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Purpose: To determine the incidence of VTE and clinical outcomes in a cohort of cancer patients and COVID-19 infection, and to establish possible predictive factors of VTE., Methods/patients: A single-center retrospective cohort study was performed to determine the incidence of VTE and mortality in 118 cancer patients with SARS-CoV-2 infection from March to August 2020. We calculated individual Khorana Risk and CATS-MICA scores in order to evaluate their utility to identify risk of VTE or death. Continuous variables were compared using Wilcoxon or Student's T test, and categorical variables were compared using the Chi-Square or Fisher's exact text among patients with and without VTE. A Log-Rank test was performed to detect mortality differences between the groups., Results: A total of 118 patients were included. VTE global incidence was 4.2% (n = 5), and mortality 25.4% (n = 30). Obesity (p = 0.05), recent chemotherapy (p = 0.049) and use of steroids (p = 0.006) were related to higher risk of VTE in the univariate analysis, although they were not confirmed in the multivariate analysis as independent risk factors. Statistically significant differences in all-cause, COVID-19-related and cancer-related mortality according to the Khorana risk score (KRS) were observed. CATS-MICA score (CMS) also showed statistically significant differences in mortality between low- and high-risk patients. Prediction of risk of VTE development with these scores showed a tendency towards significance., Conclusions: In this cohort, VTE incidence was similar to previously reported in the general population with SARS-CoV-2 infection. KRS was associated with overall and specific-cause mortality, and might be a useful prognostic tool in this setting., Competing Interests: Declarations. Conflict of interest: MMAJ declares consulting or advisory role: Celgene, Sanof, Pfzer, Bristol-Myers Squibb, LEO Pharma, Daiichi Sankyo, Bayer, Halozyme; speakers’ bureau: Rovi; research funding: Sanof, LEO Pharma and patents, royalties, other intellectual property: risk assessment model in venous thromboembolism in patients with cancer. OML has participated as speaker in meetings sponsored by Leo Pharma, Rovi, Menarivi, Servier. MM reports honoraria from SeaGen, Lilly, AstraZeneca, Pfizer, Daiichi Sankyo, Roche; consulting fees from Roche, Novartis, AstraZeneca, Daiichi Sankyo, SeaGen, Lilly, Sanofi; advisory board of Novartis and holds leadership roles in GEICAM (Board of Directors), TRIO. LJC, GA, JDS, SAJ, CVJL, BAC and MB declare no conflict of interests. Ethical approval: The study has been performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments. This study is an observational, non-interventionist trial. Informed consent: Signed informed consent was obtained from all the patients., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background : Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of approximately 13% for advanced stages. While the majority of PDAC cases are sporadic, a significant subset is attributable to hereditary and familial predispositions, accounting for approximately 25% of cases. This article synthesizes recent advancements in the understanding, detection, and management of hereditary pancreatic cancer (PC). Results : Our review highlights the critical role of genetic testing (GT) in identifying high-risk individuals (HRIs), with germline pathogenic variants (PVs) found in up to 20% of hereditary PDAC cases. Since the implementation of next-generation sequencing (NGS) panels in 2014, detection capabilities have been significantly enhanced. HRIs can be included in screening programs that facilitate the early detection of PDAC. Early detection strategies, including the use of microribonucleic acid (miRNAs) signatures and novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) have shown promising results. The identification of germline pathogenic variants (PVs) or mutations in homologous recombination (HR) genes plays a predictive role in the response to various treatments, prolonging patient survival. Discussion : Universal germline testing for PDAC, as recommended by the National Comprehensive Cancer Network (NCCN), is now a standard practice, facilitating the identification of at-risk individuals and enabling targeted surveillance and intervention. Multidisciplinary management, integrating genetic counseling, imaging, and gastrointestinal services, is essential for optimizing outcomes. Conclusions : Advances in genetic testing and biomarker research are transforming the landscape of hereditary PC management. Early detection and personalized treatment strategies are pivotal in improving survival rates. Ongoing multi-institutional research efforts are crucial for validating biomarkers and developing preventive measures, ultimately aiming to reduce the burden of this aggressive cancer.

