Temporal relationship between sarcoidosis and malignancies in a nationwide cohort of 1942 patients.

PURPOSE: To investigate the phenotype of sarcoidosis according to the time when a malignancy is diagnosed (preexisting to the diagnosis of sarcoidosis, concomitant, or sequential) and to identify prognostic factors associated with malignancies in a large cohort of patients with sarcoidosis. METHODS: We searched for malignancies in the SARCOGEAS cohort, a multicenter nationwide database of consecutive patients diagnosed with sarcoidosis according to the ATS/ESC/WASOG criteria. Solid malignancies were classified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) nomenclature, and hematological malignancies using the 2016 WHO classification. We excluded patients with a biopsy-proven diagnosis of sarcoidosis based exclusively on demonstrating granulomas in tissues also involved by malignant cells. RESULTS: Out of 1942 patients with sarcoidosis, 233 (12%) developed 250 malignancies, including solid (n = 173), hematological (n = 57), and both types of malignancies (n = 3). Concerning the time interval between the diagnoses of both conditions, 83 (36%) patients were diagnosed with malignancy at least 1 year before sarcoidosis diagnosis, 22 (9%) had s synchronous diagnosis of both diseases, and 118 (51%) developed malignancies at least 1 year after the diagnosis of sarcoidosis (the remaining cases developed malignancies in different time intervals). The multivariate-adjusted model showed that individuals with sarcoidosis who developed a malignancy had an hazard ratio (HR) of 2.27 [95% confidence interval (CI), 1.62-3.17] for having an asymptomatic clinical phenotype at diagnosis of sarcoidosis and that spleen (presence vs. absence: HR = 2.06; 95% CI, 1.21-3.51) and bone marrow (presence vs. absence: HR = 3.04; 95% CI, 1.77-5.24) involvements were independent predictors for the development of all-type malignancies. No predictive factors were identified when the analysis was restricted to the development of solid malignancies. The analysis limited to the development of hematological malignancies confirmed the presence of involvement in the spleen (HR = 3.73; 95% CI, 1.38-10.06) and bone marrow (presence vs. absence: HR = 8.00; 95% CI, 3.15-20.35) at the time of sarcoidosis diagnosis as predictive factors. CONCLUSION: It is essential to consider the synchronous or metachronous timing of the diagnosis of malignancies in people with sarcoidosis. We found that half of the malignancies were diagnosed after a diagnosis of sarcoidosis, with spleen and bone marrow involvement associated with a four to eight times higher risk of developing hematological malignancies. Key messages What is already known on this topic Malignancies are one of the comorbidities more frequently encountered in people with sarcoidosis What this study adds Malignancies occur in 12% of patients with sarcoidosis Malignancy may precede, coincide with, or follow the diagnosis of sarcoidosis One-third were identified before sarcoidosis, and half were diagnosed after Spleen and bone marrow involvement are risk factors for developing hematological malignancies How this study might affect research, practice or policy Patients with sarcoidosis should be regularly monitored for neoplasms, informed of the increased risk, and educated on early detection. Those with spleen or bone marrow involvement must be closely followed.

Ceramides in the central control of metabolism.

Central ceramides regulate energy metabolism by impacting hypothalamic neurons. This allows ceramides to integrate endocrine signals - such as leptin, ghrelin, thyroid hormones, or estradiol - and to modulate the central control of puberty. In this forum article we discuss recent evidence suggesting that specific ceramide species and neuronal populations are involved in these effects.

[Reversible cerebral vasoconstriction syndrome. Recurrence of thunderclap headaches after treatment with corticosteroids]. / Síndrome de vasoconstricción cerebral reversible. Recurrencia de cefaleas en trueno tras tratamiento con corticoides.

