Long-term cardiovascular outcomes in a population-based multicentric cohort of northern Portugal: Validation of the ESC/EAS prognostic risk classification.

BACKGROUND: Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions. OBJECTIVE: To assess the association of CV-risk categories and criteria with long-term CV events. METHODS: Observational cohort study between 2000-2019 on patients aged 40-80 years, followed by 14 primary care centers assisted by 1 hospital in Portugal. Follow-up began when electronic health records data allowed for CV-risk classification and dynamic reassessment per 2019 ESC/EAS Guidelines. Inclusion criteria required at least one appointment with a primary care physician within three years before follow-up initiation. We assessed the 10-year adjusted hazard-ratio of combined CV death and non-fatal Atherosclerotic Cardiovascular Disease (ASCVD) hospitalization, across SCORE risk categories and criteria, using Cox proportional hazards models adjusted for sex, age, competing comorbidities, and medication. RESULTS: The study included 161 681 observations from 87 035 unique patients. During the observation period, 71 787 patients were classified as low/moderate, 51 476 as high and 38 418 as very-high CV-risk categories. In the very-high group, prevalent comorbidities were hypertension (69%), hypercholesterolemia (69%) and type 2 diabetes (61%), and 13% were hospitalized for ASCVD. The adjusted 10-year hazard ratio of the composite of CV death or ASCVD hospitalization was 2.10 (95% CI: 1.91-2.32) for high-risk and 3.56 (95% CI: 3.21-3.96) for very-high-risk patients (low-risk as reference). CONCLUSION: Our study reinforces the prognostic relevance of CV-risk stratification for long-term prediction of CV death and ASCVD hospitalization in an unselected cohort, independently of sex, age, competing comorbidities and medication.

Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Convergent and environmentally associated chromatic polymorphism in Bryconops Kner, 1858 (Ostariophysi: Characiformes: Iguanodectidae).

Bryconops Kner, 1858, includes two well defined subgenera based on morphological evidence, with each containing at least one species (B. (Bryconops) caudomaculatus and B. (Creatochanes) melanurus) with a very wide distribution, within which regional populations present color variations. To test if phenotypic variation is related to cladogenetic events, we performed tests for phylogenetic independence and determined the strength of convergence for color characters in relation to water type, as the variation between clear, black and white waters is considered to be one of the major driving forces in the evolution of Amazonian fishes. Color characters for fins above the median line of the body were generally found to be independent from phylogeny and the Wheatsheaf test strongly supports convergence of the dorsal fin color between populations of species in the same type of water, with a similar trend suggested for the color of the dorsal lobe of the caudal fin. This means that simple color characters cannot necessarily be relied upon for taxonomic revisions of the genus as local phenotypic variants may represent environmentally determined plasticity or convergent evolution. Further studies are required to determine the validity of these characters.

Building Bridges between People with Stroke, Families, and Health Professionals: Development of a Blended Care Program for Self-Management.

Evidence-informed interventions for stroke self-management support can influence functional capability and social participation. People with stroke should be offered self-management support after hospital discharge. However, in Portugal, there are no known programs of this nature. This study aimed to develop a person-centered and tailored blended care program for post-stroke self-management, taking into account the existing evidence-informed interventions and the perspectives of Portuguese people with stroke, caregivers, and health professionals. An exploratory sequential mixed methods approach was used, including qualitative methods during stakeholder consultation (stage 1) and co-production (stage 2) and quantitative assessment during prototyping (stage 3). After ethical approval, recruitment occurred in three health units. Results from a literature search led to the adaptation of the Bridges Stroke Self-Management Program. In stage one, 47 participants were interviewed, with two themes emerging: (i) Personalized support and (ii) Building Bridges through small steps. In stage two, the ComVida program was developed, combining in-person and digital approaches, supported by a workbook and a mobile app. In stage three, 56 participants evaluated prototypes, demonstrating a strong level of quality. Understandability and actionability of the developed tools obtained high scores (91-100%). The app also showed good usability (A-grade) and high levels of recommendation (5 stars).

Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.

A Modular Microfluidic Organoid Platform Using LEGO-Like Bricks.

