Testing the Aquatic Toxicity of 2D Few-Layer Graphene Inks Using Rainbow Trout (Oncorhynchus mykiss): In Vivo and In Vitro Approaches to Support an SSbD Assessment.

Graphene-based conductive inks offer attractive possibilities in many printing technology applications. Often, these inks contain a mixture of compounds, such as solvents and stabilizers. For the safe(r) and sustainable use of such materials in products, potentially hazardous components must be identified and considered in the design stage. In this study, the hazards of few-layer graphene (FLG)-based ink formulations were tested in fish using in vitro (RTL-W1 cell line) and in vivo aquatic ecotoxicity tests (OECD TG 203). Five ink formulations were produced using different processing steps, containing varying amounts of solvents and stabilizers, with the end products formulated either in aqueous solutions or in powder form. The FLG ink formulations with the highest contents of the stabilizer sodium deoxycholate showed greater in vitro cytotoxic effects, but they did not provoke mortality in juvenile rainbow trout. However, exposure led to increased activities of the cytochrome P450 1a (Cyp1a) and Cyp3a enzymes in the liver, which play an essential role in the detoxification of xenobiotics, suggesting that any effects will be enhanced by the presence of the stabilizers. These results highlight the importance of an SSbD approach together with the use of appropriate testing tools and strategies. By incorporating additional processing steps to remove identified cytotoxic residual solvents and stabilizers, the hazard profile of the FLG inks improved, demonstrating that, by following the principles of the European Commission's safe(r) and sustainable by design (SSbD) framework, one can contribute to the safe(r) and sustainable use of functional and advanced 2D materials in products.

Toxic Effects of Different Coating-Related Functionalized Nanoparticles on Aquatic Organisms.

The peculiar physico-chemical characteristics of nanomaterials (NMs) and the use of different coatings to improve their expected properties result in a huge amount of nanoforms, which vary in chemical composition, size, shape and surface characteristics. This makes it almost impossible to test all the nanoforms available, and efforts have been made to establish grouping or read-across strategies. The aim of this work was to find a behavior pattern of effect among nanoforms of different metallic core nanoparticles (NPs) (TiO2, CeO2 and Ag NP) with the same coatings (sodium citrate, poly (ethylene glycol), dodecylphosphonic acid or oleylamine). Daphnia magna, rainbow trout and two fish cell lines (PLHC-1 and RTH-149) were exposed to a range of concentrations (up to 100 mg/L) of the uncoated or coated NPs. Ag NPs were the most toxic, followed by CeO2 NPs and finally by TiO2 NPs. The results show that a clear pattern of toxicity in the studied species could not be established related to the coatings. However, it was possible to confirm different inter-species sensitivities. RTH-149 was the most sensitive cell line, and Daphnia magna was more sensitive than fish. Moreover, some differences in coating-core interactions were found between the metal oxide and the metal NPs in Daphnia magna.

Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective.

Two-dimensional (2D) materials have attracted tremendous interest ever since the isolation of atomically thin sheets of graphene in 2004 due to the specific and versatile properties of these materials. However, the increasing production and use of 2D materials necessitate a thorough evaluation of the potential impact on human health and the environment. Furthermore, harmonized test protocols are needed with which to assess the safety of 2D materials. The Graphene Flagship project (2013-2023), funded by the European Commission, addressed the identification of the possible hazard of graphene-based materials as well as emerging 2D materials including transition metal dichalcogenides, hexagonal boron nitride, and others. Additionally, so-called green chemistry approaches were explored to achieve the goal of a safe and sustainable production and use of this fascinating family of nanomaterials. The present review provides a compact survey of the findings and the lessons learned in the Graphene Flagship.

Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors. METHODS: This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC. RESULTS: Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed. CONCLUSIONS: The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier. TRIAL REGISTRATION NUMBER: NCT03953560.

Fish acute toxicity of nine nanomaterials: Need of pre-tests to ensure comparability and reuse of data.