INTRODUCTION: Reversible cerebral vasoconstriction syndrome is a clinicoradiological entity with a self-limiting course that manifests with recurrent episodes of thunderclap headache, and is associated with certain triggers. Recurrence is very rare, and the pathophysiology is thought to be related to altered autoregulation of the cerebrovascular tone. We present a clinical case that raises questions about possible recurrences and triggers. CASE REPORT: A 44-year-old woman with a history of multiple sclerosis treated with interferon beta-1b who had four episodes of thunderclap headache while resting, after completing a course of corticosteroids due to a flare-up of optic neuritis. Three years earlier, the patient had presented several episodes of explosive-onset headache during a self-limited period of one month, only occurring during sexual intercourse. In the year prior to our assessment, she had suffered three thunderclap headaches with similar characteristics, but they were triggered only by intense physical exercise. She had not consulted a physician about these events. A cranial computed tomography scan was performed after the administration of contrast media and a cerebral arteriography, which were consistent with cerebral vasoconstriction syndrome, and its reversibility was confirmed three months later. CONCLUSIONS: Reversible cerebral vasoconstriction syndrome shares a phenotypic expression with primary exertion headaches. It is associated with drugs with vasoactive effects, including interferons, and corticosteroids are associated with a worse prognosis, and such their administration should be avoided.

TITLE: Síndrome de vasoconstricción cerebral reversible. Recurrencia de cefaleas en trueno tras tratamiento con corticoides.Introducción. El síndrome de vasoconstricción cerebral reversible es una entidad clinicorradiológica de curso autolimitado que se manifiesta con episodios de cefalea en trueno recurrentes y que se asocia a determinados desencadenantes. La recidiva es muy poco frecuente y la fisiopatología se cree que está en relación con la alteración de la autorregulación del tono vascular cerebral. Presentamos un caso clínico que plantea cuestiones sobre posibles recurrencias y desencadenantes. Caso clínico. Mujer de 44 años con antecedente de esclerosis múltiple en tratamiento con interferón beta-1b que consultó por cuatro episodios de cefalea en trueno en reposo, tras finalizar un ciclo de corticoides por un brote de neuritis óptica. Tres años antes, la paciente había presentado varios episodios de cefalea de inicio explosivo durante un período autolimitado de un mes, únicamente producidos en el contexto de relaciones sexuales. El año previo a nuestra valoración padeció en tres ocasiones cefalea en trueno de características similares, pero exclusivamente desencadenadas con el ejercicio físico intenso. No había consultado por estos eventos. Se realizó una tomografía computarizada craneal tras la administración de contraste y una arteriografía cerebral, que fueron compatibles con síndrome de vasoconstricción cerebral, y se confirmó su reversibilidad tres meses después. Conclusiones. El síndrome de vasoconstricción cerebral reversible comparte expresión fenotípica con el grupo de cefaleas primarias por esfuerzo físico. Se asocia a fármacos con efectos vasoactivos, entre los que se encuentran los interferones, y los corticoides se asocian a un peor pronóstico, por lo que es importante evitar su administración.

Treatment patterns and factors associated with adherence in pulmonary arterial hypertension.