The convergence of organoid and organ-on-a-chip (OoC) technologies is urgently needed to overcome limitations of current 3D in vitro models. However, integrating organoids in standard OoCs faces several technical challenges, as it is typically laborious, lacks flexibility, and often results in even more complex and less-efficient cell culture protocols. Therefore, specifically adapted and more flexible microfluidic platforms need to be developed to facilitate the incorporation of complex 3D in vitro models. Here, a modular, tubeless fluidic circuit board (FCB) coupled with reversibly sealed cell culture bricks for dynamic culture of embryonic stem cell-derived thyroid follicles is developed. The FCB is fabricated by milling channels in a polycarbonate (PC) plate followed by thermal bonding against another PC plate. LEGO-like fluidic interconnectors allow plug-and-play connection between a variety of cell culture bricks and the FCB. Lock-and-play clamps are integrated in the organoid brick to enable easy (un)loading of organoids. A multiplexed perfusion experiment is conducted with six FCBs, where thyroid organoids are transferred on-chip within minutes and cultured up to 10 d without losing their structure and functionality, thus validating this system as a flexible, easy-to-use platform, capable of synergistically combining organoids with advanced microfluidic platforms.

Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet.

BACKGROUND: Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult. RESULTS: Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance the MEME Suite, adding the capacity to handle custom alphabets. We adapt the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet. Using these methods, we identify modification-sensitive transcription factor binding motifs. We confirm established binding preferences, such as the preference of ZFP57 and C/EBPß for methylated motifs and the preference of c-Myc for unmethylated E-box motifs. CONCLUSIONS: Using known binding preferences to tune model parameters, we discover novel modified motifs for a wide array of transcription factors. Finally, we validate our binding preference predictions for OCT4 using cleavage under targets and release using nuclease (CUT&RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications.

The sound of silence: Quantification of typical absence seizures by sonifying EEG signals from a custom-built wearable device.

OBJECTIVE: To develop and validate a method for long-term (24-h) objective quantification of absence seizures in the EEG of patients with childhood absence epilepsy (CAE) in their real home environment using a wearable device (waEEG), comparing automatic detection methods with auditory recognition after seizure sonification. METHODS: The waEEG recording was acquired with two scalp electrodes. Automatic analysis was performed using previously validated software (Persyst® 14) and then fully reviewed by an experienced clinical neurophysiologist. The EEG data were converted into an audio file in waveform format with a 60-fold time compression factor. The sonified EEG was listened to by three inexperienced observers and the number of seizures and the processing time required for each data set were recorded blind to other data. Quantification of seizures from the patient diary was also assessed. RESULTS: Eleven waEEG recordings from seven CAE patients with an average age of 8.18 ± 1.60 years were included. No differences in the number of seizures were found between the recordings using automated methods and expert audio assessment, with significant correlations between methods (ρ > .89, p < .001) and between observers (ρ > .96, p < .001). For the entire data set, the audio assessment yielded a sensitivity of .830 and a precision of .841, resulting in an F1 score of .835. SIGNIFICANCE: Auditory waEEG seizure detection by lay medical personnel provided similar accuracy to post-processed automatic detection by an experienced clinical neurophysiologist, but in a less time-consuming procedure and without the need for specialized resources. Sonification of long-term EEG recordings in CAE provides a user-friendly and cost-effective clinical workflow for quantifying seizures in clinical practice, minimizing human and technical constraints.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.

Characterization and LDL-C management in a cohort of high and very high cardiovascular risk patients: The PORTRAIT-DYS study.

AIM: This study aims to characterize sociodemographic and clinical characteristics, use of lipid-lowering therapies (LLTs), and low-density lipoprotein cholesterol (LDL-C) control in a population with increased cardiovascular (CV) risk. METHODS: A cross-sectional observational study that uses electronic health records of patients from one hospital and across 14 primary care health centers in the North of Portugal, spanning from 2000 to 2020 (index date). Patients presented at least (i) 1 year of clinical data before inclusion, (ii) one primary care appointment 3 years before the index date, and (iii) sufficient data for CV risk classification. Patients were divided into three cohorts: high CV risk; atherosclerotic cardiovascular disease (ASCVD) risk equivalents without established ASCVD; evidence of ASCVD. CV risk and LDL-C control were defined by the 2019 and 2016 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidemia guidelines. RESULTS: A total of 51 609 patients were included, with 23 457 patients classified as high CV risk, 19 864 with ASCVD equivalents, and 8288 with evidence of ASCVD. LDL-C control with 2016 ESC/EAS guidelines was 32%, 10%, and 18% for each group, respectively. Considering the ESC/EAS 2019 guidelines control level was even lower: 7%, 3%, and 7% for the same cohorts, respectively. Patients without any LLT prescribed ranged from 37% in the high CV risk group to 15% in patients with evidence of ASCVD. CONCLUSION: We found that LDL-C control was very low in patients at higher risk of CV events. An alarming gap between guidelines on dyslipidemia management and clinical implementation persists, even in those at very high risk or with established ASCVD.

Chromatographic Methods Developed for the Quantification of Quercetin Extracted from Natural Sources: Systematic Review of Published Studies from 2018 to 2022.

