sections from a subgroup of patients from which urine samples were studied. In conclusion, we have validated and patented a 7-miRNAs urine profile able to diagnose and stratify BC patients; BladdermiRaCan will enable the global use of our model. The experimentally verified target proteins identified for these miRNAs may unravel novel therapeutic targets.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious conditions affecting the pulmonary circulation and with a challenging prognosis despite treatment advancements (1, 2). Patients with CTEPH can be categorized into two subgroups: surgical CTEPH, characterized by proximal pulmonary artery obstruction that can be surgically treated, and nonsurgical CTEPH (3–5). MicroRNAs (miRNAs) (6–9), acting as negative regulators of protein translation, circulate freely or within extracellular microvesicles (EVs) (10).

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of acute pulmonary embolism (PE) in which delayed diagnosis significantly affects patient health outcomes. This case-control study aimed to identify a set of microRNAs (miRNAs) in plasma with diagnostic potential to differentiate patients with CTEPH from those with PE. Methods: Two groups were analysed: 22 patients with confirmed CTEPH and 13 patients with PE, followed by validation in an independent cohort of 48 CTEPH and 37 PE patients. Results: Using real-time PCR, eight miRNAs were identified as significantly different between the groups: miR-574-3p, miR-146b-5p, miR-193a-5p, miR-885-5p, miR-122-5p, miR-365a-3p, miR-142-3p and miR-192-5p. These miRNAs target key biological pathways, including vascular smooth muscle contraction, apoptosis and VEGF signalling, underlying the pathophysiology of CTEPH. The miRNA panel demonstrated strong diagnostic accuracy with an area under the curve of 0.843 in the validation cohort. Conclusions: The results highlight the potential of miRNA biomarkers as a diagnostic tool for early detection of CTEPH, representing a paradigm shift in its management, but further validation in larger cohorts is necessary to confirm their applicability. These insights could pave the way for improved clinical outcomes through timely diagnosis and targeted interventions.

BACKGROUND: Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. Its poor prognosis is largely attributed to late-stage diagnosis, highlighting the need for sensitive, minimally invasive biomarkers for early detection. In this study, we aimed to identify circulating cell-free DNA (cfDNA) methylation-based biomarkers for LC through genome-wide profiling of plasma-derived cfDNA from patients with LC (stages I-IV) using the Infinium DNA MethylationEPIC array (> 850,000 CpGs). A relaxed elastic net penalized logistic regression model was applied to identify differentially methylated CpGs between LC patients and non-neoplastic controls, and selected candidates were validated in an independent cohort. RESULTS: A 21-CpG episignature was identified, predominantly hypomethylated in LC, which distinguished cases (n = 25) from controls (n = 8) with a cross-validated area under the curve (AUC) of 0.70. Two CpGs with the largest effect sizes (associated with EMP2 and IKZF2) were selected for validation. Digital droplet PCR (ddPCR) analysis in an independent cohort of 47 individuals (23 LC patients and 24 controls) confirmed significant hypomethylation at the EMP2 locus (median % methylation: 73.60% in tumors vs. 86.83% in controls; p = 0.0034), achieving an AUC of 0.75. CONCLUSIONS: Our findings support the utility of methylome-wide cfDNA profiling for LC biomarker discovery. EMP2 promoter methylation represents a promising candidate for the minimally invasive detection of LC across heterogeneous clinical presentations.

Background: Malnutrition in amyotrophic lateral sclerosis (ALS) is associated with disease severity, and epigenetic regulation may be involved. The aim of this study was to assess the methylation levels of specific DNA sequences from the nuclear and mitochondrial genomes in a population with ALS to elucidate their relationship with nutritional status and the evolution of the disease. Methods: Patients with ALS were evaluated between 2013 and 2021 (n = 66). They were categorized according to their nutritional status, using the Global Leadership Initiative on Malnutrition (GLIM) criteria, and disease progression, using the ALS Functional Rating (ALSFRS-R) Scale. DNA samples were extracted from leukocytes at the time of diagnosis for analysis of DNA methylation levels of markers of oxidative stress, mitochondrial function and global methylation (D-loop, GSTP1, and LINE-1). Results: According to the GLIM criteria, 29 (43.9%) patients had malnutrition (22.7%—moderate; 21.2%—severe), which was positively correlated with ALS disease progression (r = 0.414; p < 0.01) and death (r = 0.687; p < 0.01). Mortality occurred in 43.9% of the patients (median time to death, 18.7 (1.7–82.7) months). A significant association was observed between DNA methylation levels of the D-loop, GSTP1, and the CpG1 site of LINE-1 and malnutrition, disease progression at diagnosis, and death. The D-loop was the best predictor of malnutrition (AUC, 0.79; p < 0.01), disease progression (AUC, 0.70; p < 0.01), and mortality (AUC, 0.71; p < 0.01). Conclusions: This study revealed, for the first time, the early detection of D-loop methylation levels as a potential biomarker of nutritional status in patients with ALS, which may be useful for personalized nutritional management aimed at counteracting disease progression.

