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Blanka Halamoda Kenzaoui1, Maya R Vilà2, Josep M Miquel2, Feride Cengelli1, Lucienne Juillerat-Jeanneret11Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland; 2Leitat Technological Center, Barcelona, SpainAbstract: Nanoparticles (NPs) are in clinical use or under development for therapeutic imaging and drug delivery. However, relatively little information exists concerning the uptake and transport of NPs across human colon cell layers, or their potential to invade three-dimensional models of human colon cells that better mimic the tissue structures of normal and tumoral colon. In order to gain such information, the interactions of biocompatible ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) (iron oxide core 9–10 nm) coated with either cationic polyvinylamine (aminoPVA) or anionic oleic acid with human HT-29 and Caco-2 colon cells was determined. The uptake of the cationic USPIO NPs was much higher than the uptake of the anionic USPIO NPs. The intracellular localization of aminoPVA USPIO NPs was confirmed in HT-29 cells by transmission electron microscopy that detected the iron oxide core. AminoPVA USPIO NPs invaded three-dimensional spheroids of both HT-29 and Caco-2 cells, whereas oleic acid-coated USPIO NPs could only invade Caco-2 spheroids. Neither cationic aminoPVA USPIO NPs nor anionic oleic acid-coated USPIO NPs were transported at detectable levels across the tight CacoReady™ intestinal barrier model or the more permeable mucus-secreting CacoGoblet™ model.Keywords: iron oxide nanoparticles, human colon cells, spheroids, transport, gastrointestinal barrier

Enzymatic browning caused by polyphenol oxidases, tyrosinase and laccase, continues to be one of the main problems in winemaking. Therefore, wineries are very interested in studying the mechanisms of browning and procedures for decreasing the use sulphur dioxide. This research proposes a model to study tyrosinase activity from grape must using different substrates: one monophenol (p-hydroxybenzoic acid), two diphenols (caftaric acid and (-)-epicatechin) and one triphenol (gallic acid). The kinetic constants of tyrosinase, Vmax and K M , indicate that caftaric acid is the best substrate for tyrosinase, followed in decreasing order by (-)-epicatechin, gallic acid and p-hydroxybenzoic acid. This last acid does not appear to be susceptible to browning by the action of grape must tyrosinase. The influence of pH, temperature and ethanol on grape must tyrosinase were also determined and the results indicate that tyrosinase Vmax increases when pH and temperature are higher and that the presence of ethanol reduces it., 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. Published by Elsevier Ltd.)

Background-Aim: Methylmalonic acid (MMA) is currently the best biomarker of functional vitamin B12 deficiency. However, for a correct interpretation of the patient's results it is necessary to know its biological variation (BV). No BV data are available for urine MMA values, as measured by mass spectrometry. Hence, the aim of this study was to estimate the within- and between-person coefficients of variation (CV w, CV g ) for MMA in a healthy population, and the associated index of individuality (II), as well as to define quality specifications based on BV and the reference change value (RCV)., Methods: Random urine samples from 34 healthy volunteers were collected over four consecutive weeks. Samples were stored at -80 °C until analysis in a single analytical run. MMA excretion was quantified by tandem liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Results were normalized to urine creatinine. The coefficients of variation were estimated by CV-ANOVA. Confidence intervals (95 %) were calculated. Quality specifications were defined according to international recommendations., Results: A total of 128 samples were included. The coefficients of variation were CV w  = 35.7 % (26.1-45.3) and CV g  = 67.7 % (58.3-77.0). The associated II was 0.5 and the RCV was 88.1 %., Conclusion: Considering the II obtained, MMA in urine has high individuality, therefore, RCV is better to evaluate serial clinical results. Our results will contribute to a better clinical interpretation of this biomarker and will represent a great aid when defining analytical performance specifications for this magnitude., 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 Elsevier B.V. All rights reserved.)

Objective: To investigate differences in arterial involvement patterns on 18 F-FDG PET-CT between predominant cranial and isolated extracranial phenotypes of giant cell arteritis (GCA)., Methods: A retrospective review of 18 F-FDG PET-CT findings was conducted on 140 patients with confirmed GCA. The patients were divided into two groups: the cranial group, which presented craniofacial ischemic symptoms either at diagnosis or during follow-up, and the isolated extracranial group which never exhibited such manifestations., Results: Of the 140 patients (90 women), 99 (71%) were considered to have a predominantly cranial phenotype, while 41 (29%) had isolated extracranial GCA. Patients with the extracranial phenotype were younger (p = 0.001), had lower TAB positivity (25%), and experienced longer diagnostic delays (p = 0.004). Polymyalgia rheumatica was more common in the extracranial group (p = 0.029), which also showed fewer constitutional symptoms, milder increases in acute phase reactants, and more frequent limb claudication and aortic complications, although these differences were not statistically significant. When comparing arterial involvement on 18 F-FDG PET-CT, we observed statistically significant differences. The extracranial phenotype showed greater involvement across all segments of the thoracic aorta (p = 0.001), as well as in the abdominal aorta (p = 0.005), subclavian (p = 0.021), iliac (p = 0.004), and femoral arteries (p = 0.025). In contrast, the cranial phenotype exhibited a higher frequency of vertebral artery involvement (p < 0.001)., Conclusion: Significant differences in arterial involvement patterns on 18 F-FDG PET-CT were observed between phenotypes. These findings may explain atypical symptoms such as inflammatory lower back pain or limb claudication and the increased risk of aortic complications in extracranial GCA., Competing Interests: Declarations. Ethics approval: The study has bee approved by of our institutional ethics committee (Clinical Research Ethics Committee of Bellvitge University Hospital-IDIBELL). The local ethics committee confirm that the findings in this report were based on normal clinical practice and were therefore suitable for dissemination. Since our study was performed retrospectively, we were relieved by the ethics committee of our hospital from obtaining informed consent. Informed consent was not obtained from the patients, but their clinical records and information were anonymized prior to analysis. This study was conducted inaccordance with the principles of the Declaration of Helsinki and the International Conference for Harmonization. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Use of AI and AI-assisted technologies in the writing process: No., (© 2024. The Author(s).)