Introduction: Currently, the status of serological screening for toxoplasmosis in pregnant women in Spain is unknown, and there is no official recommendation. The objective of this study is to show the current practice of gestational screening for toxoplasmosis in hospitals belonging to the Spanish Network for Research on Congenital Toxoplasmosis (REIV-TOXO)., Methods: An electronic survey was sent between April 2021 and September 2021 to investigators from 118 hospitals of REIV-TOXO, representing all Spanish regions. Nine items related to gestational screening for toxoplasmosis were collected. This information was compared with cases of congenital toxoplasmosis (CT) identified in REIV-TOXO to determine if these were diagnosed in the presence of gestational screening., Results: During the study period, serological screening was performed in 53.3% (63/118) hospitals, with variations between regions and even among hospitals within the same region. Testing performed in each trimester was the most common practice (57.7%), followed by a single determination (24.4%). 89.4% of CT cases between January 2015 and September 2021 were diagnosed due to gestational screening., Conclusion: The decision to perform gestational screening for toxoplasmosis in Spain is highly heterogeneous, with significant local and regional differences. Despite this, screening still allows the diagnosis of most CT cases. It is urgent to have current epidemiological data to inform decision-making in public health., (Copyright © 2023 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Some regions of Spain are withdrawing their pregnancy screening program for congenital toxoplasmosis (CT). The Spanish Research Network of Congenital Toxoplasmosis (REIV-TOXO) was created to describe the current status of CT in Spain. The aims of this study were to describe the epidemiological and clinical characteristics of CT and to evaluate the effect of prenatal treatment on clinical outcomes to inform decision-making policies., Methods: Ambispective observational study including CT cases recorded in the REIV-TOXO database that includes 122 hospitals (2015-2022). Inclusion criteria were one or more of the following: positive PCR in maternal amniotic fluid; positive Toxoplasma gondii-specific IgM or IgA antibodies at birth; positive PCR in the placenta, newborn blood, urine or CSF; increase of specific IgG levels during infant follow-up; or specific IgG persistence beyond age 12 months., Findings: Fifty-six newborns (54 pregnancies) were included. Prenatal screening allowed 92.8% of cases to be identified. The time of maternal infection was well documented in 90.7% of cases, with 61.1% occurring in the third trimester. A total of 66.6% (36/54) pregnant women received antiparasitic treatment: 24/36 spiramycin, 8/36 pyrimethamine, sulfadiazine, and folinic acid, and 4/36 both treatments sequentially. Most cases were asymptomatic at birth (62.5%, 35/56), and 84% (47/56) newborns completed one year of treatment. Median follow-up was 24 months (IQR = 3-72): 14.2% children exhibited new complications, mainly ocular. Newborns born to mothers treated prenatally had four-fold lower risk of CT clinical features at birth (p = 0.03) and six-fold lower risk of further complications during follow-up (p = 0.04) with no treatment-related differences during pregnancy., Conclusions: While diagnosis based only on neonatal assessment misses a significant number of CT cases, prenatal screening allows treatment to be started during pregnancy, with better clinical outcomes at birth and during follow-up. REIV-TOXO provides valuable information about CT in Spain, highlighting the need for universal maternal screening., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guarch-Ibáñez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development., Competing Interests: Declaration of Competing Interest none, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding-enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To describe the molecular profile of a real-world cohort of patients with metastatic urothelial carcinoma (mUC) and to evaluate the benefit of next-generation sequencing (NGS) panels in guiding therapy in patients with mUC and the outcomes of DNA-matched treatments recommended by a multidisciplinary molecular tumor board (MMTB)., Methods: This was a single-center analysis of a real-world cohort of adult patients with mUC included in an ongoing trial that aimed to evaluate the clinical utility of NGS for solid tumors. Genomic analysis was performed for each patient, most of them using the Ion Torrent Oncomine Focus Assay. Genomic results were discussed during MMTB meetings., Results: We included 43 patients with mUC treated with platinum-based combinations and immunotherapy. Twenty-five patients (58.1%; 95% CI 43.4-72.9) had at least one tumor pathogenic alteration. The MMTB classified 16 (48.5%) of the 33 tumor pathogenic alterations found in our real-world cohort of mUC patients as ESCAT I, which is the maximum grade of actionability. After excluding patients who were not candidates for targeted therapies, the MMTB provided guidance on matched therapy for seven patients. Among these patients, three achieved a partial response for an overall response rate of 42.9%, a median progression-free survival of 7.3 months (95% CI 6.7-7.9) and a median overall survival of 10.9 months (95% CI 2.4-19.5)., Conclusions: We recommend that all patients with mUC undergo NGS at diagnosis given the high percentage of patients with pathogenic alterations in our real-world cohort and the efficacy data of patients treated with targeted therapies., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated., Methods: A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report., Results: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases., Conclusions: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a serious complication in patients undergoing cardiac surgery with extracorporeal circulation (ECC) that increases postoperative complications and mortality. CSA-AKI develops due to a combination of patient- and surgery-related risk factors that enhance renal ischemia-reperfusion injury. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin reduce renal glucose reabsorption, improving tubulo-glomerular feedback, reducing inflammation and decreasing intraglomerular pressure. Preclinical studies have observed that SGLT2i may provide significant protection against renal ischemia-reperfusion injury due to their effects on inadequate mitochondrial function, reactive oxygen species activity or renal peritubular capillary congestion, all hallmarks of CSA-AKI. The VERTIGO (EValuating the Effect of periopeRaTIve empaGliflOzin) trial is a Phase 3, investigator-initiated, randomized, double-blind, placebo-controlled, multicenter study that aims to explore whether empagliflozin can reduce the incidence of adverse renal outcomes in cardiac surgery patients., Methods: The VERTIGO study (EudraCT: 2021-004938-11) will enroll 608 patients that require elective cardiac surgery with ECC. Patients will be randomly assigned in a 1:1 ratio to receive either empagliflozin 10 mg orally daily or placebo. Study treatment will start 5 days before surgery and will continue during the first 7 days postoperatively. All participants will receive standard care according to local practice guidelines. The primary endpoint of the study will be the proportion of patients that develop major adverse kidney events during the first 90 days after surgery, defined as ≥25% renal function decline, renal replacement therapy initiation or death. Secondary, tertiary and safety endpoints will include rates of AKI during index hospitalization, postoperative complications and observed adverse events., Conclusions: The VERTIGO trial will describe the efficacy and safety of empagliflozin in preventing CSA-AKI. Patient recruitment is expected to start in May 2024., Competing Interests: A.C. reports consultancy and speaker fees from Vifor Pharma and Novo Nordisk, honoraria for educational events from AstraZeneca, and grants or contracts from Alexion and LFB Biotechnologies. E.B.-M. reports grants or contracts from Alexion and LFB Biotechnologies, and travel grants from Gilead. V.F. reports honoraria for educational events from AstraZeneca and travel fees from NovoNordisk. M.F. reports grants or contracts from Alexion and LFB Biotechnologies. Á.G.-P. reports grants from Medtronic. D.P. reports consulting fees and honoraria for educational events from Edwards, Medtronic, Atricure, BBraun and Abbott. J.B.-M. reports grants or contracts from Baxter, Alexion and LFB Biotechnologies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis., (© 2024. The Author(s).)