Background: Long-term mortality after hospital discharge in community-acquired pneumonia (CAP) is a neglected issue. A validated, accurate score predicting mortality is needed. This study aimed to derive and validate the Long-term Pneumonia Mortality Index (L-PMI). Methods: L-PMI derivation used data from a Spanish multicentre prospective cohort study with a 1-year follow-up. A logistic regression model for predicting 1-year mortality risk was developed. Performance of the model was assessed by estimating the area under the receiver operator characteristic curve. The model was externally validated using two independent multicentre CAP cohorts from Germany and the USA, and one multicentre COVID-19 cohort from Spain. We then derived a score from the validated prediction model to ease its application. Findings The final L-PMI included 7 variables: age, smoking history, nursing home resident, Charlson comorbidity index, CURB-65 score, use of non-invasive or invasive mechanical ventilation, and in-hospital cardiovascular events. The L-PMI showed high discrimination for mortality in the derivation cohort: AUC 0.82 (95% confidence interval (CI) [0.78, 0.85]). In the validation cohorts, the AUC of the model ranged from 0.78 (0.73, 0.83) to 0.75 (0.73, 0.77) for CAPNETZ and USA cohorts, respectively, and 0.88 (0.84, 0.93) for COVID-19 cohort. L-PMI (range 0-28 points) allows classification of patients according to their mortality risk into low (0–5), intermediate (6-10), and high-risk (>10) groups with an AUC of 0.80 (0.76, 0.84). Interpretation The L-PMI is a novel clinical prediction score that identifies pneumonia patients at risk of mortality up to 1 year after hospital discharge.

Abstract Objective Infants born after threatened preterm labour (TPL) are at heightened risk for executive function (EF) deficits. This study examined the association between perinatal factors and infants EF development, focusing on prematurity. Design A prospective cohort study Setting Obstetrics Hospitalization Unit at La Fe University and Polytechnic Hospital in Valencia (Spain) Population A total of 179 mother-child pairs from pregnancy to 30-months-of-age, concretely 60 controls compared to 119 TPL-group: 27 full-term, 55 late-preterm, 37 very-preterm. Methods Assessments occurred at three times: during TPL or control visit, after delivery and at 30-months-of-age (infant’s EF via BRIEF-P). Data included medical records, sociodemographic and maternal scores (STAI, BDI, TQ). Main Outcome Measures A Bayesian network analysis of perinatal factors (infant sex, maternal age, multiple pregnancy, IVF, parental education, birthweight, TPL-group, and maternal scores) influencing EF (inhibition, shifting, emotional control, planning, and working memory). Results TPL groups exhibited reduced EF performance compared to controls being very-preterm infants most affected. Other predictors of EF deficits included increased maternal anxiety at TPL, lower birthweight percentile, male sex, maternal age, and parents without university education. A history of trauma exacerbated maternal anxiety, which negatively impacted birthweight percentile and birth timing. Conclusions The manifestation of EF deficits in TPL infants at higher risk for EF problems exhibits a phenotype influenced by prematurity. Maternal anxiety at TPL is a key perinatal risk factor that must be managed for prevention. Funding Authors receipted support by Carlos III Health Institute, Spanish Ministry of Science and Innovation, and European Regional Development Fund.

Background/Objectives: Tracheal replacement remains an unmet necessity in airway pathology treatment. We describe a decellularization and cryopreservation tracheal replacement protocol tested in vivo. Methods: A prospective experimental cohort study is conducted in which tracheas from white New Zealand rabbits (n = 32) are decellularized and cryopreserved, sterilized with gamma radiation, and tutorized with a stent. Bilateral, pedicled fasciomuscular flaps are harvested, implanting one cryopreserved and one non-cryopreserved in each of 16 rabbits, dividing them into four groups (remaining tracheas implanted at 2, 4, 8, and 12 weeks, respectively). After removal, the tracheas are both histologically and biomechanically evaluated. Results: Decellularization is effective, with minimal effects on the biomechanical characteristics of the trachea. Implantation results in a well-vascularized organ, with no inflammatory or tissular rejection cellular response. Organs achieve all basal histological and biomechanical characteristics within 8 weeks of implantation, with no differences observed between cryopreserved and non-cryopreserved scaffolds. Conclusions: The present decellularization and cryopreservation protocol yields biocompatible, well-tolerated by the host tracheas with analogous histological and biomechanical characteristics to native ones.