Fish acute toxicity tests are commonly used in aquatic environmental risk assessments, being required in different international substances regulations. A general trend in the toxicity testing of nanomaterials (NMs) has been to use standardized aquatic toxicity tests. However, as these tests were primarily developed for soluble chemical, issues regarding particle dissolution, agglomeration or sedimentation during the time of exposure are not considered when reporting the toxicity of NMs. The aim of this study was to characterize the NM behaviour throughout the fish acute test and to provide criteria to assay the toxicity of nine NMs based on TiO2, ZnO, SiO2, BaSO4, bentonite, and carbon nanotubes, on rainbow trout following OECD Test Guideline (TG) nº203. Our results showed the importance of conducting a preliminary test (without fish) when working with NMs. They provide valuable information on, sample monitoring, agglomeration, sedimentation, dissolution, actual concentrations of NMs, needed to design the test. Among the NMs tested, only bentonite nanoparticles were stable during the 96-h pre-test and test in aquarium water. In contrast, the remaining NMs exhibited considerable loss and sedimentation within the first 24 h. The high sedimentation observed for almost all NMs highlights the need of consistently measuring the concentrations throughout the entire duration of the fish acute toxicity test to make reliable concentration-response relationships. Notable differences emerged in LC50 values when using actual concentrations as nominal concentrations overestimated concentrations by up to 85.6%. Among all NMs tested, only ZnO NMs were toxic to rainbow trout. A flow chart was specifically developed for OECD TG 203, aiding users in making informed decisions regarding the selection of test systems and necessary modifications to ensure accurate, reliable, and reusable toxicity data. Our findings might contribute to the harmonization of TG 203 improving result reproducibility and interpretability and supporting the development of read-across and QSAR models.

Short- and long-term outcomes of subtotal ear canal ablation and lateral bulla osteotomy in French bulldogs.

The objective of this retrospective study was to report the overall peri-operative complications and short- to long-term outcomes of subtotal ear canal ablation and lateral bulla osteotomy in French bulldogs with otitis media. Medical records from 2018 to 2021 were reviewed for preoperative neurological signs, surgical technique, postoperative complications, and long-term outcomes. Postoperative complications, such as a head tilt, nystagmus, ataxia, facial nerve dysfunction, as well as skin or wound infection, were recorded. Eighteen client-owned dogs (20 ears) were included in the study. Postoperative complications were observed in 5/18 dogs (6/20 ears) with 2 of them being considered major complications. Referring veterinarians and owner telephone follow-up (mean: 33 mo, range: 17 to 56 mo) were obtained for all patients. Total recovery was reported in 9/18 dogs (11/20 ears) with a postoperative improvement of the vestibular signs and facial nerve paresis within 8 wk. All dogs maintained the pinnas' natural, erect morphology, and movement.

L'objectif de cette étude rétrospective était de rapporter les complications peropératoires globales et les résultats à court et à long terme de l'ablation subtotale du conduit auditif et de l'ostéotomie de la bulle latérale chez les bouledogues français atteints d'otite moyenne. Les dossiers médicaux de 2018 à 2021 ont été examinés pour les signes neurologiques préopératoires, la technique chirurgicale, les complications postopératoires et les résultats à long terme. Les complications postopératoires, telles qu'une inclinaison de la tête, un nystagmus, une ataxie, un dysfonctionnement du nerf facial, ainsi qu'une infection de la peau ou des plaies, ont été enregistrées. Dix-huit chiens de propriétaires (20 oreilles) ont été inclus dans l'étude. Des complications postopératoires ont été observées chez 5/18 chiens (6/20 oreilles) dont 2 ont été considérées comme des complications majeures. Les vétérinaires référents et le suivi téléphonique des propriétaires (moyenne : 33 mois, intervalle : 17 à 56 mois) ont été obtenus pour tous les patients. Une récupération totale a été rapportée chez 9/18 chiens (11/20 oreilles) avec une amélioration postopératoire des signes vestibulaires et une parésie du nerf facial en 8 semaines. Tous les chiens ont conservé la morphologie et le mouvement naturels et dressés des pinnas.(Traduit par Docteur Serge Messier).

The Potentiating Effect of Graphene Oxide on the Arylhydrocarbon Receptor (AhR)-Cytochrome P4501A (Cyp1A) System Activated by Benzo(k)fluoranthene (BkF) in Rainbow Trout Cell Line.