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hearing loss (HL) is a heterogenous trait with pathogenic variants in more than 200 genes that have been discovered in studies involving small and large HL families. Over one-third of families with hereditary HL remain etiologically undiagnosed after screening for mutations in the recognized genes. Genetic heterogeneity complicates the analysis in multiplex families where variants in more than one gene can be causal in different individuals even in the same sibship. We employed exome or genome sequencing in at least two affected individuals with congenital or prelingual-onset, severe to profound, non-syndromic, bilateral sensorineural HL from four multiplex families. Bioinformatic analysis was performed to identify variants in known and candidate deafness genes. Our results show that in these four families, variants in a single HL gene do not explain HL in all affected family members, and variants in another known or candidate HL gene were detected to clarify HL in the entire family. We also present a variant in TOGARAM2 as a potential cause underlying autosomal recessive non-syndromic HL by showing its presence in a family with HL, its expression in the cochlea and the localization of the protein to cochlear hair cells. Conclusively, analyzing all affected family members separately can serve as a good source for the identification of variants in known and novel candidate genes for HL., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Objectives: We explored the current evidence on coronary disease treatment comparing the survival of 2 therapeutic strategies: coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stent (DES)., Methods: PubMed, Embase, and Google Scholar were searched for randomized clinical trials comparing CABG versus PCI with DES. The end point was overall mortality. Two statistical approaches were used: the generic inverse variance method, which was used to pool the incident rate ratios, and the pooled meta-analysis of Kaplan-Meier-derived individual patient data., Results: Eight randomized clinical trials comparing 4975 patients undergoing CABG and 4992 patients undergoing PCI were included in our meta-analysis. Generic inverse variance method showed a statistically significant survival benefit of the CABG group (incident rate ratio, 1.21; 95% confidence interval, 1.09-1.35; P < .01). The Kaplan-Meier estimates of survival at 1, 5, and 10 years of the CABG group were 97.1%, 90.3%, and 80.3%, respectively. The Kaplan-Meier estimates of survival at 1, 5, and 10 years of the PCI group were 97.0%, 87.7%, and 76.4%, respectively. The log-rank analysis confirmed a statistically significant benefit in term of overall mortality of the CABG group (hazard ratio, 1.24; 95% confidence interval, 1.11-1.38; P = .0001)., Conclusions: The present meta-analysis suggests that CABG provides a consistent survival benefit over PCI with DES., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. This disease is especially worrying in children since it can seriously alter their development. Presently, a specific diagnostic test or definitive biomarker set for confirming long COVID is lacking, relying instead on the protracted presence of symptoms post-acute infection., Methods: We measured the levels of 13 biomarkers in 105 saliva samples (49 from children with long COVID and 56 controls), and the Pearson correlation coefficient was used to analyse the correlations between the levels of the different salivary biomarkers. Multivariate logistic regression analyses were performed to determine which of the 13 analysed salivary biomarkers were useful to discriminate between children with long COVID and controls, as well as between children with mild and severe long COVID symptoms., Results: Pediatric long COVID exhibited increased oxidant biomarkers and decreased antioxidant, immune response, and stress-related biomarkers. Correlation analyses unveiled distinct patterns between biomarkers in long COVID and controls. Notably, a multivariate logistic regression pinpointed TOS, ADA2, total proteins, and AOPP as pivotal variables, culminating in a remarkably accurate predictive model distinguishing long COVID from controls. Furthermore, total proteins and ADA1 were instrumental in discerning between mild and severe long COVID symptoms., Discussion: This research sheds light on the potential clinical utility of salivary biomarkers in diagnosing and categorizing the severity of pediatric long COVID. It also lays the groundwork for future investigations aimed at unravelling the prognostic value of these biomarkers in predicting the trajectory of long COVID in affected individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tyrkalska, Pérez-Sanz, Franco-Martínez, Rubio, Tvarijonaviciute, Martínez-Subiela, Méndez-Hernández, González-Aumatell, Carreras-Abad, Domènech-Marçal, Cerón, Cayuela, Mulero and Candel.)

Introduction: Capsular polysaccharide (CPS) serotype-specific Immunoglobulin G (IgG) in cord blood has been proposed as a correlate of protection against invasive Group B Streptococcus (iGBS) disease. Although protective levels are required in infants throughout the window of vulnerability up to 3 months of age, little is known regarding the kinetics of GBS-specific IgG over this period., Methods: We enrolled 33 healthy infants born to mothers colonized with GBS. We collected cord blood and infant blood samples either at one (21-35 days), two (49-63 days), or three months of age (77-91 days). We measured GBS serotype-specific CPS IgG concentrations and calculated the decay rate using a mixed-effects model. We further explored whether the antibody kinetics were affected by common maternal and infant factors and estimated the correlation between IgG concentration at birth and one, two, and three months of age., Results: The half-life estimate of IgG concentration for homologous and non-homologous GBS serotypes in paired samples with detectable IgG levels at both time points was 27.4 (95 % CI: 23.5-32.9) days. The decay rate did not vary by maternal age (p = 0.7), ethnicity (p = 0.1), gravida (p = 0.1), gestation (p = 0.7), and infant sex (p = 0.1). Predicted IgG titres above the assay lower limit of quantification on day 30 strongly correlated with titres at birth (Spearman correlation coefficient 0.71 [95 % CI: 0.60-0.80])., Conclusion: Our results provide a basis for future investigations into the use of antibody kinetics in defining a serocorrelate of protection against late-onset iGBS disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Paul Heath reports financial support was provided by National Institute for Health Research. MV is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. PTH has conducted studies on behalf of St George’s University of London funded by GBS vaccine manufacturers, including Minervax and Pfizer, but receives no personal funding for these activities. KLD is supported by Future Leaders Fellowships by UK Research and Innovation Future Leaders Fellowship (MR/S016570/1) and has conducted studies on behalf of St George’s University of London funded by GBS vaccine manufacturers, including Minervax and Pfizer, but receives no personal funding for these activities. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

The current study explores whether individual differences in the dimensional adjectives (e.g., big, tall) children understand , relates to individual differences in two non-verbal spatial abilities, spatial scaling and mental transformations, in bilingual children. The inclusion of English-Spanish bilingual children broadens the work in this area which has previously focused strictly on English language. Ninety-two English-Spanish bilingual children between 37.65 and 71.87 months (42 male) participated in the study. Results show number of dimensional adjectives preschool children comprehend utilizing a new interactive, tablet-based task relates to performance on non-verbal spatial tasks. This research supports hypothesized relations between spatial language comprehension and spatial abilities, introduces an effective tool for examining spatial language comprehension in young children, and improves generalizability by including a bilingual sample and testing comprehension in both English and Spanish.

In this study, we demonstrate the applicability of nitrogen microwave inductively coupled atmospheric pressure mass spectrometry (MICAP-MS) for Ca, Fe, and Se quantification in human serum using isotope dilution (ID) analysis. The matrix tolerance of MICAP-MS in Na matrix was investigated, revealing that high Na levels can suppress the signal intensity. This suppression is likely due to the plasma loading and the space charge effect. Moreover, 40 Ca and 44 Ca isotopic fractionation was noted at elevated Na concentration. Nine certified serum samples were analyzed using both external calibration and ID analysis. Overestimation of Cr, Zn, As, and Se was found in the results of external calibration, which might result from C-induced polyatomic interference and signal enhancement, respectively. Further investigations performed with methanol showed a similar enhancement effect for Zn, As, and Se, potentially supporting this assumption. The mass concentrations determined with ID analysis show metrological compatibility with the reference values, indicating that MICAP-MS combined with ID analysis can be a promising method for precise Ca, Fe, and Se determination. Moreover, this combination reduces the influence of matrix effects, broadening the applicability of MICAP-MS for samples with complex matrixes., (© 2024. The Author(s).)