Background: Rapid identification of bloodstream pathogens and associated antimicrobial resistance (AMR) profiles by molecular tests from positive blood cultures (PBCs) have the potential to improve patient management and clinical outcomes., Objectives: A systematic review and meta-analysis were conducted to evaluate diagnostic test accuracy (DTA) of molecular tests from PBCs for detecting pathogens and AMR in the clinical setting., Methods: ., Data Sources: Medline, Embase, Cochrane, conference proceedings, and study bibliographies were searched., Study Eligibility Criteria: Studies evaluating DTA of commercially available molecular tests vs. traditional phenotypic identification and susceptibility testing methods in patients with PBCs were eligible., Participants: Patients with PBCs., Tests: Commercially available molecular tests., Reference Standard: Traditional phenotypic identification and susceptibility testing methods (standard of care, SOC)., Assessment of Risk of Bias: Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2., Methods of Data Synthesis: Summary DTA outcomes were estimated using bivariate random-effects models for gram-negative bacteria (GNB), gram-positive bacteria (GPB), yeast, GNB-AMR, GPB-AMR, and specific targets when reported by ≥ 2 studies (PROSPERO CRD42023488057)., Results: Seventy-four studies including 24 590 samples were analysed, most of which had a low risk of bias. When compared with SOC, molecular tests showed 92-99% sensitivity, 99-100% specificity, 99-100% positive predictive value, and 97-100% negative predictive value for identifying total GNB (43 studies), GPB (38 studies), yeast (24 studies), GNB-AMR (35 studies), and GPB-AMR (39 studies). For individual pathogen targets, 93-100% sensitivity, 98-100% specificity, 86-100% positive predictive value, and 99-100% negative predictive value were estimated. Five of seven AMR genes had 91-99% sensitivity and 99-100% specificity. Sensitivity was lower for IMP (four studies; 62%; 95% CI, 34-83%) and VIM (four studies; 70%; 95% CI, 38-90%) carbapenemases, where genes were not detected or were not harboured in Pseudomonas aeruginosa (i.e. low prevalence). Performance of molecular tests in detecting AMR was generally comparable when grouped by geographical region (Europe, North America, and East Asia)., Discussion: High DTA support the use of molecular tests in identifying a broad panel of pathogens and detecting AMR in GNB and GPB., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Heterozygous variants in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson's Disease (PD). GBA1-PD patients exhibit earlier disease onset, severe motor impairment, and heightened cognitive decline. Deep Brain Stimulation (DBS) offers motor improvement for PD patients, but its cognitive effects, particularly in GBA1-PD, are debated., Methods: This study involved 96 PD patients who underwent subthalamic nucleus DBS at Hospital de la Santa Creu i Sant Pau between 2004 and 2023. Clinical and neuropsychological assessments were conducted pre- and post-surgery, focusing on Mattis Dementia Rating Scale (MDRS) and Frontal Systems Behavior Scale (FrSBe). Patients were categorized into GBA1-PD and non-GBA1-PD groups, with non-GBA1-PD further divided into cognitive fast-progressors and slow-progressors., Results: GBA1 variants were present in 13.5 % of patients. GBA1-PD patients showed greater cognitive decline over time, particularly in attention, conceptualization, and memory, compared to non-GBA1-PD. Non-GBA1-PD fast-progressors exhibited significant cognitive deterioration in initiation and conceptualization within the first year post-DBS. Motor outcomes improved similarly across all groups, but slow-progressors showed a greater reduction in Levodopa Equivalent Daily Dose (LEDD)., Conclusions: GBA1-PD patients experience more rapid cognitive decline, particularly in posterior-cortical and fronto-striatal functions. Additionally, a subset of non-GBA1-PD patients shows significant early cognitive decline post-DBS, especially in executive functions. Baseline MDRS scores do not predict cognitive outcomes, highlighting the need for further research to refine prognostic tools. Despite cognitive challenges, GBA1-PD patients benefit from DBS in terms of motor outcomes, underscoring the importance of individualized assessments for DBS suitability, regardless of genetic status., 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 Elsevier Ltd. All rights reserved.)

Objective: The treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains challenging due to the scarcity of proven effective therapeutic options. This study aimed to investigate the effectiveness and safety of Janus kinase inhibitors (JAKi) in RA-ILD., Methods: We systematically reviewed the literature to identify studies evaluating the efficacy and safety of JAK inhibitors in RA-ILD. A meta-analysis was performed using the random-effects model., Results: The literature search identified seven observational studies assessing the safety and efficacy of JAKi in RA-ILD and three studies analyzing the risk of developing de novo ILD in RA patients treated with JAKi. Among 183 patients with RA-ILD, the pooled analysis demonstrated an increase of 2.07 % in %pFVC (95 % CI: 0.57-3.58; p = 0.007) and 3.12 % in %pDLCO (95 % CI: 2.11-4.12; p < 0.001). Thoracic HRCT scans showed improvement in 11 % of patients (95 % CI: 0.01-0.29). The pooled proportion of patients experiencing worsening of pre-existing ILD was 5 % (95 % CI: 0.01-0.11). Adverse events were reported in 14 % of cases (95 % CI: 0.08-0.21), with the frequency of clinically significant infections ranging from 4.5 % to 25 %. The risk of developing de novo ILD in patients receiving JAKi was low, with an incidence rate of 0.20 per 1000 person-years (95 % CI: 0.14-0.25). Comparisons with abatacept and rituximab suggested similar efficacy and safety profiles., Conclusion: JAKi are well tolerated and might be a viable treatment option for RA-ILD, offering comparable safety and efficacy to abatacept and rituximab., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests related to the preparation of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA), potentially benefiting from FGFR inhibitors (FGFRi). We aimed to assess the feasibility of detecting FGFR2 fusions in plasma and explore plasma biomarkers for managing FGFRi treatment., Experimental Design: We conducted a retrospective study in 18 patients with iCCA and known FGFR2 fusions previously identified in tissue samples from prior FGFRi treatment. Both tissue and synchronous plasma samples were analyzed using a custom hybrid capture gene panel with next-generation sequencing (VHIO-iCCA panel) and validated against commercial vendor results. Longitudinal plasma analysis during FGFRi was performed. Subsequently, we explored the correlation between plasma biomarkers, liver enzymes, tumor volume, and clinical outcomes., Results: Sixteen patients (88.9%) were positive for FGFR2 fusion events in plasma. Remarkably, the analysis of plasma suggests that lower levels of ctDNA are linked to clinical benefits from targeted therapy and result in improved progression-free survival and overall survival. Higher concentrations of cell-free DNA before FGFRi treatment were linked to worse overall survival, correlating with impaired liver function and indicating compromised cell-free DNA removal by the liver. Additionally, increased ctDNA or the emergence of resistance mutations allowed earlier detection of disease progression compared with standard radiologic imaging methods., Conclusions: VHIO-iCCA demonstrated accurate detection of FGFR2 fusions in plasma. The integration of information from various plasma biomarkers holds the potential to predict clinical outcomes and identify treatment failure prior to radiologic progression, offering valuable guidance for the clinical management of patients with iCCA., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The growing diffusion of artificial intelligence, data science and digital health has highlighted the role of collection of data and biological samples, thus raising legal and ethical concerns regarding its use and dissemination. Further, the expansion of biobanking, from the basic collection of frozen specimens to the virtual biobanks of specimens and associated data that exist today, has given a revolutionary potential on healthcare systems, particularly in the field of neurological diseases, due to the inaccessibility of central nervous system and the need of non-invasive investigation approaches. Informed Consent (IC) is considered mandatory in all research studies and specimen collections, and must specifically take into account the ethical respect to the individuals to whom the used biological material and data belong., Methods: We evaluated the attitudes of patients with neurological diseases (NP) and healthy volunteers (HV) towards the donation of biological samples to a biobank for future research studies on neurological diseases, and limitations on the use of data, related to the requirements set by the General Data Protection Regulation (GDPR). The study involved a total of 1454 subjects, including 502 HVs and 952 NPs, recruited at Santa Lucia Foundation IRCCS, Rome, from 2020 to 2024., Results: We found that (i) almost all subjects agreed with the participation in biobanking (ii) and authorization to genetic studies (HV = 99.1%; NP = 98.3%); Regarding the return of results, (iii) we found a statistically significant difference between NP and HV, the latter preferring not to be informed of potential results (HV = 43%; NP = 11.3%; p < 0.0001); (iv) a small number limited the sharing inside European Union (EU) (HV = 4.6%; NP = 6.6%), whereas patients were more likely to refuse transfer outside EU (HV = 7.4%; NP = 10.7% p = 0.05); (v) nearly all patients agreed with the use of additional health data from EMR for research purposes (98.9%)., Conclusions: Consent for the donation of material for research purposes is crucial for biobanking and biomedical research studies that use biological material of human origin. Here, we have shown that choices regarding participation in a neurological biobank can be different between HVs and NPs, even if the benefit for research and scientific progress is recognized. NP have a strong interest in being informed of possible results but limit sharing of samples, highlighting a perception of greater individual or relative benefit, while HV prefer a wide dissemination and sharing of data but not to have the return of the results, favoring a possible benefit for society and knowledge. The results underline the need to carefully manage biological material and data collected in biobanks, in compliance with the GDPR and the specific requests of donors., (© 2024. The Author(s).)