OBJECTIVE: Improving understanding of actual pulmonary hypertension (PH) treatment adherence patterns is crucial to properly treating these patients. We aimed to primarily assess adherence to treatments used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) specific therapies, identify potential factors related to it and secondly describe its treatment patterns. METHODS: A 6-month observational cross-sectional study in a tertiary care hospital was conducted. Patients with PH-targeted therapy who picked it up in the ambulatory hospital pharmacy and who had been on treatment with the same drug for at least 1 year were included. Adherence was assessed as: 1) Proportion of days covered (PDC); and 2) Simplified Medication Adherence Questionnaire (SMAQ). PDC ≥80% was considered adherent. Statistical analyses were performed to evaluate the study outcomes. Logistic regressions were estimated to identify the association between baseline characteristics and factors associated with adherence. P < 0.05 indicated statistical significance. RESULTS: A total of 63 patients with 127 different treatments were included, 71.4% were females with a mean age (SD) of 59 (15) years. PAH was the most common diagnosis (74.6%). Double therapy was used in 39.7% of patients, being the combination of Macitentan + Tadalafil and Ambrisentan + Tadalafil the most prescribed. Endothelin receptor antagonists were the most used treatment (40.2%). Adherence according to PDC was 93.7%, showing no great differences depending on the targeted drug used, and according to SMAQ 61.9%. The agreement degree of both methods was slight (65.1%; Kappa 0.12). Only female sex (OR: 0.23, 95% CI: 0.06-0.90; p = 0.035) was associated with worse adherence in the SMAQ method but not in the PDC. Adverse events were reported by a 55.6% of participants and the perception of effective treatment was high (95.2%). CONCLUSIONS: Adherence to PH therapy differs depending on the assessment method; PDC showed greater adherence rate than SMAQ. According to SMAQ, female sex may have a negative impact on adherence in this cohort, but PDC revealed no factors influencing it. No notable differences in adherence between treatment types were found and generally patients felt the treatments were effective in controlling their disease.

PHIRI: lessons for an extensive reuse of sensitive data in federated health research.

BACKGROUND: The extensive and continuous reuse of sensitive health data could enhance the role of population health research on public decisions. This paper describes the design principles and the different building blocks that have supported the implementation and deployment of Population Health Information Research Infrastructure (PHIRI), the strengths and challenges of the approach and some future developments. METHODS: The design and implementation of PHIRI have been developed upon: (i) the data visiting principle-data does not move but code moves; (ii) the orchestration of the research question throughout a workflow that ensured legal, organizational, semantic and technological interoperability and (iii) a 'master-worker' federated computational architecture that supported the development of four uses cases. RESULTS: Nine participants nodes and 28 Euro-Peristat members completed the deployment of the infrastructure according to the expected outputs. As a consequence, each use case produced and published their own common data model, the analytical pipeline and the corresponding research outputs. All the digital objects were developed and published according to Open Science and FAIR principles. CONCLUSION: PHIRI has successfully supported the development of four use cases in a federated manner, overcoming limitations for the reuse of sensitive health data and providing a methodology to achieve interoperability in multiple research nodes.

Chronic obstructive pulmonary disease related to wood smoke and impact of the combined exposure to tobacco.

BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 highlights the need to explore aetiotypes of chronic obstructive pulmonary disease (COPD) beyond the tobacco-smoking COPD. Exposure to wood smoke (WS) is a risk factor for COPD in women, but the effect of the combined exposure to tobacco smoke (TS) in the general population and among COPD patients, and the characteristics of WS-COPD are unclear. METHOD: This was an analysis of data from PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude), a random cross-sectional population-based study (n = 5,539) focusing on the effect of combined WS and TS exposure and WS-COPD characterisation. RESULTS: Prevalence of COPD was significantly higher in those exposed to both WS and TS (16.0%) than in those exposed to WS (6.7%) or TS (7.8%) only (P < 0.001). Exposure to WS was associated with COPD in men (OR 1.53, P = 0.017). WS-COPD individuals were more frequently female, older, shorter and had higher forced expiratory volume in 1 sec (FEV1) (all P < 0.05). Those exposed to both WS and TS had more symptoms and worse airflow limitation (P < 0.001). CONCLUSIONS: This was the first random population-based study showing that WS is an associated risk factor for COPD also in men, and that people exposed to both WS and TS have a significantly higher prevalence of COPD. Similarly, COPD subjects exposed to both types of smoke have more symptoms and greater airflow obstruction. This suggests an additive effect of WS and TS.