Gastrointestinal adenocarcinomas are often reported in South American camelids (SAC). We describe here cases of gastroduodenal adenocarcinoma in an adult alpaca ( Vicugna pacos ) and a llama ( Llama glama ); both SACs were anorectic and lethargic before death. At autopsy, a prominent and firm caudal C3-pyloric-duodenal junction with stricture and ulceration was present in both animals, as were hemorrhages in various organs and hydrothorax. Microscopically, scattered nests, cords, and tortuous acini of neoplastic epithelial cells were embedded in desmoplastic stroma and invaded the submucosa and muscle layers of the gastroduodenal junction. The mucosa was necrotic, with gram-negative rods in the alpaca and colonies of gram-positive cocci in the llama. No tumor metastases were observed. The neoplastic cells immunolabeled for pancytokeratin. Escherichia coli was isolated from the alpaca and Streptococcus lutetiensis from the llama; septicemia was the cause of death in both animals. Although adenocarcinomas arising from gastric compartments and intestinal segments have been reported in SACs, adenocarcinoma of the caudal C3-pyloric-duodenal junction has not been reported previously in these species, to our knowledge., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development., (© The Author(s) 2023. Published by Oxford University Press behalf of Society for the Study of Reproduction.)

We present the case of a 69-year-old male diagnosed with stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6 proteins, but somatic wild type MSH2 and MSH6 genes with Oncomine Comprehensive Assay (OCA) genomic sequencing panel. In his cancer family history, there was a maternal aunt with sigmoid colon adenocarcinoma also missing MSH2 and MSH6 protein expression. Subsequently, we will discuss whether or not we are facing a hereditary cancer syndrome.

The oncogenic KRAS mutation is associated with increased tissue factor expression and thus hypercoagulability. In this regard, numerous studies published in the last decade have shown that KRAS mutations are an important risk factor for the development of thromboembolic phenomena in neoplasms of the digestive tract, such as colorectal cancer. On the other hand, some recently published studies suggest that KRAS mutations are also associated with an increased risk of developing thromboembolic phenomena in pancreatic cancer. Based on these premises, we have conducted a single-centre retrospective study on a cohort of patients with pancreatic cancer. Our aim is to demonstrate whether there is an association between the presence of KRAS mutations in our cohort of pancreatic cancer patients and an increased risk of developing thromboembolic phenomena.

Catecholamines norepinephrine and dopamine have been implicated in numerous physiological processes within the central nervous system. Emerging evidence has highlighted the importance of tightly regulated monoamine levels for placental functions and fetal development. However, the complexities of synthesis, release, and regulation of catecholamines in the fetoplacental unit have not been fully unraveled. In this study, we investigated the expression of enzymes and transporters involved in synthesis, degradation, and transport of norepinephrine and dopamine in the human placenta and rat fetoplacental unit. Quantitative PCR and Western blot analyses were performed in early-to-late gestation in humans (first trimester vs. term placenta) and mid-to-late gestation in rats (placenta and fetal brain, intestines, liver, lungs, and heart). In addition, we analyzed the gene expression patterns in isolated primary trophoblast cells from the human placenta and placenta-derived cell lines (HRP-1, BeWo, JEG-3). In both human and rat placentas, the study identifies the presence of only PNMT, COMT, and NET at the mRNA and protein levels, with the expression of PNMT and NET showing gestational age dependency. On the other hand, rat fetal tissues consistently express the catecholamine pathway genes, revealing distinct developmental expression patterns. Lastly, we report significant transcriptional profile variations in different placental cell models, emphasizing the importance of careful model selection for catecholamine metabolism/transport studies. Collectively, integrating findings from humans and rats enhances our understanding of the dynamic regulatory mechanisms that underlie catecholamine dynamics during pregnancy. We identified similar patterns in both species across gestation, suggesting conserved molecular mechanisms and potentially shedding light on shared biological processes influencing placental development., (© 2024. The Author(s).)

Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Cifkova et al.)

Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.

GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development., (© 2024. The Author(s).)

Background: Morganella morganii is a Gram-negative enteric rod found in the intestinal tracts of humans, mammals, and reptiles as normal flora. It is highly implicated in urinary tract infections, wound infections, and septicemia. The cerebral nervous system, especially brain abscess attributed to M. morganii , remains extremely rare. To the best of the author's knowledge, only eight documented cerebral brain abscesses caused by M. morganii have been reported in the literature., Case Description: A 48-year-old man presented with headache, fever, and irritability two months after endoscopic endonasal repair of the cranial base defect. Following imaging studies, a large left frontal abscess was found. The patient underwent a fine-needle aspiration through a burr hole following antimicrobial therapy., Conclusion: We report this case to create awareness among neurosurgeons and microbiologists that M. morganii , even though uncommon, is a cause of cerebral brain abscess. Prompt surgical management and appropriate antimicrobial therapy is the treatment of choice., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Surgical Neurology International.)

Background: Rhodococcus equi is a Gram-positive microorganism that causes infections, particularly in immunocompromised patients. Treatment duration can be prolonged. While vancomycin is an effective drug in this scenario, its use may lead to renal damage. Studies have shown that continuous vancomycin infusion appears to be a safe strategy in terms of adverse effects compared to bolus administration., Case Description: We present the case of a 71-year-old female liver transplant recipient. After being diagnosed with a mediastinal infection caused by Rhodococcus equi with poor response to initial therapy, she required 12 months of continuous intravenous domiciliary infusion of vancomycin combined with oral levofloxacin and rifampicin. There was no drug-related complication throughout the follow-up., Conclusions: The use of continuous vancomycin infusion has emerged as a safer, more efficient, and cost-effective alternative to intermittent administration. We want to emphasise the uniqueness of this case, where despite the unprecedented treatment duration, no adverse effects occurred., Learning Points: Vancomycin therapy based on continuous infusion represents a safer and cheaper strategy than classic intermittent administration.The use of continuous infusion facilitates the management of complex infections with outpatient antimicrobial therapy., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Background: The pro-inflammatory ATP-gated P2X7 receptor is widely expressed by immune and non-immune cells. Nanobodies targeting P2X7, with potentiating or antagonistic effects, have been developed. Adeno-associated virus (AAV)-mediated gene transfer represents an efficient approach to achieve long-term in vivo expression of selected nanobody-based biologics. This approach (AAVnano) was used to validate the relevance of P2X7 as a target in dextran sodium sulfate (DSS)-induced colitis in mice., Results: Mice received an intramuscular injection of AAV vectors coding for potentiating (14D5-dimHLE) or antagonistic (13A7-Fc) nanobody-based biologics targeting P2X7. Long-term modulation of P2X7 activity was evaluated ex vivo from blood samples. Colitis was induced with DSS in mice injected with AAV vectors coding for nanobody-based biologics. Severity of colitis, colon histopathology and expression of chemokines and cytokines were determined to evaluate the impact of P2X7 modulation. A single injection of an AAV vector coding for 13A7-Fc or 14D5-dimHLE efficiently modulated P2X7 function in vivo from day 15 up to day 120 post-injection in a dose-dependent manner. An AAV vector coding for 13A7-Fc significantly ameliorated DSS-induced colitis and significantly reduced immune cell infiltration and expression of chemokines and proinflammatory cytokines in colonic tissue., Conclusions: We have demonstrated the validity of AAVnano methodology to modulate P2X7 functions in vivo. Applying this methodological approach to a DSS-induced colitis model, we have shown that P2X7 blockade reduces inflammation and disease severity. Hence, this study confirms the importance of P2X7 as a pharmacological target and suggests the use of nanobody-based biologics as potential therapeutics in inflammatory bowel disease., (© 2024. The Author(s).)