Background : Lower respiratory tract infections (LRTIs) are a significant cause of primary care consultations. Differentiating between viral and bacterial infections is critical for effective treatment and to minimize unnecessary antibiotic use. This study investigates the impact of combining lung ultrasound (LUS) with capillary blood C-reactive protein (CRP) rapid testing on clinical decision-making for patients with LRTIs. Objectives : The primary objective is to assess how the integration of CRP testing and LUS influences antibiotic prescription decisions. The study aims to quantify the percentage change in antibiotic prescriptions before and after performing LUS, following history taking, clinical examination, and CRP testing. Methods : This analytical observational study will be conducted in six primary care centers within the Health Region of Lleida, Catalonia, serving a mixed urban and rural population of approximately 105,000 residents. The study will recruit 196 patients aged 18 and over, presenting with LRTI symptoms and not treated with antibiotics in the preceding 14 days. Participants will undergo CRP testing followed by LUS during their consultation. Statistical analyses, including linear regression, bivariate analysis, Pearson or Spearman correlation, and logistic regression, will be used to evaluate the impact of LUS on clinical decisions and its predictive value in diagnosing bacterial infections. Results and Conclusions : This study will provide insights into the role of LUS combined with CRP testing in improving diagnostic accuracy and guiding antibiotic prescription decisions in primary care. The findings aim to enhance treatment protocols for LRTIs, reducing unnecessary antibiotic use and improving patient outcomes.

Background: In response to the rising population of nursing home residents with frailty and multimorbidity, optimizing medication safety through drug utilization review and addressing medication-related problems (MRPs) is imperative. Clinical decision support systems help reduce medication errors and detect potential MRPs, as well as medication reviews performed by a multidisciplinary team, but these combined assessments are not commonly performed. The objective of this study was to evaluate the impact on medication plans of a multidisciplinary team intervention in nursing homes, by analyzing the medication plan before and after the intervention and assessing whether the recommendations given had been implemented., Methods: A multicenter before-after study, involving five nursing homes, assessed the impact of a multidisciplinary team intervention, to estimate effectiveness related to the review of the prescribed medications. The follow-up period for each patient was 12 months or until death if prior, from July 2020 to February 2022, and involved 483 patients. The clinical pharmacologist coordinated the intervention and reviewed all the prescribed medications to make recommendations, focused on the completion of absent data, withdrawal of a drug, verification of whether a drug was adequate, the substitution of a drug, and the addition of drugs. Since the intervention was performed during the COVID-19 pandemic, optimization of psychotropic drugs and absorbent pads were limited., Results: The intervention had an impact with recommendations given for 398 (82.4%) of the patients and which were followed by 58.5% of them. At least one drug was withdrawn in 293 (60.7%) of the patients, with a mean of 2.3 (SD 1.7). As for the total of 1,097 recommendations given, 355 (32.4%) were followed. From the intervention, antipsychotics, antidepressants, benzodiazepines, statins, and diuretics were the most frequently withdrawn., Conclusion: The findings underscore the impact of targeted interventions to reduce inappropriate medications and enhance medication safety in nursing homes. The proposed recommendations given and followed show the importance of a multidisciplinary team, coordinated by a clinical pharmacologist, for a patient-centered approach to make medication reviews regularly, with the help of clinical decision support systems, to help reduce potential MRPs and polypharmacy., 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 © 2024 Anderssen-Nordahl, Fernández-Liz, Sabaté Gallego, Bosch Ferrer, Sánchez-Arcilla Rosanas, Cervera León, Magrinyà and Barceló-Colomer.)

The objective of this study was to examine changes in healthcare-seeking behaviors and diagnostic practices around foodborne illness during the COVID-19 pandemic in a large university-based health system. A retrospective cohort study of individuals diagnosed with pathogens commonly transmitted through food between 2015 and 2020 was undertaken using electronic medical record data. Regression models were used to compare measured incidence rates of various foodborne pathogens as well as associated healthcare-seeking behaviors during the pandemic year of 2020 to previous years. Incidence of campylobacteriosis, cholera, and norovirus in 2020 significantly decreased, respectively, by 65.5% ( p < 0.01), 90.1% ( p = 0.02), and 73.0% ( p = 0.03) compared with an average from 2017- to 019. Average annual visits for patients included in our sample significantly increased by 8.0% when comparing the average from 2017-2019 to 2020 ( p < 0.01). These results suggest that the pandemic impacted healthcare use related to foodborne disease either due to reduced exposure to foodborne pathogens or reduced willingness to seek healthcare.

Chorea is a hyperkinetic movement disorder associated with various underlyingconditions, including autoimmune diseases such as antiphospholipid syndrome (APS). APS can manifest with a wide range of neurological symptoms, including chorea. We present a case of a 77-year-old man with subacute generalized chorea secondary to primary APS. Notably, the patient exhibited a left patellar crossed-reflex, a phenomenon rarely documented in chorea cases, the pathophysiology of which has not yet been elucidated. In summary, this case challenges the traditional demographics of antiphospholipid syndrome (APS) by suggesting a potential link between APS and late-age patients. It emphasizes the importance of considering APS in late-onset chorea cases., (© 2024. The Author(s).)

Colorectal cancer (CRC) is a significant global health issue where early detection is crucial for improving treatment outcomes and survival rates. This comprehensive review assesses the utility of stool-based tests in CRC screening, including traditional fecal occult blood tests (FOBT), both chemical (gFOBT) and immunochemical techniques (FIT), as well as multitarget stool DNA (mt-sDNA) as a novel and promising biomarker. The advancements, limitations and the impact of false positives and negatives of these methods are examined. The review analyzed various studies on current screening methods, focusing on laboratory tests and biomarkers. Findings indicate that while FIT and mt-sDNA tests offer enhanced sensitivity and specificity over traditional guaiac-based FOBT, they also come with higher costs and potential for increased false positives. FIT shows better patient adherence due to its ease to use, but incorrect usage and interpretation of FOBT can lead to significant diagnostic errors. In conclusion, despite the improvements in FOBT methods like FIT in CRC detection, careful consideration of each method's benefits and drawbacks is essential. Effective CRC screening programs should combine various methods tailored to specific population needs, aiming for early detection and reduced mortality rates.