CONTEXTE: L'Initiative mondiale pour les maladies pulmonaires obstructives chroniques (Global Initiative for Chronic Obstructive Lung Disease, GOLD) 2023 met en évidence l'importance d'explorer les différents étiotypes de la maladie pulmonaire obstructive chronique (COPD, pour l'anglais « chronic obstructive pulmonary disease ¼) en dehors de la COPD liée au tabagisme. L'exposition à la fumée de bois (WS, pour l'anglais « wood smoke ¼) représente un facteur de risque de la COPD chez les femmes, cependant, l'impact de l'exposition simultanée à la fumée de tabac (TS, pour l'anglais « tobacco smoke ¼) chez la population générale et chez les patients atteints de COPD, ainsi que les caractéristiques spécifiques de la WS-COPD, demeurent peu clairs. MÉTHODES: Il s'agit d'une étude transversale aléatoire basée sur la population (n = 5 539) qui analyse les données de PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude). L'étude se concentre sur l'effet de l'exposition combinée à la WS et à la TS ainsi que sur la caractérisation de la WS-COPD. RÉSULTATS: La prévalence de la COPD était significativement plus élevée chez les personnes exposées à la fois à la WS et à la TS (16,0%) que chez celles exposées uniquement à la WS (6,7%) ou à la TS (7,8%) (P < 0,001). L'exposition à la WS était associée à la COPD chez les hommes (OR 1,53 ; P = 0,017). Les personnes atteintes de WS-COPD étaient plus fréquemment des femmes, d'un âge plus avancé, de plus petite taille et présentaient un volume expiratoire maximal en 1 seconde (FEV1) plus élevé (tous P < 0,05). Les personnes exposées à la fois à la WS et à la TS ont montré plus de symptômes et une plus grande limitation du débit d'air (P < 0,001). CONCLUSION: Il s'agit de la première étude aléatoire basée sur la population qui démontre que la WS est un facteur de risque lié à la COPD, même chez les hommes, et que les individus exposés à la fois à la WS et à la TS présentent une prévalence significativement plus élevée de la COPD. De plus, les personnes souffrant de COPD qui sont exposés aux deux types de fumée manifestent davantage de symptômes et une obstruction pulmonaire plus sévère. Cela laisse supposer qu'il y a un effet cumulatif de la WS et de la TS.

Extrauterine growth restriction in very-low-birthweight infants: prevalence and concordance according to Fenton, Olsen, and INTERGROWTH-21st growth charts in a multicenter Spanish cohort.

Multiple criteria and growth references have been proposed for extrauterine growth restriction (EUGR). We hypothesized that these may impact the diagnosis of EUGR. The objective was to evaluate the prevalence of EUGR with its different definitions and the concordance according to Fenton, Olsen, and INTERGROWTH-21st in very-low-birthweight (VLBW) infants. This is an observational, retrospective, and multicenter study including VLBW infants from the Spanish SEN1500 Network from 2011 to 2020. Patients with major congenital anomalies, embryopathies, and gestational age less than 24 weeks were excluded. EUGR prevalence was calculated at discharge with cross-sectional, longitudinal, "true" cross-sectional, and "true" longitudinal definitions. Concordance was assessed with Fleiss' kappa coefficient. 23582 VLBW infants from 77 NICUs were included. In total, 50.4% were men with a median of gestational age of 29 (4) weeks. The prevalence of EUGR (cross-sectional, longitudinal, and "true") was variable for weight, length, and head circumference. Overall, the prevalence was higher with Fenton and lower with Olsen (cross-sectional and "true" cross-sectional) and INTERGROWTH-21st (longitudinal and "true" longitudinal). Agreement among the charts by weight was good only for cross-sectional EUGR and moderate for longitudinal, "true" cross-sectional, and "true" longitudinal. Concordance was good or very good for EUGR by length and head circumference.Conclusions: The prevalence of EUGR with the most commonly used definitions was variable in the cohort. Agreement among growth charts was moderate for all the definitions of EUGR by weight except cross-sectional and good or very good for length and head circumference. The choice of reference chart can impact the establishment of the diagnosis of EUGR. What is known: • EUGR has been defined in the literature and daily practice considering weight, length and head circumference with multiple criteria (cross-sectional, longitudinal, and "true" definition) • Different growth charts have been used for EUGR diagnosis What is new: • Prevalence of EUGR is variable depending on the definition and growth chart used in our cohort of VLBW infants • For the most frequently EUGR criteria used, traditionally considering weight, concordance among Fenton, Olsen and INTERGROWTH-21st growth charts is only moderate for all the definitions of EUGR by weight except cross-sectional definition. Concordance among the charts is good or very good for the different criteria of EUGR by head circumference and length.