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord -/- , Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord -/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord -/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord -/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord -/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

We present the case of a 38-year-old woman who, in the context of a 22-week gestation, was diagnosed with diffuse gastric adenocarcinoma. The age of the patient and the way in which the cancer presented itself, make genetic counseling mandatory to rule out hereditary diffuse gastric carcinoma syndrome. This rare entity, of autosomal dominant inheritance and closely linked to mutations in the CDH1 (in most cases) and CTNNA1 genes, is associated with a greater predisposition to develop malignant neoplasms of the breast and stomach. Genetic sequencing ruled out hereditary diffuse gastric cancer syndrome. Unfortunately, 24 months after the cesarean section, our patient dies.

We investigated the extent to which parents' prosocial talk and negations relate to the quantity and diversity of parents' spatial language production. We also examined similar associations among children. Participants included 51 children of ages 4-7 years and their parents recruited from South Florida. Most of the dyads included mothers and were Hispanic and bilingual. Dyads constructed a Lego house for 10 min. Sessions were transcribed and coded for instances of parent prosocial talk (praises, reflective statements, and behavior descriptions), child general positive statements (all positive contributions to the interaction), and parent and child negations (criticisms, corrections, and disapprovals) using the Dyadic Parent-Child Interaction Coding System. Transcripts were also coded for quantity and diversity of spatial language including shape terms (e.g., square ), dimensional adjectives (e.g., little ), orientations (e.g., turn ), locations (e.g., middle ), and spatial features/properties (e.g., edge ). Parents' prosocial language, but not negations, were significantly associated with the quantity and diversity of parents' spatial language. Children's general positive statements were significantly associated with children's spatial language quantity. Exploratory data analyses also revealed significant associations between parent-child talk about shapes, dimensions, and spatial features and properties. Findings suggest that variability in parent-child prosocial and spatial talk during collaborative spatial play relates to aspects of their own-and each other's-spatial language production. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Serotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells., Methods: We employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells., Results: Using the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance., Conclusions: Taken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aim: The aim of this study was two-fold. Firstly, to describe the influence of an augmented reality (AR)-based online educational experience on the academic performance and learning determinants of nursing students related to the study of leg ulcer care. We also set out to compare these online results with those obtained in the same experience developed a year before but in a face-to-face design., Background: Undergraduate education in nursing aims to train students towards an acceptable level of competence for professional practice. Sometimes, some essential clinical areas of knowledge are particularly challenging for both students and nurse educators. One of these is the care of chronic wounds, particularly in leg ulcers where nurses play a key role. Currently face-to-face teaching methods are evolving to more active contexts and alternative means such as online learning and AR are becoming widely used, garnering encouraging results., Design: A quasi-experimental design was used. Two experiments were carried out to meet the aims of the study, the first one was a pre-test post-test design in one group and the second one a post-test two experimental groups design., Methods: Participants were undergraduate nursing students from the School of Nursing of the University of Santiago de Compostela (Spain). The two experimental groups received the same training but in different environments: online during 2019/2020 (n = 111) and onsite during 2018/2019 (n = 72). The instruments selected were a knowledge and skills test and two validated questionnaires., Results: Regarding academic performance, the study demonstrated significant differences towards learning after the AR-based online experience (Z = -9.074; p ≤ 0.001). The participants also showed good results in relation to the learning determinants studied. Compared with students receiving AR-based face-to-face teaching, the students with the online learning approach scored better in the dimensions Autonomous Learning (U=3104.5; p = 0.020) and 3D Comprehension (U=3167.0; p = 0.035). However, the participants in the onsite experience scored higher in the Attention dimension (U=3163.0; p = 0.035)., Conclusions: AR positively influences academic performance and diverse educational variables when this experience is carried out online. Since both the online and face-to-face experience show statistically significant benefits in different dimensions of the learning determinants, the need to improve the AR learning experience through blended-learning environments should be promoted., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from your journal and publishing company., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We aimed to quantify how the vaccine efficacy of BNT162b2, messenger RNA-1273, AD26.COV2-S, and ChAdOx1 nCoV-19 against detected infection by the SARS-CoV-2 Delta and Omicron variants varied by time since the last dose, vaccine scheme, age, and geographic areas., Methods: We analyzed 3,261,749 community polymerase chain reaction tests conducted by private laboratories in France from December 2021 to March 2022 with a test-negative design comparing vaccinated to unvaccinated individuals., Results: Efficacy against detected infection by Delta was 89% (95% confidence interval, 86-91%) at 2 weeks, down to 59% (56-61%) at 26 weeks and more after the second dose. Efficacy against Omicron was 48% (45-51%) at 2 weeks, down to 4% (2-5%) at 16 weeks after the second dose. A third dose temporarily restored efficacy. Efficacy against Omicron was lower in children and the elderly. Geographical variability in efficacy may reflect variability in the ratio of the number of contacts of vaccinated vs unvaccinated individuals. This ratio ranged from 0 to +50% across departments and correlated with the number of restaurants and bars per inhabitant (beta = 15.0 [0.75-29], P-value = 0.04), places that only vaccinated individuals could access in the study period., Conclusion: SARS-CoV-2 vaccines conferred low and transient protection against Omicron infection., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe disease temporarily related to SARS-CoV-2. We aimed to describe the epidemiological, clinical, and laboratory findings of all MIS-C cases diagnosed in children < 18 years old in Catalonia (Spain) to study their trend throughout the pandemic. This was a multicenter ambispective observational cohort study (April 2020-April 2022). Data were obtained from the COVID-19 Catalan surveillance system and from all hospitals in Catalonia. We analyzed MIS-C cases regarding SARS-CoV-2 variants for demographics, symptoms, severity, monthly MIS-C incidence, ratio between MIS-C and accumulated COVID-19 cases, and associated rate ratios (RR). Among 555,848 SARS-CoV-2 infections, 152 children were diagnosed with MIS-C. The monthly MIS-C incidence was 4.1 (95% CI: 3.4-4.8) per 1,000,000 people, and 273 (95% CI: 230-316) per 1,000,000 SARS-CoV-2 infections (i.e., one case per 3,700 SARS-CoV-2 infections). During the Omicron period, the MIS-C RR was 8.2 (95% CI: 5.7-11.7) per 1,000,000 SARS-CoV-2 infections, which was significantly lower (p < 0.001) than that for previous variant periods in all age groups. The median [IQR] age of MIS-C was 8 [4-11] years, 62.5% male, and 80.2% without comorbidities. Common symptoms were gastrointestinal findings (88.2%) and fever > 39 °C (81.6%); nearly 40% had an abnormal echocardiography, and 7% had coronary aneurysm. Clinical manifestations and laboratory data were not different throughout the variant periods (p > 0.05).  Conclusion: The RR between MIS-C cases and SARS-CoV-2 infections was significantly lower in the Omicron period for all age groups, including those not vaccinated, suggesting that the variant could be the main factor for this shift in the MISC trend. Regardless of variant type, the patients had similar phenotypes and severity throughout the pandemic. What is Known: • Before our study, only two publications investigated the incidence of MIS-C regarding SARS-CoV-2 variants in Europe, one from Southeast England and another from Denmark. What is New: • To our knowledge, this is the first study investigating MIS-C incidence in Southern Europe, with the ability to recruit all MIS-C cases in a determined area and analyze the rate ratio for MIS-C among SARS-CoV-2 infections throughout variant periods. • We found a lower rate ratio of MISC/infections with SARS-CoV-2 in the Omicron period for all age groups, including those not eligible for vaccination, suggesting that the variant could be the main factor for this shift in the MISC trend., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Idiopathic inflammatory myopathies (IIM) are autoimmune inflammatory disorders leading to skeletal muscle weakness and disability. The pathophysiology of IIM is poorly understood due to the scarcity of animal disease models. Genetic deletion of Icos or Icosl (inducible T cell co-stimulator/ligand) in non-obese diabetic (NOD) mice leads to muscle disease. Our aim was to characterise Icos -/- NOD myopathy and to search for novel autoantibodies (aAbs) in this model., Methods: Diabetes, weight, myopathy incidence/clinical score and grip strength were assessed over time. Locomotor activity was analysed with the Catwalk XT gait analysis system. Muscle histology was evaluated in haematoxylin/eosin and Sirius red-stained sections, and immune infiltrates were characterised by immunofluorescence and flow cytometry. 2D gel electrophoresis of muscle protein extracts and mass spectrometry were used to identify novel aAbs. NOD mice were immunised with troponin T3 (TNNT3) in incomplete Freund's adjuvant (IFA) and R848. An addressable laser bead immunoassay (ALBIA) was developed to measure aAb IgG serum levels., Results: Icos -/- NOD mice did not exhibit diabetes but developed spontaneous progressive myositis with decreased muscle strength and altered locomotor activity. Muscle from these mice exhibited myofibre necrosis, myophagocytosis, central nuclei, fibrosis and perimysial and endomysial cell infiltrates with macrophages and T cells. We identified anti-TNNT3 aAbs in diseased mice. Immunisation of NOD mice with murine TNNT3 protein led to myositis development, supporting its pathophysiological role., Conclusions: These data show that Icos -/- NOD mice represent a spontaneous model of myositis and the discovery of anti-TNNT3 aAb suggests a new autoantigen in this model., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objective: To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients., Methods: A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies., Results: Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated., Conclusion: A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study., (Copyright © 2022. Published by Elsevier España, S.L.U.)