Objectives: The presence of macro-B12 is a cause of factual hypervitaminemia B12. Precipitation with polyethylene glycol (PEG) is a simple method of removing high-molecular-weight biomolecules. However, "free" molecule may co-precipitate. This fact requires the establishment of reference intervals for the post-precipitation result. The main aims of the study were to: 1) establish post-PEG RIs for vitamin B12; 2) compare the two criteria for defining the presence of macro-B12; 3) evaluate the joint usefulness of percentage post-PEG vitamin B12 recovery and post-PEG RIs to inform the real vitamin B12 status; and 4), propose interpretative comments for ease of interpretation., Methods: Prospective study in which 488 serum samples from "healthy" individuals were included and analyzed to determine recovery and RIs following PEG precipitation. Subsequently, a retrospective analysis was carried out in order to evaluate the joint usefulness of both definitions for a suspicion of macro-B12. A total of 297 cases were included., Results: Recovery and post-PEG RIs determined on an Alinity i platform ranged from 60 to 107 % and from 118 to 506 pmol/L, respectively. McNemar's test revealed statistically significant differences between both criteria for estimating interference. However, both methodologies showed good agreement. In 27 cases, the presence of macro-B12 coexisted with true hypervitaminemia B12. No case of coexistence of macro-B12 with vitamin B12 deficiency was detected in our series., Conclusions: Laboratory reports should include total vitamin B12 concentration, recovery and post-PEG vitamin B12 concentration with their adjusted RIs to better assess the body vitamin status., Competing Interests: Competing interests: The authors state no conflicts of interest., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Respiratory viruses contribute to high morbidity and mortality in Africa. In 2020, the Ohio State University's Global One Health Initiative, in collaboration with the Ethiopian Public Health Institute and the US Centers for Disease Control and Prevention, took action to strengthen Ethiopia's existing respiratory virus surveillance system through decentralization of laboratory testing and scale-up of national and regional capacity for detecting respiratory viruses. In August 2022, four regional laboratories were established, thereby raising the number of reference laboratories conducting respiratory virus surveillance to five. This article highlights lessons learned during implementation and outlines processes undertaken for laboratory scale-up and decentralization., (Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene 2024.)

Objective: To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD)., Methods: Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants., Results: Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: ∆%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and ∆%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: ∆%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and ∆%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases., Conclusion: Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients., (© 2024. The Author(s).)

Background: Classical pulmonary thromboembolism (TE) and local pulmonary thrombosis (PT) have been suggested as mechanisms of thrombosis in COVID-19. However, robust evidence is still lacking because this was mainly based on retrospective studies, in which patients were included when TE was suspected., Methods: All patients with COVID-19 pneumonia underwent computed tomography and pulmonary angiography in a prospective study. The main objective was to determine the number and percentage of thrombi surrounded by lung opacification (TSO) in each patient, as well as their relationship with percentage of lung involvement (TLI), to distinguish classical TE (with a random location of thrombi that should correspond to a percentage of TSO equivalent to the TLI) from PT. We determined TLI by artificial intelligence. Analyses at patient level (TLI and percentage of TSO) and at thrombi level (TLI and TSO) were performed., Results: We diagnosed TE in 70 out of 184 patients. Three (2-8) thrombi/patient were detected. The percentage of TSO was 100% (75-100) per patient, and TLI was 19.9% (4.6-35.2). Sixty-five patients (92.9%) were above the random scenario with higher percentage of TSO than TLI. Most thrombi were TSO (n = 299, 75.1%). When evaluating by TLI (<10%, 10%-20%, 20%-30% and >30%), percentage of TSO was higher in most groups. Thrombi were mainly in subsegmental/segmental arteries, and percentage of TSO was higher in all locations., Conclusions: Thrombi in COVID-19 were found within lung opacities in a higher percentage than lung involvement, regardless of TLI and clot location, supporting the hypothesis of local PT rather than "classic TE"., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

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.

Introduction: The assessment of the cervical spine (CS) in axial spondyloarthritis (axSpA) and its radiographic characteristics, including the zygapophyseal joints (ZJ), may be helpful for an accurate diagnosis, establishing a prognosis and enhancing treatment decisions., Objectives: To describe the prevalence and characteristics of CS involvement in patients with axSpA and perform a comparison between groups according to cervical radiographic damage., Methods: Patients who fulfilled the Assessment of SpondyloArthritis International Society classification criteria were included from January 2011 to January 2021. Sociodemographic, clinical, radiographic and treatment variables were gathered. Patients were categorised into 'CS group' (Bath Ankylosing Spondylitis Radiology Index ≥2 or De Vlam score ≥3 for ZJ) and 'no CS group' as controls. ZJ fusion and interobserver reliability in ZJ scoring were analysed., Results: A total of 340 patients were included, 244 (71.7%) men, with mean age 57±15 years. CS involvement was observed in 181 (53.2%) patients. Patients in the CS group, as compared with no CS group, were predominantly men, older, had a higher body mass index, higher prevalence of smoking, showed higher disease activity, worse functionality and mobility, as well as more structural damage. Sixty-nine patients with CS involvement had ZJ fusion at some level. These patients showed worse mobility and more radiographic damage. Overall, ZJ involvement was observed in 99 patients (29.1%), 20 of whom did not present with vertebral body involvement., Conclusion: Radiographic evaluation of CS is relevant in patients with axSpA and should be assessed routinely. Evaluation of the ZJ is particularly significant, as it is related to higher disease activity and worse function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

One of the problems that most seriously affects oenology today is enzymatic browning, especially when grapes are infected by grey rot. We studied the capacity of glutathione (GSH) and a specific inactivated dry yeast rich in glutathione (IDY-GSH) to protect white grape must from browning compared to that of sulphur dioxide (SO 2 ). The results indicate that SO 2 drastically reduces the oxygen consumption rate (by around 72%), protects hydroxycinnamic acids from oxidation and prevents grape must against browning even in the presence of laccase. Specifically, the presence of SO 2 reduced the colour's blue-yellow component ( b *) by around 91% in control conditions and around 76% in the presence of laccase. GSH, pure or in the form of IDY-GSH, also reduces the oxygen consumption rate (by 23% and 36%, respectively) but to a lesser extent than SO 2 . GSH also favours the formation of grape reaction product (GRP) from hydroxycinnamic acids and effectively protects grape must against browning in healthy grape conditions. Specifically, the presence of GSH reduced b * by around 81% in control conditions. Nevertheless, in the presence of laccase, it was not effective enough, reducing b * by around 39% in the case of pure GSH and 24% in the case of IDY-GSH. Therefore, both forms of GSH can be considered as interesting alternative tools to SO 2 for preventing browning in white grape must, but only when the grapes are healthy.

Objective: To investigate the usefulness of 18 F-FDG PET-CT for assessing large-vessel (LV) involvement in patients with suspected giant cell arteritis (GCA) and a negative temporal artery biopsy (TAB)., Methods: A retrospective review of our hospital databases was conducted to identify patients with suspected GCA and negative TAB who underwent an 18 F-FDG PET-CT in an attempt to confirm the diagnosis. The gold standard for GCA diagnosis was clinical confirmation after a follow-up period of at least 12 months., Results: Out of the 127 patients included in the study, 73 were diagnosed with GCA after a detailed review of their medical records. Of the 73 patients finally diagnosed with GCA, 18 F-FDG PET-CT was considered positive in 61 cases (83.5%). Among the 54 patients without GCA, 18 F-FDG PET-CT was considered positive in only eight cases (14.8%), which included 1 case of Erdheim-Chester disease, 3 cases of IgG4-related disease, 1 case of sarcoidosis, and 3 cases of isolated aortitis. Overall, the diagnostic performance of 18 F-FDG PET-CT for assessing LV involvement in patients finally diagnosed with GCA and negative TAB yielded a sensitivity of 83.5%, specificity of 85.1%, and a diagnostic accuracy of 84% with an area under the ROC curve of 0.844 (95% CI: 0.752 to 0.936). The sensitivity was 89% in occult systemic GCA and 100% in extracranial LV-GCA., Conclusion: Our study confirms the utility of 18 F-FDG PET-CT in patients presenting with suspected GCA and a negative TAB by demonstrating the presence of LV involvement across different subsets of the disease., (© 2024. The Author(s).)