The increasing use of graphene oxide (GO) will result in its release into the environment; therefore, it is essential to determine its final fate and possible metabolism by organisms. The objective of this study was to assess the possible role of the aryl hydrocarbon receptor (AhR)-dependent cytochrome P4501A (Cyp1A) detoxification activities on the catabolism of GO. Our hypothesis is that GO cannot initially interact with the AhR, but that after an initial degradation caused by other mechanisms, small fractions of GO could activate the AhR, inducing Cyp1A. The environmental pollutant benzo(k)fluoranthene (BkF) was used for the initial activation of the AhR in the rainbow trout (Oncorhynchus mykiss) cell line RTL-W1. Pre-, co-, and post-exposure experiments with GO were performed and Cyp1A induction was monitored. The strong stimulation of Cyp1A observed in cells after exposure to GO, when BkF levels were not detected in the system, suggests a direct action of GO. The role of the AhR was confirmed by a blockage of the observed effects in co-treatment experiments with αNF (an AhR antagonist). These results suggest a possible role for the AhR and Cyp1A system in the cellular metabolism of GO and that GO could modulate the toxicity of environmental pollutants.

Severity and Changes in OCD Dimensions during COVID-19: A Two-Year Longitudinal Study.

BACKGROUND: The COVID-19 pandemic appears to be associated with a worsening of obsessive-compulsive symptoms in both young people and adults with OCD and it is necessary to analyze the variables involved in this worsening over time. The main aim of this study was to examine long-term changes in total severity and obsessive-compulsive dimensions in obsessive-compulsive patients during the COVID-19 pandemic. METHOD: A total 250 OCD patients were selected from various associations, clinical centers and hospitals. We discarded 75 as they did not meet the inclusion criteria. A total of 175 obsessive-compulsive participants aged between 16 and 58 years old (M = 33.33, SD = 9.42) were evaluated in obsessive-compulsive symptom severity and dimensions OCD assessed using the Y-BOCS and D-YBOCS scales in T1 (April-June 2020) and in T2 (March-April 2022). The evaluation was carried out through an online survey and face-to-face with a professional clinician at both time points. RESULTS: Intragroup differences in severity were observed, reaching higher scores for patients with contamination, somatic, aggressive and religious. Some patients changed their main dimension, increasing the percentage of patients with contamination and somatic obsessions. CONCLUSIONS: COVID-19 was associated with both changes in severity and also affected some dimensions more than others, particularly those related to the virus itself (contamination and somatic).

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Pancreatic panniculitis revisited: A series of 34 patients.

BACKGROUND: Pancreatic panniculitis is a rare form of panniculitis generally associated with acute or chronic pancreatitis, and less frequently with pancreatic carcinoma. Clinically, it presents with subcutaneous nodules usually located in the lower extremities, however, it presents an almost pathognomonic histopathological finding with enzymatic fat necrosis in the adipose tissue. METHODS: In this retrospective case series of five hospitals, biopsy specimens of cutaneous lesions of pancreatic panniculitis were reviewed. Clinical information was obtained through medical records. RESULTS: A total of 34 cases were included, 23 women and 11 men, aged between 31 and 92 years. The most common associated pancreatic disease was acute pancreatitis (23 cases) and its main triggering cause was gallstones (17 cases). In two patients it was related to chronic pancreatitis and six cases were associated with malignancy. Histopathological findings were always the key to diagnosis. In the biopsies reviewed, mostly lobular panniculitis with the characteristic necrosis of the adipocytes was observed. In addition, nine of the cases presented with Splendore-Hoeppli phenomenon. CONCLUSIONS: We present the largest series of pancreatic panniculitis. Clinically, the female predominance and biliary lithiasis as the main cause of acute pancreatitis are to be emphasized. Histopathologically, a peripheral eosinophilic striated rim surrounding aggregates of ghost adipocytes consistent with Splendore-Hoeppli is an additional clue to its diagnosis.

Comparison of National Surgical Quality Improvement Program Surgical Risk Calculator and Trauma and Injury Severity Score Risk Assessment Tools in Predicting Outcomes in High-Risk Operative Trauma Patients.