The placenta represents a non-neuronal organ capable of transporting and metabolizing monoamines. Since these bioactive molecules participate in numerous processes essential for placental and fetal physiology, any imbalance in their levels during pregnancy may affect brain development, projecting a higher risk of behavioral disorders in childhood or adulthood. Notably, the monoamine system in the placenta is a target of various psychoactive drugs and can be disrupted in several pregnancy pathologies. As research in pregnant women poses significant ethical restrictions, animal models are widely employed to study monoamine homeostasis as a mechanism involved in fetal programming. However, detailed knowledge of monoamine transport in the rat placenta is still lacking. Moreover, relatability to the human placental monoamine system is not examined. The present study provides insights into the transplacental monoamine dynamics between maternal and fetal circulation. We show that norepinephrine maternal-to-fetal transport is <4% due to high metabolism within the trophoblast. In contrast, dopamine maternal-to-fetal transport exceeds 25%, likely through passive transport across the membrane. In addition, we show high clearance of norepinephrine and dopamine from the fetal circulation mediated by the organic cation transporter 3 (OCT3). Altogether, we present transcriptional and functional evidence that the in situ rat placenta perfusion represents a suitable model for (patho)physiological investigation of dopamine and norepinephrine homeostasis in the fetoplacental unit. With the rapid advancements in drug discovery and environmental toxicity, the use of rat placenta as a preclinical model could facilitate screening of possible xenobiotic effects on monoamine homeostasis in the placenta., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Oxidative stress is the result of an imbalance between the formation of reactive oxygen species (ROS) and the levels of enzymatic and non-enzymatic antioxidants. The assessment of biological redox status is performed by the use of oxidative stress biomarkers. An oxidative stress biomarker is defined as any physical structure or process or chemical compound that can be assessed in a living being (in vivo) or in solid or fluid parts thereof (in vitro), the determination of which is a reproducible and reliable indicator of oxidative stress. The use of oxidative stress biomarkers allows early identification of the risk of developing diseases associated with this process and also opens up possibilities for new treatments. At the end of the last century, interest in oxidative stress biomarkers began to grow, due to evidence of the association between the generation of free radicals and various pathologies. Up to now, a significant number of studies have been carried out to identify and apply different oxidative stress biomarkers in clinical practice. Among the most important oxidative stress biomarkers, it can be mentioned the products of oxidative modifications of lipids, proteins, nucleic acids, and uric acid as well as the measurement of the total antioxidant capacity of fluids in the human body. In this review, we aim to present recent advances and current knowledge on the main biomarkers of oxidative stress, including the discovery of new biomarkers, with emphasis on the various reproductive complications associated with variations in oxidative stress levels., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Maternal inflammation in pregnancy represents a major hallmark of several pregnancy complications and a significant risk factor for neurodevelopmental and neuropsychiatric disorders in the offspring. As the interface between the mother and the fetus, the placenta plays a crucial role in fetal development and programming. Moreover, studies have suggested that the placenta responds to an inflammatory environment in a sex-biased fashion. However, placenta-mediated immunoregulatory mechanisms are still poorly understood., Methods: Therefore, we have developed a model of ex vivo precision-cut placental slices from the rat term placenta to study acute inflammatory response. Rat placental slices with a precise thickness of 200 µm were generated separately from male and female placentas. Inflammation was stimulated by exposing the slices to various concentrations of LPS or Poly I:C for 4 and 18 hours., Results: Treatment of placental slices with LPS significantly induced the expression and release of proinflammatory cytokines TNF-α, IL-6, and IL-1β. In contrast, Poly I:C treatment resulted in a less-pronounced inflammatory response. Interestingly, the female placenta showed higher sensitivity to LPS than male placenta. Anti-inflammatory agents, curcumin, 1α,25- dihydroxyvitamin D3, and progesterone attenuated the LPS-induced proinflammatory cytokine response at both mRNA and protein levels., Discussion: We conclude that rat placental slices represent a novel alternative model to study the role of sexual dimorphism in the acute inflammatory response and immune activation in pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Anandam, Abad, Synova, Vinas-Noguera, Bolboli, Vokral, Karahoda and Staud.)