Graphene-based Field-Effect Transistors (FETs) integrated with microstrip patch antennas offer a promising approach for terahertz signal radiation. In this study, a dual-stage simulation methodology is employed to comprehensively investigate the device's performance. The initial stage, executed in MATLAB, delves into charge transport dynamics within a FET under asymmetric boundary conditions, employing hydrodynamic equations for electron transport in the graphene channel. Electromagnetic field interactions are modeled via Finite-Difference Time-Domain (FDTD) techniques. The second stage, conducted in COMSOL Multiphysics, focuses on the microstrip patch antenna's radiative characteristics. Notably, analysis of the S11 curve reveals minimal reflections at the FET's resonant frequency of 1.34672 THz, indicating efficient impedance matching. Examination of the radiation pattern demonstrates the antenna's favorable directional properties. This research underscores the potential of graphene-based FETs for terahertz applications, offering tunable impedance matching and high radiation efficiency for future terahertz devices.

Despite emerging evidence and advances in the management of atopic dermatitis there a lack of consensus regarding the diagnostic criteria, therapeutic approach, method to assess severity, and patient follow-up for this condition. An expert consensus study was conducted to provide recommendations on the management of patients with moderate-to-severe atopic dermatitis. The study used Delphi-like methodology based on a literature review, a summary of the scientific evidence, and a 2-round survey. The agreement of 60 panellists on 21 statements was evaluated. Consensus was pre-defined as ≥ 80% agreement of all respondents. In the first round 6 statements reached consensus. Unanimous consensus was achieved regarding therapeutic goals and patient satisfaction (maintained in the long term and periodic goals reassessment recommended every 3-6 months). In the second round, half of the statements reached consensus, all related to patient follow-up, treatment goals, and atopic comorbidities. The statements that did not reach consensus were related to diagnosis (biomarkers, allergy, and food testing) and starting patients on conventional systemic treatment rather than advanced treatment. The study assessed expert opinion regarding a variety of topics related to the clinical approach to patients with moderate-to-severe atopic dermatitis, in order to provide guidance on the diagnosis and management of patients with atopic dermatitis.

Introduction: The expansion of higher education is a worldwide phenomenon. To our knowledge, there are no studies analyzing the trends in demands of enrollment in health-related studies in Spain. Therefore, the objective was to analyze the change in demand (the number of requests for enrollment divided by the number of offered places) for undergraduate health-related studies in Spain during the period 2015-2021 as well as compare the change by region in the pre (2015-2019) and pandemic (2020-2021) period., Methods: This is an observational (ecological type) study with temporal series analyses using data from public (non-for-profit) higher education institutions from the Integrated University Information System. For the analysis by region, we calculated the demand of all twelve undergraduate health-related degrees and the percentages of change between both periods using the Wilcoxon test. The Joinpoint Regression program was used to analyze the trends in demand for each degree during the 7-year period., Results: Significant ( p < 0.001) increases in demand during the pandemic period were observed in all regions. During the pandemic, medicine, biomedicine, nursing, odontology and pharmacy presented a higher demand in comparison with data collected before the pandemic started. In contrast, this pattern was not confirmed in the following cases: physiotherapy, occupational therapy, podiatry, psychology, social work, human nutrition and dietetics. By regions, Navarra, Asturias, and La Rioja presented the most drastic changes. In regions with the biggest number of universities, such as Catalonia, Andalusia and Madrid, the change observed was smaller., Competing Interests: The authors declare that they have no competing interests., (© 2023 Jerez-Roig et al.)

Breast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection., Significance: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image. See related commentary by Cunningham and Turner, p. 2125. This article is featured in Selected Articles from This Issue, p. 2109., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: To examine the performance of the new 2022 American College of Rheumatology (ACR)/EULAR classification criteria for giant cell arteritis (GCA) in routine clinical care, compared with the 1990 ACR GCA classification criteria., Methods: The fulfilment of 2022 ACR/EULAR and 1990 ACR criteria was tested in our real-life cohort of GCA patients with proven vasculitis by temporal artery biopsy or imaging (a necessary pre-requisite to apply the new criteria is the presence of a confirmed diagnosis of medium- or large-vessel vasculitis). The performance of classification criteria was evaluated in all patients with GCA across different subsets of the disease. Patients with GCA were compared with unselected controls with suspected GCA., Results: A total of 136 patients with proven GCA were identified. The new criteria had a sensitivity of 92.6% and a specificity of 85.2%. According to the clinical phenotypes, the sensitivity was 98.8% in cranial GCA, 92% in extracranial large vessel (LV) GCA and 75% in occult systemic GCA. These data are much better than those observed with the 1990 ACR classification criteria, which showed a sensitivity of 66.1% and a specificity of 85.1% for the total sample, with a sensitivity of 89.1% in cranial GCA, 24% in extracranial LV-GCA and 35.7% in occult systemic GCA. Ten (7.4%) patients in our cohort did not fulfil either of the criteria sets (8 with occult systemic GCA and 2 with extracranial LV-GCA). The sensitivity of the new criteria in patients with occult systemic and extracranial LV-GCA could be greatly improved assigning more weight (3 points) to some imaging findings (axillary involvement and FDG-PET activity throughout the aorta)., Conclusion: Our study confirms that the new classification criteria are more sensitive in real-life settings than the old ACR criteria across all clinical phenotypes., Competing Interests: Declaration of Competing Interest The authors declare that there are no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Staphylococcus aureus causes a wide range of infections from mild skin and soft tissue to severe life-threatening bacteremia. The pathogenicity of S. aureus infections is related to various bacterial surface components and extracellular proteins such as toxic-shock syndrome (TSS) toxin and Panton-Valentine leukocidin (PVL). In this study we determine the antimicrobial resistance of isolated strains and their virulence genes in Ethiopia., Methods: A total of 190 archived S. aureus isolates from four Ethiopia Antimicrobial Resistance (AMR) Surveillance sites were analyzed. The identification of S. aureus was done by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF Biotyper) and antimicrobial susceptibility test (AST) was done using VITEK ® 2. Multiplex PCR was used to detect mecA, mecC, pvl and spa genes and super-antigens ( sea, seb, sec, seh and sej staphylococcal enterotoxins)., Results: A total of 172 isolates were confirmed as S. aureus , 9 (5.23%) were methicillin-resistant S. aureus (MRSA) and 163 (94.76%) were methicillin-susceptible S. aureus (MSSA). AST showed that 152 (88.4%) isolates were resistant to penicillin; 90 (52.32%) resistant to trimethoprim-sulfamethoxazole; and 45 (26.16%) resistant to tetracycline. A total of 66 (38.37%) isolates harbored at least one staphylococcal enterotoxin gene and 31 (46.96%) isolates had more than one. The most frequent enterotoxin gene encountered was seb 28 (16.28%). The TSST-1 gene was detected in 23 (13.37%). Presence of staphylococcal enterotoxin gene showed significant association with antibiotic resistance to cefoxitin, benzylpenicillin, oxacillin, erythromycin, clindamycin, tetracycline and SXT. The pvl gene was detected in 102 (59.3%) of isolates. Isolates from patients below 15 years of age showed significantly high numbers of pvl gene (P = 0.02). Presence of sej (P = 0.011) and TSST-1 (P <0.001) genes were associated with the presence of pvl gene., Conclusion: In this study, isolates were highly resistant to oral antibiotics and the pvl, seb, sea and TSST-1 genes were prevalent., Competing Interests: Dr Joan-Miquel Balada-Llasat reports grants, personal fees from BioMerieux, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Ibrahim et al.)