BACKGROUND: The Trauma and Injury Severity Score (TRISS) uses anatomic/physiologic variables to predict outcomes. The National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP-SRC) includes functional status and comorbidities. It is unclear which of these tools is superior for high-risk trauma patients (American Society of Anesthesiologists Physical Status (ASA-PS) class IV or V). This study compares risk prediction of TRISS and NSQIP-SRC for mortality, length of stay (LOS), and complications for high-risk operative trauma patients. METHODS: This is a prospective study of high-risk (ASA-PS IV or V) trauma patients (≥18 years-old) undergoing surgery at 4 trauma centers. We compared TRISS vs NSQIP-SRC vs NSQIP-SRC + TRISS for ability to predict mortality, LOS, and complications using linear, logistic, and negative binomial regression. RESULTS: Of 284 patients, 48 (16.9%) died. The median LOS was 16 days and number of complications was 1. TRISS + NSQIP-SRC best predicted mortality (AUROC: .877 vs .723 vs .843, P = .0018) and number of complications (pseudo-R2/median error (ME) 5.26%/1.15 vs 3.39%/1.33 vs 2.07%/1.41, P < .001) compared to NSQIP-SRC or TRISS, but there was no difference between TRISS + NSQIP-SRC and NSQIP-SRC with LOS prediction (P = .43). DISCUSSION: For high-risk operative trauma patients, TRISS + NSQIP-SRC performed better at predicting mortality and number of complications compared to NSQIP-SRC or TRISS alone but similar to NSQIP-SRC alone for LOS. Thus, future risk prediction and comparisons across trauma centers for high-risk operative trauma patients should include a combination of anatomic/physiologic data, comorbidities, and functional status.

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype.

Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95-19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27-547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22-438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91-0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01-9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45-79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12-117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52-519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14-142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94-89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77-804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88-0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31-100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01-9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study. / Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA.

OBJECTIVES: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications. MATERIAL AND METHODS: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. RESULTS: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). CONCLUSION: ED treatment of SVT varies and is often suboptimal. The incidence of thromboembolic complications after SVT is high. Starting anticoagulation in the ED delays the development of complications. Patients with a history of thromboembolic disease are more at risk of complications.

OBJETIVO: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. METODO: El estudio multicentrico (18 SUH) ALTAMIRA (fActores de riesgo, compLicaciones y evaluación del manejo de la TVS de Miembros Inferiores en hospitales españoles atendidos en los seRvicios de urgenciAs) creó un cohorte retrospectivo de pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. RESULTADOS: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1%) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6%). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). CONCLUSIONES: El tratamiento en urgencias de la TVS aislada es heterogéneo y con frecuencia subóptimo. La incidencia de complicaciones de ETV es elevada. El tratamiento anticoagulante iniciado en urgencias supone un retraso en el desarrollo de complicaciones. Los pacientes con ETV previa tienen más riesgo de complicaciones.

Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA / Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study

Objetivos: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. Métodos: Estudio de cohorte retrospectivo, multicéntrico (18 SUH), que incluyó pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. Resultados: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1 %) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6 %). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). (AU)

Objectives: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications.Methods: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. Results: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). (AU)

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.

Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review.

The objective of this systematic review was to provide a compilation of all the literature available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in accordance with the PRISMA guidelines. It included all the literature published up to 1 November 2022 and was carried out in four databases (Medline [PubMed], Scopus, Web of Science, and Embase), using the PICO strategy, with relevant keywords related to the objective. The quality of the studies included was evaluated with an assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI (rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC. The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the available evidence concerning the association between 13 SNPs in the main genes involved in the vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1, CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains sparse for each of the polymorphisms examined, so these findings should be treated with caution.

Association between Single Nucleotide Polymorphisms Related to Vitamin D Metabolism and the Risk of Developing Asthma.

Asthma is a chronic non-communicable disease that affects all age groups. The main challenge this condition poses is its heterogeneity. The role of vitamin D in asthma has aroused great interest, correlating low vitamin D levels and polymorphisms in the genes involved in its metabolic pathway with the risk of asthma. The aim of this study was to evaluate the influence of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolism on the susceptibility to asthma. An observational case-control study was performed, including 221 patients with asthma and 442 controls of Caucasian origin from southern Spain. The SNPs CYP24A1 (rs6068816, rs4809957), CYP27B1 (rs10877012, rs4646536, rs703842, rs3782130), GC (rs7041), CYP2R1 (rs10741657) and VDR (ApaI, BsmI, FokI, Cdx2, TaqI) were analyzed by real-time PCR, using TaqMan probes. The logistic regression model adjusted for body mass index revealed that in the genotype model, carriers of the Cdx2 rs11568820-AA genotype were associated with a higher risk of developing asthma (p = 0.005; OR = 2.73; 95% CI = 1.36-5.67; AA vs. GG). This association was maintained in the recessive model (p = 0.004). The haplotype analysis revealed an association between the ACTATGG haplotype and higher risk of asthma for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130 and rs10877012 genetic polymorphisms (p = 0.039). The other SNPs showed no effect on risk of developing asthma. The Cdx2 polymorphism was significantly associated with the susceptibility of asthma and could substantially act as a predictive biomarker of the disease.