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

Introduction: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the µ-opioid receptor antagonists naloxone and nalmefene. Methods: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Results: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Conclusion: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Enteroblastic adenocarcinoma of the ampulla of Vater / Adenocarcinoma enteroblástico de la ampolla de Vater

Adenocarcinoma with enteroblastic differentiation is a rare histologic subtype of adenocarcinoma of the gastrointestinal tract that shows unique histologic and immunohistochemical features that resemble fetal intestinal epithelium. This histological subtype has been widely described in the stomach, where it most frequently appears, but, in other locations, it is misdiagnosed because of the poor experience in routine diagnostic setting. Here we present a case of an 87-year-old male with an adenocarcinoma of the ampulla of Vater with enteroblastic differentiation with a literature review of the cases described of this subtype in this location to date. The anatomical peculiarity of the ampulla, joined with the infrequent nature of this histological subtype, makes this case of great interest to aid to better characterize the biological behavior of these tumors. (AU)

El adenocarcinoma con diferenciación enteroblástica es un subtipo histológico poco frecuente de adenocarcinoma gastrointestinal que muestra características histológicas e inmunohistoquímicas únicas que se asemejan al epitelio intestinal fetal. Este subtipo histológico ha sido ampliamente descrito en el estómago, donde aparece con mayor frecuencia, pero en otras localizaciones es mal diagnosticado debido a la poca experiencia en el diagnóstico de rutina. Presentamos un caso de un varón de 87 años con adenocarcinoma de ampolla de Vater con diferenciación enteroblástica, junto a una revisión bibliográfica de los casos descritos de este subtipo en esta localización hasta el momento. La peculiaridad anatómica de la ampolla, sumada al carácter poco frecuente de este subtipo histológico, dotan a este caso de gran interés para ayudar a caracterizar mejor el comportamiento biológico de estos tumores. (AU)

Tear Cytokines as Predictive Biomarkers of Success in Contact Lens Discomfort Management.

PURPOSE: To analyze changes in tear levels of inflammatory mediators in symptomatic contact lens (CL) wearers after refitting with daily disposable CLs and to identify potential biomarkers of success in CL discomfort (CLD) management. METHODS: Symptomatic CL wearers (CLDEQ-8 ≥ 12) were refitted (V1) with daily disposable CLs (Delefilcon A). After one month (V2), participants were classified into the post-fitting non-symptomatic (CLDEQ <12) and symptomatic (CLDEQ ≥12) groups. At each visit, the participants were clinically evaluated, tears were collected, and 20 inflammatory mediators and substance P (SP) were measured using multiplex immunobead analysis and ELISA, respectively. The detection rates and concentrations were compared between visits and groups, and logistic regression models were performed. RESULTS: Forty-three subjects (32 women/11 men; mean age: 23.2 ± 4.9 years) were enrolled. The IL-1ß and IL-9 detection rates were higher at V2 (p ≤ 0.044). The detection rates of IL-1ß, IL-9, MIP-1α/CCL3, and MMP-9 at V1 (p ≤ 0.045) and IL-17A at V2 (p ≤ 0.014) were higher in the post-fitting symptomatic group. The tear IL-9 concentration was increased at V2 (p = 0.018). The tear concentrations of fractalkine/CX3CL1, IL-2, IL-6, IL-10, MCP-3/CCL7, MIP-1ß, NGF, RANTES/CCL5, and TNF-α were higher in the post-fitting symptomatic group (p ≤ 0.044). Additionally, levels of fractalkine/CX3CL1, IL-2, IL-6, IL-10, RANTES/CCL5, and TNF-α at V1 were significantly associated with the post-fitting grouping (p ≤ 0.044). CONCLUSIONS: Low tear concentrations of specific inflammatory mediators may be used as a predictive biomarker of success for refitting symptomatic CL wearers with daily disposable CLs. However, complementary treatments might be required for symptomatic CL wearers with higher levels of these inflammatory molecules.