Diagnostic tools that can rapidly identify and characterize microbes growing in blood cultures are important components of clinical microbiology practice because they help to provide timely information that can be used to optimize patient management. This publication describes the bioMérieux BIOFIRE Blood Culture Identification 2 (BCID2) Panel clinical study that was submitted to the U.S. Food & Drug Administration. Results obtained with the BIOFIRE BCID2 Panel were compared to standard-of-care (SoC) results, sequencing results, PCR results, and reference laboratory antimicrobial susceptibility testing results to evaluate the accuracy of its performance. Results for 1,093 retrospectively and prospectively collected positive blood culture samples were initially enrolled, and 1,074 samples met the study criteria and were included in the final analyses. The BIOFIRE BCID2 Panel demonstrated an overall sensitivity of 98.9% (1,712/1,731) and an overall specificity of 99.6% (33,592/33,711) for Gram-positive bacteria, Gram-negative bacteria and yeast targets which the panel is designed to detect. One hundred eighteen off-panel organisms, which the BIOFIRE BCID2 Panel is not designed to detect, were identified by SoC in 10.6% (114/1,074) of samples. The BIOFIRE BCID2 Panel also demonstrated an overall positive percent agreement (PPA) of 97.9% (325/332) and an overall negative percent agreement (NPA) of 99.9% (2,465/2,767) for antimicrobial resistance determinants which the panel is designed to detect. The presence or absence of resistance markers in Enterobacterales correlated closely with phenotypic susceptibility and resistance. We conclude that the BIOFIRE BCID2 Panel produced accurate results in this clinical trial., Competing Interests: The authors declare a conflict of interest. This info is included in the body of the manuscript: Authors received research funds paid to their institutions from BIOFIRE Diagnostics, LLC, which is now known as bioMérieux, Inc. K.H., B.K., and D.Y.L. are employed by the study sponsor. D.D.R. was employed by University Hospitals Cleveland Medical Center during this study. D.D.R. has received research support from Altona, BD, bioMérieux, Bio-Rad, Cepheid, Cleveland Diagnostics, Luminex, HelixBind, Hologic, Qiagen, Q-Linea, Specific Diagnostics, Thermo Fisher, and Vela; and D.D.R. has or has had advisory relationships with Luminex, Next Gen Diagnostics, Renascent Diagnostics, Roche, and Seegene. A.L. has received research funding from BIOFIRE, Cepheid, and Luminex. J.-M.B.-L. has served as a consultant for bioMérieux and also participated in other BIOFIRE clinical studies. A.H. has received industry sponsored grant funding from bioMérieux (BIOFIRE), and Beckman Coulter, and she has consulted for Bio-Rad. G.J.B. has given educational seminars sponsored by BIOFIRE and has also served on a BIOFIRE advisory panel. R.S. has received honoraria from bioMérieux for speaking engagements.

The aim of this study was to determine whether the pandemic has reinforced the choice of pursuing health-related bachelor's degrees, and to identify underlying factors that could contribute to that impact. This is a cross-sectional study using an online survey of 2,344 students of nursing, physiotherapy, medicine, psychology and podiatry who started health-related bachelor's degrees after the COVID-19 outbreak in Spanish higher education institutions. The pandemic influenced the choice of these studies by increasing the desire to help others (33.2%), by increasing citizenship values (28.4%), and by increasing the desire to contribute to improving the situation of the country (27.5%). Women had a significantly greater influence on the increase in social values related to the practice of the profession produced by the pandemic, whereas men and the bachelor's degree in podiatry were more influenced by salary prospects. An increased desire to help others was significantly higher among women and nursing and medical students. Podiatry and psychology were the degrees were most influenced by the pandemic, as more students decided to pursue them, something they had previously doubted, while in nursing, psychology, and medicine the pandemic reinforced their interest in pursuing the degree the most. Students personally affected by COVID-19 reported being more influenced in reconsidering their professional path and in reinforcing their desire to pursue the health-related studies., (© 2023. The Author(s).)

Background-Aim: Most laboratory requests focus on the detection of possible vitamin B12 deficiency. In this context, methylmalonic acid (MMA) is reported as the best biomarker. The aim of our study was to establish the biological reference interval for MMA in urine, and assess the influence of age, sex, and vitamin B12 status on MMA concentrations., Methods: This is a prospective observational study considering individuals with normal results for blood count and liver and kidney function. Individuals who presented supplementation, any pathology or treatment that could cause cobalamin metabolism disorders, and pregnant women were excluded. Likewise, individuals whose vitamin B12 result presented antibody-mediated interference were excluded. Individuals were grouped by age-group and sex. Reference intervals were determined by non-parametric calculation (percentiles 1-99)., Results: It was established a single reference interval [0.52 (CI 90% : 0.50-0.54) - 5.75 (CI 90% : 5.57-6.17) mmolMMA/mol creatinine], with 100 % of individuals with MMA above the upper limit of reference presenting a total vitamin B12 concentration ≤ 238 pmol/L., Conclusion: The establishment of optimal reference intervals for methylmalonic acid excretion in urine is crucial in individuals with a suspicion of functional vitamin B12 deficiency. However, the possibility of establishing a cut-off value for total vitamin B12 suggesting subclinical deficiency remains a challenge for this magnitude., 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 © 2023 Elsevier B.V. All rights reserved.)

Objective: The search for new glucocorticoid-sparing disease-modifying anti-rheumatic drugs continues to be an unmet need in large vessel vasculitis (LVV). This report aims to assess the effectiveness and safety of leflunomide (LEF) in Takayasu arteritis (TA) and giant cell arteritis (GCA)., Methods: We systematically reviewed the literature, searching for studies evaluating the efficacy of LEF in LVV. A meta-analysis was conducted using the random-effects method., Results: The literature search identified eight studies that assessed LEF in TAK and seven in GCA. All were uncontrolled observational studies with a high risk of bias, implying a low or very-low certainty of evidence. In TAK, the pooled proportion of patients achieving at least a partial remission was 75% (95% CI: 0.64-0.84), angiographic stabilization was observed in 86% (0.77-0.94) and relapses in 12% (0.05-0.21). The mean reduction in the prednisolone dose (MRPD) after LEF treatment was 15.7 mg/d (10.28-21.16). Adverse events were observed in 8% of patients (0.02-0.16). Comparison of LEF with methotrexate (MTX) or cyclophosphamide revealed LEF to be superior in terms of remission induction, relapse prevention, and tolerance. When compared with tofacitinib, both drugs demonstrated comparable efficacy. In GCA, the pooled proportion of patients achieving at least a partial remission was 60% (0.17-0.95). The MRPD after LEF treatment was 15.63 mg/d (1.29-32.55) and 53% of the patients were able to discontinue glucocorticoids (0.25 - 0.80). Relapses were observed in 21% of cases (0.14- 0.28) and adverse events in 28% (0.12-0.46). Comparison of LEF with MTX showed similar efficacy and tolerance., Conclusion: LEF is well tolerated and might be effective for patients with TAK and GCA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Compassion is oriented towards perceiving and relieving suffering. Hence, its development is beneficial for mental health. Many interventions aimed at cultivating compassion in patients have been empirically supported. This meta-analysis analyses the effectiveness of compassion-focused therapy (CFT) in decreasing self-criticism, a vulnerability factor that has been related to several mental health problems, and in increasing self-soothing., Methods: A literature search was conducted in the PsycInfo, Web of Science, Medline and Scopus databases, through which 7 controlled trials (N = 640) and 7 observational studies (N = 207) were retrieved., Results: The results of the meta-analysis determine that CFT decreases the level of self-criticism and increases the ability to experience soothing. The size of the effect varies depending on the design of the study and the subscale of the test used to measure self-criticism (Forms of Self-Criticizing/Attacking and Self-Reassuring Scale)., Conclusions: CFT has proven to be an effective intervention for reducing self-criticism. However, given that the number of studies is small and that only half of them are controlled trials, the results must be interpreted cautiously. More randomized controlled trials comparing CFT with other therapies are needed to determine the effect of this intervention on self-criticism with more scientific evidence., (© 2022 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background-Aim: High vitamin B12 concentrations are considered a common finding in clinical practice. Thanks to immunoassay accessibility, vitamin B12 has become a usual test in routine health checkups. However, these analytical methods usually present antibody-mediated interferences. Our aim was to propose an algorithm for the screening of antibody-mediated analytical interferences on vitamin B12 immunoassays on the Alinity platform., Methods: Observational, prospective, case-control study was performed during 12 months. Individuals with persistently elevated cobalamin concentrations [>554 pmol/L] were considered as cases in the absence of supplementation or other justifying cause. Individuals under treatment with vitamin B12, or in the context of alcoholism were included as controls. A thorough interference study by macromolecules in immunoassays was performed in serum samples: PEG precipitation, rheumatoid factor, heterophile antibodies and gel permeation chromatography (GPC). Albumin, total B12, IgG and IgM were measured in every GPC collected fraction and chromatograms were drafted., Results: Up to 45% of cases presented interference by B12-immunocomplexes and the precipitation for all of them was >50%. The individual with the lowest interfered vitamin B12 result was 661 pmol/L., Conclusion: The presence of antibody-mediated interferences, mainly B12-immunocomplexes, is a relatively common phenomenon. A simple algorithm for the screening of interferences is useful and reliable in ruling out healthy individuals and highly cost-effective., 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 © 2023 Elsevier B.V. All rights reserved.)