Impact of Omalizumab in Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Most patients with asthma can control their symptoms with a basic standard of medical care and with maintenance and rescue medication. However, between 5% and 10% of asthmatics worldwide do not achieve control of their symptoms and have recurrent exacerbations and respiratory difficulties. The objective of the study was the real-life evaluation of the clinical improvement of patients with severe eosinophilic asthma treated with omalizumab, together with the search for biomarkers associated with the response. An observational retrospective cohort study was conducted that included patients with severe uncontrolled allergic asthma being treated with omalizumab. Three types of response were evaluated: lower use of oral corticosteroids, improvement in lung function, and reduction in exacerbations. A total of 110 patients under treatment with omalizumab were included, with a mean age of 48 ± 16 years. After 12 months had elapsed, significant reductions were found in the number of exacerbations, use of oral cortico-steroids and doses of inhaled corticosteroids (p < 0.001). Lung function and asthma control improved significantly (p < 0.001; p = 0.004) and eosinophil levels were significantly reduced (p = 0.004). Low scores in the Asthma Control Test were associated with the oral corticosteroid-saving effect; lower previous FEV1 levels and absence of chronic obstructive pulmonary disease (COPD) were related to improvement in lung function, and prior FEV1 values higher than 80% and absence of gastroesophageal reflux disease (GERD) with a reduction in exacerbations. The results of this study confirm the clinical benefit obtained after the introduction of omalizumab and the possible predictive biomarkers of response to the treatment.

Impact of Anti-IL5 Therapies on Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Severe Uncontrolled Asthma (SUA) counts for more than 25% of cases of severe asthma. The main factors that impair the quality of life of these patients are high doses of oral corticosteroids, the presence of exacerbations, and reduced lung function. The objective of this study was to evaluate, in real life, the clinical improvement of patients with SUA treated with anti-interleukin 5 (IL5) therapies: mepolizumab and benralizumab, together with the search for biomarkers associated with the response. We conducted a retrospective observational cohort study that included patients with severe uncontrolled eosinophilic asthma in a tertiary hospital receiving biological therapies. Three types of response were evaluated: improvement in lung function, reduction in exacerbations, and decrease in the use of oral corticosteroids. After 12 months of treatment, significant reductions were found in the number of exacerbations, the use of oral corticosteroids, and blood eosinophil levels for both biological therapies (p < 0.001). Lung function improved, achieving a significant improvement in %FEV1 (p < 0.001), as well as asthma control, with a significant increase in asthma control test (ACT) scores in both therapies. The markers associated with the corticosteroid-saving effect were the low doses of oral corticosteroids and absence of exacerbations for mepolizumab, and higher blood eosinophilia, absence of chronic obstructive pulmonary disease (COPD), and reduction in oral corticosteroid cycles for benralizumab. The greatest improvement in lung function in both therapies was linked to lower previous FEV1 levels and absence of other respiratory diseases. The reduction in exacerbations was associated with absence of exacerbations the previous year for mepolizumab and never smokers for benralizumab. The results of this real-life study confirm the clinical benefit obtained after the introduction of an anti-IL5 biological therapy and the possible predictive biomarkers of response to treatment.

Towards harmonisation of testing of nanomaterials for EU regulatory requirements on chemical safety - A proposal for further actions.

Over the recent years, EU chemicals legislation, guidance and test guidelines have been developed or adapted for nanomaterials to facilitate safe use of nanomaterials. This paper provides an overview of the information requirements across different EU regulatory areas. For each information requirement, a group of 22 experts identified potential needs for further action to accommodate guidance and test guidelines to nanomaterials. Eleven different needs for action were identified, capturing twenty-two information requirements that are specific to nanomaterials and relevant to multiple regulatory areas. These were further reduced to three overarching issues: 1) resolve issues around nanomaterial dispersion stability and dosing in toxicity testing, in particular for human health endpoints, 2) further develop tests or guidance on degradation and transformation of organic nanomaterials or nanomaterials with organic components, and 3) further develop tests and guidance to measure (a)cellular reactivity of nanomaterials. Efforts towards addressing these issues will result in better fit-for-purpose test methods for (EU) regulatory compliance. Moreover, it secures validity of hazard and risk assessments of nanomaterials. The results of the study accentuate the need for a structural process of identification of information needs and knowledge generation, preferably as part of risk governance and closely connected to technological innovation policy.