Autotrophic adaptive laboratory evolution of the acetogen Clostridium autoethanogenum delivers the gas-fermenting strain LAbrini with superior growth, products, and robustness.

Microbes able to convert gaseous one-carbon (C1) waste feedstocks are increasingly important to transition to the sustainable production of renewable chemicals and fuels. Acetogens are interesting biocatalysts since gas fermentation using Clostridium autoethanogenum has been commercialised. However, most acetogen strains need complex nutrients, display slow growth, and are not robust for bioreactor fermentations. In this work, we used three different and independent adaptive laboratory evolution (ALE) strategies to evolve the wild-type C. autoethanogenum to grow faster, without yeast extract and to be robust in operating continuous bioreactor cultures. Multiple evolved strains with improved phenotypes were isolated on minimal media with one strain, named "LAbrini", exhibiting superior performance regarding the maximum specific growth rate, product profile, and robustness in continuous cultures. Whole-genome sequencing of the evolved strains identified 25 mutations. Of particular interest are two genes that acquired seven different mutations across the three ALE strategies, potentially as a result of convergent evolution. Reverse genetic engineering of mutations in potentially sporulation-related genes CLAU_3129 (spo0A) and CLAU_1957 recovered all three superior features of our ALE strains through triggering significant proteomic rearrangements. This work provides a robust C. autoethanogenum strain "LAbrini" to accelerate phenotyping and genetic engineering and to better understand acetogen metabolism.

Biodegradation behaviour of pharmaceutical compounds and selected metabolites in activated sludge. A forecasting decision system approach.

Society's support upon chemicals over the last few decades has led to their increased production, application and discharge into the environment. Wastewater treatment plants (WWTPs) contain a multitude of these chemicals such us; pharmaceutical compounds (PCs). Often, their biodegradability by activated sludge microorganisms is significant for their elimination during wastewater treatment. In this paper the focus is laid on two PCs carbamazepine (CBZ) and diclofenac (DCF) and their main transformation products (TPs). Laboratory degradation tests with these two pharmaceuticals using activated sludge as inoculum under aerobic conditions were performed and microbial metabolites were analyzed by liquid chromatography-mass spectrometry (LC/MS-MS). In two different Mixed liquid Suspended Solids (MLSS) concentrations the biodegradability by activated sludge of CBZ and DCF were evaluated. Also, this article proposes a decision support system to optimize the prediction process of this type of pharmacological compounds. A study and analysis of the techniques of Support Vector Machine, Random Forest, Decision Trees and Multilayer Perceptron Network is carried out to select the most reliable and accurate predictor for the decision system. There are not significant differences in the removal of DCF with 30 mg MLSS/L and 60 mg MLSS/L. DCF was better removed than CBZ in all experiments studied. The TP detected in the samples were mainly 4-OH-DCF for DCF and 10, 11 EPOXICBZ for CBZ. The results show that the best models are obtained with Random Forest and Multilayer Perceptron Network techniques, with a model fit of more than 95% for both carbamazepine and diclofenac metabolites. Obtaining a root means square errors of 0.80 µg/L for the metabolite 4-OH-DCF for DCF with the technique Random Forest and a root means square errors of 1.13 µg/L for the metabolite 10, 11 EPOXICBZ for CBZ with the Multilayer Perceptron Network technique. Supplementary Information: The online version contains supplementary material available at 10.1007/s40201-023-00890-x.

RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction.

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.

Consensus Report and Recommendations on the Management of Late-stage Internal Derangement of the Temporomandibular Joint.

Introduction: This report investigates late-stage internal derangement (ID) of the temporomandibular joint (TMJ) with the aim of establishing a more effective and personalized treatment protocol to improve patients' quality of life (QoL). Material and methods: A consensus was reached among maxillofacial surgeons specializing in LSID, based on a literature research and collective expert experience following the Delphi method. Consensus was considered to be achieved when a response received at least 80% of votes. Results: Four expert groups were established, respectively, focusing on diagnosis, minimally invasive surgery (MIS), open surgery and joint replacement. A comprehensive approach to late-stage ID of the TMJ requires a consensus report. This underscores the need for a personalized treatment plan, considering the variability in clinical presentations and progression of this pathology. Our recommendations aim to optimize clinical outcomes and enhance patient QoL.

Two rhenium compounds with benzimidazole ligands: synthesis and DNA interactions.

Two rhenium compounds: cis-tetrachlorotetrabenzimidazoldirhenium(iii) chloride - I and tetrabenzimidazoldioxorhenium(v) - II have been synthesized and characterized. X-ray data are presented for the new complex II. I and II show strong emission that has been used to investigate their interaction with several non-canonical DNA structures. Both compounds have a quenching effect on the fluorescence intensity upon addition of the investigated oligonucleotides; I was more selective for binding G4-than II. Association constant values obtained for I and II with G-quadruplexes reached 106 M-1, which suggests a strong interaction between both complexes and these sequences. FRET-melting assays show that I and II have a rather high level of stabilization of ckit1 and ckit2 quadruplexes. I is toxic against macrophages RAW267.7 only in high concentrations, while complex II shows no toxicity against these cells. I and II accumulate inside cells in different degrees. Molecular dynamic simulation studies have provided insights into the binding modes of II with ckit1 and ckit2 G-quadruplexes. The results obtained show the DNA binding activity of the rhenium complexes and their ability to be players in the anti-cancer fight since they can bind to non-canonical DNA forms in oncogene promoters, accumulate in some cancer cells, and influence the cancer cells microenvironment.

Toward the European Health Data Space: The IMPaCT-Data secure infrastructure for EHR-based precision medicine research.

BACKGROUND: Art. 50 of the proposal for a Regulation on the European Health Data Space (EHDS) states that "health data access bodies shall provide access to electronic health data only through a secure processing environment, with technical and organizational measures and security and interoperability requirements". OBJECTIVE: To identify specific security measures that nodes participating in health data spaces shall implement based on the results of the IMPaCT-Data project, whose goal is to facilitate the exchange of electronic health records (EHR) between public entities based in Spain and the secondary use of this information for precision medicine research in compliance with the General Data Protection Regulation (GDPR). DATA AND METHODS: This article presents an analysis of 24 out of a list of 72 security measures identified in the Spanish National Security Scheme (ENS) and adopted by members of the federated data infrastructure developed during the IMPaCT-Data project. RESULTS: The IMPaCT-Data case helps clarify roles and responsibilities of entities willing to participate in the EHDS by reconciling technical system notions with the legal terminology. Most relevant security measures for Data Space Gatekeepers, Enablers and Prosumers are identified and explained. CONCLUSION: The EHDS can only be viable as long as the fiduciary duty of care of public health authorities is preserved; this implies that the secondary use of personal data shall contribute to the public interest and/or to protect the vital interests of the data subjects. This condition can only be met if all nodes participating in a health data space adopt the appropriate organizational and technical security measures necessary to fulfill their role.

Diagnostic Challenges in Aortic Stenosis.