Purpose: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA., Experimental Design: We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA&#95;PDX). The CCA&#95;PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA&#95;PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA&#95;PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues., Results: This collection of CCA&#95;PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA&#95;PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA&#95;PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD., Conclusions: Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA&#95;PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: Intimate partner violence (IPV) is a distressing reality worldwide. Victims of IPV usually experience long-term mental health disorders and maladjustments in their daily lives., Aims: To examine the prevalence of depression, anxiety, and post-traumatic stress disorder in female victims of IPV that participated in a public mental health care program, and to analyze the relationships between the type of IPV exposure, its psychological consequences, and daily life adjustment., Method: Up to 164 female victims of IPV referred by their primary care doctors to the Adult Mental Health Casntre of Sant Cugat del Vallès (Barcelona) between 2010 and 2016 were evaluated using several tests (Index of Spouse Abuse - ISA, Beck Depression Inventory - BDI-II, Sate-Trait Anxiety Inventory - STAI, the Maladjustment Scale - MS, and the Severity Symptom Scale for Post-traumatic Stress Disorder - EGS)., Results: Of the 164 referred women, 102 (62.2%) agreed to participate (mean age 44.98 years, range 19-71) and 73% scored above the cut-off point in the physical IPV dimension (ISA). Moreover, 73% had depression symptoms, 77% trait anxiety, and 87% state anxiety altered scores. Prevalence of post-traumatic stress disorder was also high (87%). IPV interfered significantly in all the aspects of the daily lives of 92% of the sample., Conclusions: The participants of the study experienced many psychological symptoms and a high level of interference with all aspects of their daily lives. These consequences were of similar magnitude amongst victims of emotional abuse compared to those who suffered physical violence.

Timely administration of appropriate antibiotic therapy is associated with better patient outcomes and lower costs of care compared to delayed appropriate therapy, yet initial treatment is often empiric since causal pathogens are typically unknown upon presentation. The challenge for clinicians is balancing selection of adequate coverage treatment regimens, adherence to antimicrobial stewardship principles to deter resistance, and financial constraints. This retrospective cohort study aimed to assess the magnitude and impact of delayed appropriate antibiotic therapy among patients hospitalized with septic arthritis (SA) in the U.S. from 2017 to 2019 using healthcare encounter data. Timely appropriate therapy was defined as the receipt of antibiotic(s) with in vitro activity against identified pathogens within two days of admission; all other patients were assumed to have received delayed appropriate therapy. Of the 517 patients admitted to hospital for SA who met all selection criteria, 26 (5.0%) received delayed appropriate therapy. In inverse-probability-treatment-weighting-adjusted analyses, the receipt of delayed appropriate therapy was associated with an additional 1.1 days of antibiotic therapy, 1.4 days in length of stay, and $3531 in hospital costs (all vs. timely appropriate therapy; all p ≤ 0.02). Timely appropriate therapy was associated with a twofold increased likelihood of antibiotic de-escalation during the SA admission.

Objectives: High manganese (Mn) levels during fetal growth or prolonged parenteral nutrition (PN) may have adverse effects on neurodevelopment. We aim to report on Mn levels and their short-term impact on clinical course in very low birth weight infants., Methods: An observational study including newborns with a gestational age (GA) ≤32 weeks and/or ≤1500 g of birth weight (BW). Newborns received intravenous supplementation of Mn at 1 µg/kg/day (Peditrace ® ) in PN and continued with fortified breast milk. Mothers answered surveys about dietary and other habits and blood levels of Mn in newborns were analyzed at days 1, 15, and 30 of life. Associations of Mn levels with mothers' and newborns' data were evaluated and adjusted for multiple comparisons., Results: One hundred and sixty premature infants were recruited. Median blood Mn levels at birth were 43.0 and 24.5 µg/L at day 30. No important association with mothers' data was found. Median [interquartile range (IQR)] duration of PN was 8 days (7-14). A prolonged PN and late oral feeding showed a nonsignificant association with lower blood Mn levels at day 30 ( P = 0.010, P threshold 0.003). Mn levels at day 15 and 30 were associated with increasing GA ( P < 0.001). Low Mn was not a significant predictor of adverse outcomes such as retinopathy of prematurity, bronchopulmonary dysplasia, or respiratory distress syndrome after adjusting for potential confounders and multiple testing., Conclusions: Mn showed lower levels with decreasing GA and prolonged PN. Using a low Mn PN solution may not raise blood Mn levels in premature infants., Competing Interests: S.V.-L., M.T., P.C., J.M.B., and E.B. are the members of the Fundació Institut d’Investigació Sanitària Illes Balears – IdISBa. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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.)

Background: The objective of this article was to assess the long-term efficacy and safety of the MV140 vaccine to prevent recurrent urinary tract infections (UTIs)., Methods: This is a prospective, descriptive, comparative and multicenter study of 1003 patients with 3 or more urinary infections for 12 months, treated with the MV140 vaccine from 2011 to 2021., Variables: Age, gender, urinary infections at 3, 6 and 12 months, distribution according to age and months of the year, smoking, use of MV140 vaccines and autovaccines., Results: Mean age was 78 and 82.7% were women. At baseline, 84.1% had 3 to 5 infections. According to age, 68.6% had >70 years. There were more consultations in March (12.3%) and fewer in August (4.4%). Smokers represented 24.6% and 21.8% follow autovaccines. Results at 3 months: 0 UTI 45%, 1 UTI 31.3%, 2 UTI 19.2%. 6 months: 0 UTI 29.3%, 1 UTI 33.2%, 2 UTI 24.3%. 12 months: 0 UTI 9%, 1 UTI 28.2%, 2 UTI 17.5%. Smokers: 0-1 UTI 80.2% (3 months), 65.5% (6 months), 53.9% (12 months). Non-smokers: 0-1 UTI 85.8% (3 months), 66.8% (6 months), 20% (12 months). p = 0.41, 0.27 and 0.21 respectively. Vaccines: 0-1 UTI 74.5% (3 months), 61% (6 months), 38.8% (12 months). Autovaccines: 0-1 UTI 82.7% (3 months), 68 % (6 months), 28.2% (12 months). p = 0.04, 0.25 and 0.63 respectively., Conclusions: MV140 reduced the number of UTI to 0-2 in 95.5% at 3 months, 86.8% at 6 months and 54.7% at 12 months. Smoking did not worsen the response of MV140. Autovaccines achieved better results than vaccines only at 3 months. Adverse effects represented 1.49%, but no patient had to abandon treatment.