Quercetin (QUE) is the most widely used flavonoid for therapeutic purposes. To improve the available knowledge about the properties of some natural products, determining the amount of QUE is crucial. The main objective of this systematic review is to identify the analytical methods validated for detecting and quantifying QUE in different matrices and characterize their sensitivity. A search was conducted until 30 June 2023 in the PubMed database for experimental studies that addressed the validation of chromatographic analytical methods to detect and quantify QUE from consumable natural products. Only studies published between 2018 and 2022, written in English, were included. The risk of bias was assessed by emphasizing methods of comparison according to previously published studies. Descriptive statistics were used to depict the obtained results. The studies were analyzed based on the type of QUE source, chromatographic method, and validation parameters. A total of 17 studies were included in this review. Plants were the most commonly analyzed source of QUE. Among the detection methods, spectrophotometry proved to be the most widely used, surpassing mass spectrometry (MS). After analyzing the bias, all the included studies mentioned/presented, totally or partially, at least four of the eight parameters.

Validation of an HPLC-DAD Method for Quercetin Quantification in Nanoparticles.

The evaluation of the efficacy of incorporation of quercetin in nanoparticles is crucial, both for the development and quality control of pharmaceutical formulations. The validation of analytical methods for the precise quantification of quercetin is useful for the evaluation of various potential quercetin delivery systems and quercetin pharmacokinetics. This work aimed to validate a high-performance liquid chromatography with diode array detection (HPLC-DAD) method for quercetin detection and quantification in nanoparticles. Different mobile phase conditions and detection wavelengths (254 and 368 nm) were tested, and the major validation parameters were assessed (precision, accuracy, linearity, sensitivity, stability, and selectivity). The best peak resolution was obtained when quercetin was analyzed at 368 nm with a mobile phase of 1.5% acetic acid and a water/acetonitrile/methanol ratio of 55:40:5. Under these conditions, quercetin also eluted rapidly (retention time of 3.6 min). The method proved to be linear (R2 > 0.995), specific, and repeatable (variation coefficient between 2.4% and 6.7%) and presented intermediate precision (variation coefficient between 7.2% and 9.4%). The accuracy of the analysis ranged between 88.6% and 110.7%, and detection and quantification limits were 0.046 and 0.14 µg/mL, respectively. Quercetin solutions were more stable when stored at 4 °C than at room temperature or -20 °C. This validated method satisfied more parameters of bias assessment than most recent methods for quercetin determination and presented itself as more sensitive and efficient than general spectrophotometric methods. The method was successfully used for the analysis of quercetin incorporation in nanoparticles and will be evaluated in the future for its adequacy for the determination of quercetin in more complex matrices.

Visceral Leishmaniasis Revealing Undiagnosed Inborn Errors of Immunity.

Visceral Leishmaniasis (VL) is a potentially fatal disease and may be associated with primary or acquired immunodeficiencies. There are few reports, in the literature, of inborn errors of immunity. Here, we report two cases of VL as a marker of inborn errors of immunity, namely, GATA2 and RAB27A deficiency. Our data suggest that VL patients should be screened for primary immunodeficiency, particularly in cases of VL relapse.

DNA metabarcoding assessment of Neotropical ichthyoplankton communities is marker-dependent.

The study of ichthyoplankton is paramount to understanding fish assemblages' reproductive dynamics. DNA metabarcoding has been applied as a rapid, cost-effective, and accurate taxonomy tool, allowing the identification of multiple individuals simultaneously. However, there remain significant challenges when using DNA metabarcoding, such as molecular marker choice according to the taxonomic resolution and length of the fragment to be sequenced, primer bias, incomplete reference databases, and qualitative inference incongruences. Here, 30 ichthyoplankton pools collected from a Neotropical river were identified at a molecular level using DNA metabarcoding to compare the resolution, sensibility, specificity, and relative read abundance (RRA) recovery of three molecular markers: the standard COI fragment (650 pb, with each end analyzed individually) and two short 12S rRNA genes markers (≅200 bp - NeoFish and MiFish markers). The combined use of the three markers increased the genera detection rates by 25%-87.5%, allowing an increased taxonomic coverage and robust taxonomic identification of complex Neotropical ichthyoplankton communities. RRA is marker-dependent, indicating caution is still needed while inferring species abundance based on DNA metabarcoding data when using PCR-dependent protocols.

Enhancing the Longevity and Functionality of Ti-Ag Dry Electrodes for Remote Biomedical Applications: A Comprehensive Study.