Background/Objectives: Proliferative verrucous leukoplakia (PVL) is an oral disorder with the greatest degree of malignant transformation. However, it is relatively rare. This study compared the clinical characteristics of patients with oral squamous cell carcinoma (OSCC) who had and had not been previously diagnosed with PVL. Methods: This case control study compared the clinical characteristics of patients classified as early (T1 and T2) or advanced (T3 and T4) OSCC according to the T size of the Tumor, Node, Metastasis (TNM) classification, including age, gender, location, and clinical type of oral squamous cell carcinoma. The analysis involved 140 patients. Group 1: 50 OSCC patients with PVL (OSCC-PVL) and Group 2: 90 OSCC patients without PVL (OSCC-noPVL). Results: The patients with OSCC-PVL were younger than those with OSCC-noPVL, but this did not reach statistical significance. Regarding patient gender, those with OSCC-PVL were much more frequently female (70%), while OSCC-noPVL was more prevalent in men (65.5%) (p < 0.01). There were also significant differences in the oral locations between the two groups: the gingiva was most prevalent in OSCC-PVL and the tongue in OSCC-noPVL. Erythroleukoplastic forms were significantly more common in OSCC-PVL (30% vs. 7.7%), while ulcerated forms were more frequent in OSCC-noPVL (63.3% vs. 42%). Finally, early T stages were much more prevalent in our patients with OSCC-PVL. Conclusions: We found that OSCC preceded by PVL was much more frequent in women, had less aggressive clinical forms, and had significantly more frequent early T stages than in OSCC-noPVL.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious conditions affecting the pulmonary circulation and with a challenging prognosis despite treatment advancements (1, 2). Patients with CTEPH can be categorized into two subgroups: surgical CTEPH, characterized by proximal pulmonary artery obstruction that can be surgically treated, and nonsurgical CTEPH (3–5). MicroRNAs (miRNAs) (6–9), acting as negative regulators of protein translation, circulate freely or within extracellular microvesicles (EVs) (10).

Objective: This study evaluates the prevalence of Obstructive Sleep Apnea (OSA) in patients with Pulmonary Embolism (PE) and its association with persistent perfusion defects. Additionally, it explores differentially expressed miRNAs in OSA patients. Methods: A prospective observational study was conducted across 10 hospitals (July 2022–October 2024), including acute PE patients. At three months, respiratory polygraphy and perfusion scintigraphy assessed OSA diagnosis and residual perfusion defects respectively. Blood samples were analyzed for miRNA expression. Statistical analyses were performed using SPSS 28.0 and R 4.3.2. Elastic-Net Generalized Linear Models identified relevant miRNAs. KEGG and mirWalk databases determined target genes while Cytoscape enabled interactome analysis. Results: 202 patients (55.9% male, mean age 63.3 ± 14.5 years) were included. OSA prevalence was 61.1%. Residual perfusion defects were independently associated with CT90 >15 [OR =1.015, 95%CI (1-1.029), p=0.044], while segmental PE location was protective [OR=0.345, 95%CI (0.136-0.876), p=0.025]. A 16-miRNA panel differentiated OSA patients with 9 showing the highest impact (coefficient >0.4): mir_32_5p, mir_328_3p, mir_128_3p, mir_132_3p, mir_136_5p, mir_1260a, mir_99b_5p, mir_335_5p, and mir_136_3p. Pathway and gene interaction analyses identified affected signaling pathways. Conclusion: OSA is highly prevalent in PE patients and may contribute to residual perfusion defects via prolonged nocturnal hypoxia, potentially leading to incomplete PE resolution and chronic complications. A 16-miRNA panel could serve as biomarker in this patients, though further validation is needed