Objective: Late presenters (LP) for HIV care are associated with higher morbidity and mortality rates. Our aim was to describe the characteristics associated with LP among adolescents in Spain. Identification of particular features may help in the design of strategies for improvement., Methods: Late-presenting adolescents diagnosed at 12-19 years of age and enrolled in the Spanish paediatric and adult HIV/AIDS cohorts (CoRIS-CoRISpe) from 2004 to 2019 were selected. LP were defined as those presenting with CD4 count <350 cells/mm 3 or an AIDS-defining event in the 6 months following HIV diagnosis. Confirmed low CD4 count in the next 3 months and before antiretroviral treatment initiation defined confirmed LP (cLP)., Results: Of 410 adolescents newly diagnosed with HIV, 303 (73.9%) had available data for assessing late presentation. Of these, 34.7% were LP and 23.7% were cLP. The median CD4 count for cLP was 235 cells/mm 3 (interquartile range 122-285). In a multivariable analysis, adolescents at the highest risk of late presentation were early adolescents (age 12-14 years; odds ratio [OR] 6.50; 95% confidence interval [CI] 2.61-18.2), middle adolescents (age 15-17 years; OR 1.85; 95% CI 0.92-3.59), and adolescents born abroad (OR 1.71; 95% CI 0.97-3.00), particularly those of African origin (OR 3.08; 95% CI 1.38-6.79)., Conclusions: One-quarter of adolescents presented late for HIV care in Spain. Early adolescents, middle adolescents, and those born abroad presented a sevenfold, twofold, and twofold higher risk of being cLP, respectively. Enhancing the awareness of HIV risk and the access to care, especially for younger and foreign adolescents, could help reduce late presentation and tackle the adolescent HIV epidemic., (© 2022 British HIV Association.)

Background: Chronic wounds are a serious public health problem worldwide. Providing optimal treatment to patients suffering from leg ulcers is a priority for nursing. Therefore, nursing students need to acquire the necessary competencies to provide evidence-based care. Augmented Reality (AR) is an emerging technology in health science education which can help nursing students achieve these skills if it is promoted by both institutions and educationalists., Objectives: To test the effectiveness of an AR-based methodology for teaching-learning aspects of the nursing curriculum (leg ulcer care), as well as to describe how AR influences different learning determinants of nursing students., Design: A quasi-experimental study was carried out., Participants/settings: The participants of the study were 137 s-year nursing students from the School of Nursing of the University of Santiago de Compostela (Spain) (average age = 21.59 years, 80.29 % females). Of them, 65 comprised the control group (Non-AR-based teaching) and 72 comprised the experimental group (AR-based teaching)., Methods: Pre-post tests were used to measure knowledge and skills about leg ulcer care in both groups. Additionally, two validated questionnaires were selected to identify the influence of AR on learning determinants in the experimental group. The study took place during the 2018/2019 academic year., Results: Significantly higher scores (7.68 vs. 6.14) were found in the knowledge post-test in the experimental group (p ≤ 0.001), while the pre-test did not show differences between groups (4.43 vs. 4.32). Also, nursing students indicated high scores in attention, autonomous learning, understanding and motivation to carry out learning objectives using AR., Conclusions: AR is a tool that improves performance related to the specific aspects of the nursing academic curriculum (leg ulcer care), while encouraging positive attitudes towards the teaching-learning process. These findings reinforce the need to include innovative methodologies in nursing classrooms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Unaccompanied and separated children (UASC) are a high-risk group for infectious diseases and information on their vaccination status is scarce. Different approaches are used to screen newly arrived minors in Europe. The aim of this study was to describe the health status and serological protection against different vaccine-preventable diseases among UASC to inform public health decision-making., Methods: Retrospective study of all UASC seen at an international health reference center in Barcelona (Spain) between January 2017 and February 2020. Screening results were analyzed using binary logistic regression with adjustment for symptoms, geographic origin, and time since arrival., Results: We studied 289 UASC (88.9% males; median age, 17 years). At least one infection was diagnosed in 136 minors (47.1%). There was a high prevalence of intestinal parasites (22.8%), latent tuberculosis infection (22.5%), and hepatitis B (5.2%), even in asymptomatic individuals, and especially among UASC from sub-Saharan Africa (odds ratio, 2.5; 95% confidence interval, 1.5-4.0, P &lt; 0.001). We did not observe a significant association between clinical symptoms and the presence of infection or differences in the prevalence of different infections according to number of months since arrival. Protection against hepatitis B virus (36%), measles (80%), and varicella (83%) was suboptimal., Conclusions: Our results highlight the importance of screening and vaccination programs for UASC arriving in Europe, especially border countries. Protocols should be adjusted according to geographic origin. Absence of symptoms does not necessarily rule out infection, highlighting the importance of screening in asymptomatic minors. These programs are a public health priority and should not be neglected during the current COVID-19 pandemic., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