This study aims to evaluate the lifespan of Ti-Ag dry electrodes prepared using flexible polytetrafluoroethylene (PTFE) substrates. Following previous studies, the electrodes were designed to be integrated into wearables for remote electromyography (EMG) monitoring and electrical stimulation (FES) therapy. Four types of Ti-Ag electrodes were prepared by DC magnetron sputtering, using a pure-Ti target doped with a growing number of Ag pellets. After extensive characterization of their chemical composition and (micro)structural evolution, the Ti-Ag electrodes were immersed in an artificial sweat solution (standard ISO-3160-2) at 37 °C with constant stirring. Results revealed that all the Ti-Ag electrodes maintained their integrity and functionality for 24 h. Although there was a notable increase in electrical resistivity beyond this timeframe, the acquisition and transmission of (bio)signals remained viable for electrodes with Ag/Ti ratios below 0.23. However, electrodes with higher Ag content (Ag/Ti = 0.31) became insulators after 7 days of immersion due to excessive Ag release into the sweat solution. This study concludes that higher Ag/Ti atomic ratios result in heightened corrosion processes on the electrode's surface, consequently diminishing their lifespan despite the advantages of incorporating Ag into their composition. This research highlights the critical importance of evaluating electrode longevity, especially in remote biomedical applications like smart wearables, where electrode performance over time is crucial for reliable and sustained monitoring and stimulation.

Investigation of the effects of phthalates on in vitro thyroid models with RNA-Seq and ATAC-Seq.

Introduction: Phthalates are a class of endocrine-disrupting chemicals that have been shown to negatively correlate with thyroid hormone serum levels in humans and to cause a state of hyperactivity in the thyroid. However, their mechanism of action is not well described at the molecular level. Methods: We analyzed the response of mouse thyroid organoids to the exposure to a biologically relevant dose range of the phthalates bis(2-ethylhexyl) phthalate (DEHP), di-iso-decylphthalate (DIDP), di-iso-nonylphthalate (DINP), and di-n-octylphthalate (DnOP) for 24 h and simultaneously analyzed mRNA and miRNA expression via RNA sequencing. Using the expression data, we performed differential expression and gene set enrichment analysis. We also exposed the human thyroid follicular epithelial cell line Nthy-ori 3-1 to 1 µM of DEHP or DINP for 5 days and analyzed changes in chromatin accessibility via ATAC-Seq. Results: Dose-series analysis showed how the expression of several genes increased or decreased at the highest dose tested. As expected with the low dosing scheme, the compounds induced a modest response on the transcriptome, as we identified changes in only mmu-miR-143-3p after DINP treatment and very few differentially expressed genes. No effect was observed on thyroid markers. Ing5, a component of histones H3 and H4 acetylation complexes, was consistently upregulated in three out of four conditions compared to control, and we observed a partial overlap among the genes differentially expressed by the treatments. Gene set enrichment analysis showed enrichment in the treatment samples of the fatty acid metabolism pathway and in the control of pathways related to the receptor signalling and extracellular matrix organization. ATAC-Seq analysis showed a general increase in accessibility compared to the control, however we did not identify significant changes in accessibility in the identified regions. Discussion: With this work, we showed that despite having only a few differentially expressed genes, diverse analysis methods could be applied to retrieve relevant information on phthalates, showing the potential of in vitro thyroid-relevant systems for the analysis of endocrine disruptors.

Novel Variant of SLC34A3 in a Compound Heterozygous Brazilian Girl with Hereditary Hypophosphatemic Rickets with Hypercalciuria.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare FGF23-independent disorder caused by biallelic variants in the SLC34A3 gene. The disease severity varies, and patients have an increased risk of developing renal complications. Phosphate supplementation is standard of care and active vitamin D analogs are not indicated as they could worsen the hypercalciuria. We report a Brazilian girl with HHRH who presented with knee pain and progressive genu valgum deformity that became apparent later in childhood (at age 8). Nephrocalcinosis was also identified at age 13. Next-generation sequencing (NGS) target panel directed to inherited forms of rickets detected compound heterozygous pathogenic variants in SLC34A3, including a novel missense variant c.1217G>T (p.Gly406Val). Compliance to oral phosphorus therapy was suboptimal and adjunctive chlorthalidone therapy improved hypercalciuria. Our case highlights the phenotypic variability of patients with HHRH and expands the growing list of SLC34A3 variants associated with this disorder. An accurate diagnosis is crucial for proper treatment, and a thiazide diuretic may be useful as adjunctive therapy for controlling hypercalciuria.

Unveiling Fungal Community Structure along Different Levels of Anthropic Disturbance in a South American Subtropical Lagoon.