OBJECTIVES: Bilateral endoscopic thoracic sympathectomy is an effective treatment for primary hyperhidrosis, yet the causes of its main side effect, compensatory sweating, remain unclear. This study aimed to identify risk factors for compensatory sweating in a long-term follow-up cohort. METHODS: Patients who underwent bilateral endoscopic thoracic sympathectomy for primary hyperhidrosis between 2010 and 2023 (n = 98) were interviewed, and preoperative data were collected. Compensatory sweating was classified as mild, moderate, or severe according to the Society of Thoracic Surgeons guidelines. Quality of life (QOL) was assessed using the Hyperhidrosis Disease Severity Scale from the International Hyperhidrosis Society. Logistic and ordinal Bayesian regression models were applied to analyse associations between predictors, compensatory sweating outcomes, and QOL. RESULTS: The procedure achieved an overall effectiveness of 94.38%, with 34.69% of patients reporting compensatory sweating, predominantly mild (26.53%). Nearly all patients (97.95%) experienced a ≥ 50% reduction in sweating, and 94.89% achieved ≥80% reduction. Higher haemoglobin levels and marijuana protected against compensatory sweating incidence and severity. Conversely, smoking and hyperhidrosis involving both hands and axillae increased compensatory sweating risk. Better QOL outcomes were correlated with higher haemoglobin levels and female sex, while worse outcomes were associated with older age, higher body mass index, and axillary involvement. CONCLUSIONS: Long-term follow-up highlights key predictors for compensatory sweating, emphasizing the importance of tailored preoperative counseling. Identifying at-risk patients, such as smokers and those with low haemoglobin levels, is essential for improving outcomes and managing expectations in the treatment of primary hyperhidrosis.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of acute pulmonary embolism (PE) in which delayed diagnosis significantly affects patient health outcomes. This case-control study aimed to identify a set of microRNAs (miRNAs) in plasma with diagnostic potential to differentiate patients with CTEPH from those with PE. Methods: Two groups were analysed: 22 patients with confirmed CTEPH and 13 patients with PE, followed by validation in an independent cohort of 48 CTEPH and 37 PE patients. Results: Using real-time PCR, eight miRNAs were identified as significantly different between the groups: miR-574-3p, miR-146b-5p, miR-193a-5p, miR-885-5p, miR-122-5p, miR-365a-3p, miR-142-3p and miR-192-5p. These miRNAs target key biological pathways, including vascular smooth muscle contraction, apoptosis and VEGF signalling, underlying the pathophysiology of CTEPH. The miRNA panel demonstrated strong diagnostic accuracy with an area under the curve of 0.843 in the validation cohort. Conclusions: The results highlight the potential of miRNA biomarkers as a diagnostic tool for early detection of CTEPH, representing a paradigm shift in its management, but further validation in larger cohorts is necessary to confirm their applicability. These insights could pave the way for improved clinical outcomes through timely diagnosis and targeted interventions.

Background: Long-term mortality after hospital discharge in community-acquired pneumonia (CAP) is a neglected issue. A validated, accurate score predicting mortality is needed. This study aimed to derive and validate the Long-term Pneumonia Mortality Index (L-PMI). Methods: L-PMI derivation used data from a Spanish multicentre prospective cohort study with a 1-year follow-up. A logistic regression model for predicting 1-year mortality risk was developed. Performance of the model was assessed by estimating the area under the receiver operator characteristic curve. The model was externally validated using two independent multicentre CAP cohorts from Germany and the USA, and one multicentre COVID-19 cohort from Spain. We then derived a score from the validated prediction model to ease its application. Findings The final L-PMI included 7 variables: age, smoking history, nursing home resident, Charlson comorbidity index, CURB-65 score, use of non-invasive or invasive mechanical ventilation, and in-hospital cardiovascular events. The L-PMI showed high discrimination for mortality in the derivation cohort: AUC 0.82 (95% confidence interval (CI) [0.78, 0.85]). In the validation cohorts, the AUC of the model ranged from 0.78 (0.73, 0.83) to 0.75 (0.73, 0.77) for CAPNETZ and USA cohorts, respectively, and 0.88 (0.84, 0.93) for COVID-19 cohort. L-PMI (range 0-28 points) allows classification of patients according to their mortality risk into low (0–5), intermediate (6-10), and high-risk (>10) groups with an AUC of 0.80 (0.76, 0.84). Interpretation The L-PMI is a novel clinical prediction score that identifies pneumonia patients at risk of mortality up to 1 year after hospital discharge.

Abstract Objective Infants born after threatened preterm labour (TPL) are at heightened risk for executive function (EF) deficits. This study examined the association between perinatal factors and infants EF development, focusing on prematurity. Design A prospective cohort study Setting Obstetrics Hospitalization Unit at La Fe University and Polytechnic Hospital in Valencia (Spain) Population A total of 179 mother-child pairs from pregnancy to 30-months-of-age, concretely 60 controls compared to 119 TPL-group: 27 full-term, 55 late-preterm, 37 very-preterm. Methods Assessments occurred at three times: during TPL or control visit, after delivery and at 30-months-of-age (infant’s EF via BRIEF-P). Data included medical records, sociodemographic and maternal scores (STAI, BDI, TQ). Main Outcome Measures A Bayesian network analysis of perinatal factors (infant sex, maternal age, multiple pregnancy, IVF, parental education, birthweight, TPL-group, and maternal scores) influencing EF (inhibition, shifting, emotional control, planning, and working memory). Results TPL groups exhibited reduced EF performance compared to controls being very-preterm infants most affected. Other predictors of EF deficits included increased maternal anxiety at TPL, lower birthweight percentile, male sex, maternal age, and parents without university education. A history of trauma exacerbated maternal anxiety, which negatively impacted birthweight percentile and birth timing. Conclusions The manifestation of EF deficits in TPL infants at higher risk for EF problems exhibits a phenotype influenced by prematurity. Maternal anxiety at TPL is a key perinatal risk factor that must be managed for prevention. Funding Authors receipted support by Carlos III Health Institute, Spanish Ministry of Science and Innovation, and European Regional Development Fund.