There is a lack of evidence of the health impacts due to long COVID among children and young people (CYP). The objective of this study is to determine the main clinical characteristics of long COVID in CYP and to investigate the academic, social, and health status impacts of long COVID in this population. An observational, descriptive, and longitudinal study on CYP who presented COVID-19 symptoms for more than twelve weeks after SARS-CoV-2 infection was performed between December 2020 and May 2021. Fifty CYP were included, with a median age of 14.1 years, 33 (66%) were female, and 17 (34%) had a relative diagnosed with long COVID. Since the initial infection and up to the first visit, CYP had persisting symptoms for a median of 4.1 months, and for 18 (36%) CYP these symptoms persisted for more than 6 months. Fatigue (100%), neurocognitive disorders (74%), muscular weakness (74%), and headache (72%) were the most reported symptoms. A total of 9 (18%) CYP could not attend school, 17 (34%) had a reduced schedule, 33 (66%) showed a decreased school performance, and 68% had stopped extracurricular activities. This preliminary study shows the impact that long COVID has on the health, academic, and social life of CYP., Competing Interests: The authors declare they have no conflict of interest.

Adenosine triphosphate (ATP) represents a danger signal that accumulates in injured tissues, in inflammatory sites, and in the tumor microenvironment. ATP promotes tumor growth but also anti-tumor immune responses notably via the P2X7 receptor. ATP can also be catabolized by CD39 and CD73 ecto-enzymes into immunosuppressive adenosine. P2X7, CD39 and CD73 have attracted much interest in cancer as targets offering the potential to unleash anti-tumor immune responses. These membrane proteins represent novel purinergic checkpoints that can be targeted by small drugs or biologics. Here, we investigated nanobody-based biologics targeting mainly P2X7, but also CD73, alone or in combination therapies. Blocking P2X7 inhibited tumor growth and improved survival of mice in cancer models that express P2X7. P2X7-potentiation by a nanobody-based biologic was not effective alone to control tumor growth but enhanced tumor control and immune responses when used in combination with oxaliplatin chemotherapy. We also evaluated a bi-specific nanobody-based biologic that targets PD-L1 and CD73. This novel nanobody-based biologic exerted a potent anti-tumor effect, promoting tumor rejection and improving survival of mice in two tumor models. Hence, this study highlights the importance of purinergic checkpoints in tumor control and open new avenues for nanobody-based biologics that may be further exploited in the treatment of cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. FK-N is a co-inventor on a patent application on P2X7-specific nanobodies. FK-N, SM, YD, BR, and TM are co-inventors on a patent application on CD73-specific nanobodies., (Copyright © 2022 Demeules, Scarpitta, Hardet, Gondé, Abad, Blandin, Menzel, Duan, Rissiek, Magnus, Mann, Koch-Nolte and Adriouch.)

Background: Three primary monoamines-serotonin, norepinephrine, and dopamine-play major roles in the placenta-fetal brain axis. Analogously to the brain, the placenta has transport mechanisms that actively take up these monoamines into trophoblast cells. These transporters are known to play important roles in the differentiated syncytiotrophoblast layer, but their status and activities in the undifferentiated, progenitor cytotrophoblast cells are not well understood. Thus, we have explored the cellular handling and regulation of monoamine transporters during the phenotypic transitioning of cytotrophoblasts along the villous pathway., Methods: Experiments were conducted with two cellular models of syncytium development: primary trophoblast cells isolated from the human term placenta (PHT), and the choriocarcinoma-derived BeWo cell line. The gene and protein expression of membrane transporters for serotonin (SERT), norepinephrine (NET), dopamine (DAT), and organic cation transporter 3 (OCT3) was determined by quantitative PCR and Western blot analysis, respectively. Subsequently, the effect of trophoblast differentiation on transporter activity was analyzed by monoamine uptake into cells., Results: We present multiple lines of evidence of changes in the transcriptional and functional regulation of monoamine transporters associated with trophoblast differentiation. These include enhancement of SERT and DAT gene and protein expression in BeWo cells. On the other hand, in PHT cells we report negative modulation of SERT, NET, and OCT3 protein expression. We show that OCT3 is the dominant monoamine transporter in PHT cells, and its main functional impact is on serotonin uptake, while passive transport strongly contributes to norepinephrine and dopamine uptake. Further, we show that a wide range of selective serotonin reuptake inhibitors affect serotonin cellular accumulation, at pharmacologically relevant drug concentrations, via their action on both OCT3 and SERT. Finally, we demonstrate that BeWo cells do not well reflect the molecular mechanisms and properties of healthy human trophoblast cells., Conclusions: Collectively, our findings provide insights into the regulation of monoamine transport during trophoblast differentiation and present important considerations regarding appropriate in vitro models for studying monoamine regulation in the placenta., (© 2022. The Author(s).)

The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines (serotonin, dopamine, norepinephrine) are crucial neuromodulators for proper placenta functions and fetal development, including cell proliferation, differentiation, and neuronal migration. Accumulating evidence suggests that even a transient disruption of monoamine balance during gestation may lead to permanent changes in the fetal brain structures and functions, projecting into adulthood. Nonetheless, little is known about the transfer of dopamine and norepinephrine across the placental syncytiotrophoblast. Employing the method of isolated membranes from the human term placenta, here we delineate the transport mechanisms involved in dopamine and norepinephrine passage across the apical microvillous (MVM) and basal membranes. We show that the placental uptake of dopamine and norepinephrine across the mother-facing MVM is mediated via the high-affinity and low-capacity serotonin (SERT/SLC6A4) and norepinephrine (NET/SLC6A2) transporters. In the fetus-facing basal membrane, however, the placental uptake of both monoamines is controlled by the organic cation transporter 3 (OCT3/SLC22A3). Our findings thus provide insights into physiological aspects of dopamine and norepinephrine transport across both the maternal and fetal sides of the placenta. As monoamine transporters represent targets for several neuroactive drugs such as antidepressants, our findings are pharmacologically relevant to ensure the safety of drug use during pregnancy., (© 2022. The Author(s).)