Studies of fungal communities through amplicon metagenomics in aquatic environments, particularly in freshwater ecosystems, are still relatively recent. Unfortunately, many of these water bodies are facing growing threats from human expansion, such as effluent discharge from various human activities. As a result, these effluents have the potential to significantly alter the characteristics of water bodies and, subsequently, impact the diversity of their resident microorganisms. In this context, our objective was to investigate whether the fungal community structure varies according to the presence of different anthropic disturbances. We expect (i) the diversity of fungi will be greater and (ii) more specific unique operational taxonomic units (OTUs) related to each ecotonal system will be found compared to other sites of a lagoon. The study was conducted in the Tramandaí Lagoon (subtropical southern Brazil) at four distinct sampling points (estuary, middle of the lagoon, crop field area, and near a residential area where the Tramandaí River flows into the lagoon). As expected, the estuary and residential zones, which are ecotones, exhibited greater fungal diversity and more specific OTUs compared to the middle of the lagoon and crop field area. Moreover, a substantial proportion of fungal taxa could not be identified at the genus level, with many only classified at the phylum level, indicating potential new lineages. These findings underscore our limited understanding of the subtropical freshwater mycobiota.

The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population.

Introduction: The imbalance between Th17 and regulatory T cells in inflammatory bowel diseases (IBD) promotes intestinal epithelial cell damage. In this scenario, T helper cell lineage commitment is accompanied by dynamic changes to the chromatin that facilitate or repress gene expression. Methods: Here, we characterized the chromatin landscape and heterogeneity of intestinal and peripheral CD4 T cellsfrom IBD patients using in house ATAC-Seq and single cell RNA-Seq libraries. Results: We show that chromatin accessibility profiles of CD4 T cells from inflamed intestinal biopsies relate to genes associated with a network of inflammatory processes. After integrating the chromatin profiles of tissue-derived CD4 T cells and in-vitro polarized CD4 T cell subpopulations, we found that the chromatin accessibility changes of CD4 T cells were associated with a higher predominance of pathogenic Th17 cells (pTh17 cells) in inflamed biopsies. In addition, IBD risk loci in CD4 T cells were colocalized with accessible chromatin changes near pTh17-related genes, as shown in intronic STAT3 and IL23R regions enriched in areas of active intestinal inflammation. Moreover, single cell RNA-Seq analysis revealed a population of pTh17 cells that co-expresses Th1 and cytotoxic transcriptional programs associated with IBD severity. Discussion: Altogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients.

Severe infections in Portuguese patients with rheumatoid arthritis under biologic treatment - a multicenter, nationwide study (SIPPRA-B Study).

INTRODUCTION: Despite years of experience with biological disease modifying anti-rheumatic drugs (bDMARD) in rheumatoid arthritis (RA), little is known about differences in infectious risk among bDMARDs. The aim of this study was to assess the incidence and type of infections in RA patients on bDMARDs and to determine possible predictors. METHODS: A retrospective multicenter cohort study that included patients registered in the Rheumatic Diseases Portuguese Registry (Reuma.pt) with RA, and exposed to at least one bDMARD until April 2021. RA patients under bDMARD and with at least one episode of severe infection (SI), defined as infection that requires hospitalization, use of parenteral antibiotics or that resulted in death, were compared to patients with no report of SI. Demographic and clinical data at baseline and at the time of each SI were collected to establish comparisons between different groups of bDMARDs. Comparisons between different bDMARDs were assessed and logistic regression was performed to identify predictors of SI. RESULTS: We included 3394 patients, 2833 (83.5%) female, with a mean age at RA diagnosis of 45.5±13.7 years. SI was diagnosed in 142 of the 3394 patients evaluated (4.2%), totaling 151 episodes of SI. At baseline, patients with SI had a significantly higher proportion of prior orthopedic surgery, asthma, interstitial lung disease, chronic kidney disease and corticosteroid use, higher mean age and longer median disease duration at first bDMARD. Nine patients died (6.0%). Ninety-two SI (60.9%) occurred with the first bDMARD, the majority leading to discontinuation of the bDMARD within 6 months (n=75, 49.7%), while 65 (43.0%) restarted the same bDMARD and 11 (7.3%) switched to another bDMARD (6 of them to a different mechanism of action). In the multivariate analysis, we found that chronic kidney disease, asthma, infliximab, corticosteroid use, interstitial lung disease, previous orthopedic surgery, higher Health Assessment Questionnaire and DAS284V-ESR are independent predictors of SI. CONCLUSION: This study described the incidence and types of SI among Portuguese RA patients on biologics, identifying several predictors of SI, both globally and with different bDMARDs. Physicians should be aware of the real-word infectious risk in RA patients on bDMARDs when making treatment decisions.