Aortic stenosis (AS) is the most prevalent degenerative valvular disease in western countries. Transthoracic echocardiography (TTE) is considered, nowadays, to be the main imaging technique for the work-up of AS due to high availability, safety, low cost, and excellent capacity to evaluate aortic valve (AV) morphology and function. Despite the diagnosis of AS being considered straightforward for a very long time, based on high gradients and reduced aortic valve area (AVA), many patients with AS represent a real dilemma for cardiologist. On the one hand, the acoustic window may be inadequate and the TTE limited in some cases. On the other hand, a growing body of evidence shows that patients with low gradients (due to systolic dysfunction, concentric hypertrophy or coexistence of another valve disease such as mitral stenosis or regurgitation) may develop severe AS (low-flow low-gradient severe AS) with a similar or even worse prognosis. The use of complementary imaging techniques such as transesophageal echocardiography (TEE), multidetector computed tomography (MDTC), or cardiac magnetic resonance (CMR) plays a key role in such scenarios. The aim of this review is to summarize the diagnostic challenges associated with patients with AS and the advantages of a comprehensive multimodality cardiac imaging (MCI) approach to reach a precise grading of the disease, a crucial factor to warrant an adequate management of patients.

Towards a survival risk prediction model for metastatic NSCLC patients on durvalumab using whole-lung CT radiomics.

Background: Existing criteria for predicting patient survival from immunotherapy are primarily centered on the PD-L1 status of patients. We tested the hypothesis that noninvasively captured baseline whole-lung radiomics features from CT images, baseline clinical parameters, combined with advanced machine learning approaches, can help to build models of patient survival that compare favorably with PD-L1 status for predicting 'less-than-median-survival risk' in the metastatic NSCLC setting for patients on durvalumab. With a total of 1062 patients, inclusive of model training and validation, this is the largest such study yet. Methods: To ensure a sufficient sample size, we combined data from treatment arms of three metastatic NSCLC studies. About 80% of this data was used for model training, and the remainder was held-out for validation. We first trained two independent models; Model-C trained to predict survival using clinical data; and Model-R trained to predict survival using whole-lung radiomics features. Finally, we created Model-C+R which leveraged both clinical and radiomics features. Results: The classification accuracy (for median survival) of Model-C, Model-R, and Model-C+R was 63%, 55%, and 68% respectively. Sensitivity analysis of survival prediction across different training and validation cohorts showed concordance indices ([95 percentile]) of 0.64 ([0.63, 0.65]), 0.60 ([0.59, 0.60]), and 0.66 ([0.65,0.67]), respectively. We additionally evaluated generalization of these models on a comparable cohort of 144 patients from an independent study, demonstrating classification accuracies of 65%, 62%, and 72% respectively. Conclusion: Machine Learning models combining baseline whole-lung CT radiomic and clinical features may be a useful tool for patient selection in immunotherapy. Further validation through prospective studies is needed.

Mechanically Robust, Inkjet-Printable Polymer Nanocomposites with Hybrid Gold Nanoparticles and Metal-like Conductivity.

Hybrid core-shell nanoparticles with metal cores and conductive polymer shells yield materials that are sinter-free and highly conductive but mechanically weak. Conventional composites of such nanoparticles are electrically insulating. Here, we introduce microscale phase-separated nanocomposites of hybrid gold-PEDOT:PPS particles in insulating poly(vinyl alcohol) (PVA). They combine electrical conductivities of up to 2.1 × 105 S/m at 10 vol % PVA with increased mechanical adhesion on polyethylene terephthalate and glass substrates. We studied the effects of the PVA molecular weight, hydrolyzation degree, and volume fraction. Composites with 10 vol % highly hydrolyzed PVA at a MW of 89-98 kDa had the highest conductivities and stabilities; highly hydrolyzed PVA even increased the conductivity of the hybrid particle layers. We propose the formation of hydrogen bonds between PVA and PEDOT:PSS that lead to demixing and the formation of stable, structured composites. Finally, we demonstrated the inkjet-printability of inks containing PVA in water with viscosities of 1.6-2.0 Pa s at 50.1 s-1 and prepared bending-resistant electrical leads.