Background: The lysis of platelets during in vitro coagulation leads to increased potassium concentrations.We aimed to establish the cut-off value for platelet count interfering serum potassium and to estimate the percentage of cases of pseudohyperkalemia and pseudonormokalemia in our hospital., Materials and Methods: Individuals diagnosed with essential thrombocytosis (2010-2019) based on the WHO criteria for the classification of myeloid neoplasms and acute leukemia were considered.The cut-off value for the interference of platelet count on serum potassium results was calculated using the reference change value. Sensitivity and specificity were calculated using a ROC-curve, and the size of the effect by the Cohen's d.The clinical impact of both phenomena was assessed by reviewing the medical records of individuals classified as such, and also looking for potential cases in 2019 on the laboratory information system., Results: Fifty-four individuals with essential thrombocytosis were included. Potassium concentration correlated with platelet count (P-value<0.001; Spearman's ρ =0.394) in serum. The cut-off value of platelet count interfering potassium was 598x10 3 /μL [CI95%: 533-662x10 3 /μL], with an associated sensitivity and specificity of 0.67 [CI95%:0.52-0.80] and 0.58 [CI95%:0.42-0.72] respectively.The medical records of patients classified as pseudohyperkalemia or pseudonormokalemia did not include any medical action for the modification of potassium levels. In 2019, up to 0.14% of the total serum potassium determinations were susceptible to be pseudohyperkalemia or pseudonormokalemia., Conclusion: This study provides a cut-off value for platelet count interfering serum potassium concentrations, and brings to light not only pseudohyperkalemia-related issues, but also the pseudonormokalemia phenomenon, which usually goes unnoticed., Competing Interests: Declaration of competing interests All authors declare no conflicts of interest., (Copyright © 2022 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.)

Objective: To analyse determinants of mortality at 15 years in a population over 60 years of age and physically active., Methods: This is a prospective longitudinal study. After 15 years of participating in an active ageing programme, participants were contacted by telephone to verify their state of health and to determine whether in that time they had had any fractures., Results: 561 individuals over 60 years of age were included, 82% of whom were women. Only differences in densitometric data, FRAX values and history of previous fracture at baseline characteristics were found between the group that died at 15 years and the group that remained alive. The only variables that were related to mortality risk were the basal data of the densitometric t-score (OR = .50, P < .001) and history of fracture in any location (OR = 2.44, P < .033)., Conclusions: The value of bone mineral density could be considered as a useful biomarker to calculate the risk of mortality in people over 60 years old with a physically active lifestyle., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Providing evidence-based interpretative comments (IC) is an integral task of clinical laboratory professionals. It may be of special relevance for coagulation testing, where pathological first-line tests could trigger more specialized tests. Our aim was to evaluate the quality of ICs provided to the physician in two samples with activated partial thromboplastin time (APTT) prolongation., Material and Methods: Two lyophilized plasma samples and their respective fictional clinical cases (case 1: heparin contamination and case 2: factor VIII deficiency) were sent to European laboratories for APTT and APTT mixing test measurement, and elaboration of ICs based on their results. The quality of ICs was evaluated in terms of analytical classification, laboratory interpretation, advice to physician, clarity, length and whether the clinical question was answered., Results: A total of 214 laboratories were included. Classification of the analytical result was stated in 57 % of comments. Laboratory interpretation was found in 91 % of comments for case 1 and 83.3 % for case 2, among which 9.3 % and 6.5 % were considered wrong, respectively. Advice for the requesting physician was provided in 65.8 % of comments for case 1 and 61.2 % for case 2, among which 36 % and 4.7 % were considered wrong, respectively. More than 70 % of comments for both cases were evaluated as clear and of an adequate length., Conclusion: A significant number of laboratories provide clear interpretations and helpful advice for the management of altered coagulation results. Nevertheless, the finding of several confusing and misleading comments highlights the need for recommendations on elaboration of interpretative comments., 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 Elsevier B.V. All rights reserved.)

Background: Unexpected prolongation of first-line coagulation tests, including activated partial thromboplastin time (APTT), should trigger further work-up by performing mixing tests to elucidate the underlying cause, direct further specific testing and clarify their possible clinical impact. The aim of our study was to assess whether methodological diversity has any impact on the APTT mixing test results and their interpretation., Material and Methods: Two lyophilized plasma samples (case 1: heparin contamination [0.5 IU/mL]; case 2: factor VIII deficiency [0.13 IU/mL]) and their respective fictional clinical cases were sent to European laboratories for APTT measurement and performance of mixing tests. Participants were surveyed about the methodology (reagents, analytical platform, reference ranges), APTT results, mixing test conditions, their classification (normal, equivocal, prolonged) and categorization of the sample (factor deficiency, presence of inhibitor, anticoagulant, unknown)., Results: A total of 269 responses were included. For case 1, all participants reported a prolonged APTT, and 91% obtained no correction in the mixing test, without differences among reagents or analytical platforms. Only 15% of them selected the presence of an anticoagulant as the single cause for the prolongation. For case 2, 99% of participants reported a prolonged APTT, while some heterogeneity in the mixing test results was found. Eighty-six percent of participants selected factor deficiency as the cause for APTT prolongation., Conclusions: Most European laboratories obtained valid results for APTT and the subsequent mixing tests, despite using different methodologies. However, their classification could be improved. Therefore, more training and periodic evaluations are recommended to harmonize protocols and ensure proper result classification and categorization., 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 Elsevier B.V. All rights reserved.)

Introduction: Staphylococcus infection-associated glomerulonephritis (SAGN), is an autoimmune sequela of infection affecting a subset of infected patients without specific predictive factors, frequently presenting with acute nephritic syndrome and propensity for chronic kidney disease. We performed a comparative genotypic and phenotypic analysis of S. aureus isolates from patients that did and those that did not develop SAGN., Methods: We had 22 culture-proven cases of SAGN from Ohio State University Wexner Medical Center (OSUWMC) from 2004 to 2016, 9 of 22 being blood cultures, with archived isolates. These, along with blood culture isolates from 12 patients with no clinical evidence of SAGN (between ages 40 to 80 years) over the same period were used for genotyping. For host demographic comparison, we used all available SAGN cases ( n  = 85, including those with positive cultures other than blood; and patients with kidney biopsies received from referring hospitals) and all OSUWMC patients with positive Staphylococcus cultures without glomerulonephritis (GN) ( n  = 23,496)., Results: Multiple sequence types (STs) suggesting strain diversity was seen in the GN isolates with mainly clonal complexes (CC) 5 and 59. Mutations in the agr operon were identified in significantly higher number of the GN isolates (83%) than non-GN isolates (16%). Significant differences in β-hemolysis and biofilm formation was also observed between the groups., Conclusion: The functionality of these agr mutants remains to be seen, but the presently known effects of reduced agr function, namely increased surface adhesins, biofilm formation, and persistent bacteremia could be important microbial factors predisposing to SAGN and testing for them early during infection could help to predict its development., (© 2022 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)