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Peter C Taylor,1 Codrina Ancuta,2 Orsolya Nagy,3 María C de la Vega,4 Andrey Gordeev,5 Radka Janková,6 Umut Kalyoncu,7 Ivan Lagunes-Galindo,3 Jadranka Morović-Vergles,8 Mariana Peixoto GU e Silva de Souza,9 Bernadette Rojkovich,10 Prodromos Sidiropoulos,11 Atsushi Kawakami12 1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 2Department of Rheumatology, “Grigore T. Popa” University of Medicine and Pharmacy, Iași, Romania; 3AbbVie Inc, North Chicago, IL, USA; 4CEIM Investigaciones Medicas, Buenos Aires, Argentina; 5V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation; 6Department of Pediatric and Adult Rheumatology, Faculty Hospital Motol, Prague, Czech Republic; 7Department of Internal Medicine, Division of Rheumatology, Hacettepe University, Ankara, Turkey; 8Department of Internal Medicine, Division of Clinical Immunology, Allergology and Rheumatology, Dubrava University Hospital, University of Zagreb School of Medicine, Zagreb, Croatia; 9Santa Casa de Belo Horizonte, Belo Horizonte, Brazil; 10Department of Rheumatology and Physiotherapy, Polyclinic of the Hospitaller Brothers of St. John of God, Semmelweis University, Budapest, Hungary; 11Faculty of Medicine, University of Crete, Heraklion, Greece; 12Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanCorrespondence: Peter C TaylorBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Headington, Oxford, OX3 7LD, UKTel +44 1865 227323Email peter.taylor@kennedy.ox.ac.ukBackground: Patients’ needs and perspectives are important determinants of treatment success in rheumatoid arthritis (RA). Assessing patients’ perspectives can help identify unmet needs and enhance the understanding of treatment benefits.Objective: The SENSE study assessed the impact of inadequate response to disease-modifying antirheumatic drugs (DMARDs) on treatment satisfaction, disease outcomes, and patient perspectives related to RA disease management.Methods: SENSE was a noninterventional, cross-sectional study conducted in 18 countries across Europe, Asia, and South America. Adult patients with poorly controlled RA of moderate/high disease activity were eligible. Patient satisfaction was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM v1.4). Treatment adherence, healthcare resource utilization (HRU), quality of life (QoL), work ability, digital health literacy (DHL), patient preference information, and treatment strategy were also assessed.Results: A total of 1624 patients were included in the study: most were female (84.2%) and middle-aged, and mean disease duration was 10.5 years. Mean TSQM global satisfaction subscore was 60.9, with only 13.5% of patients reporting good treatment satisfaction (TSQM global ≥ 80). The strongest predictor of good treatment satisfaction was treatment with advanced therapies. Most patients (87.4%) reported good treatment adherence. In general, patients had impaired QoL and work ability, high HRU, and 67.4% had poor DHL. Leading treatment expectations were “general improvement of arthritis” and “less joint pain”. Most patients preferred oral RA medications (60.7%) and rapid (≤ 1 week) onset of action (71.1%). “Increased risk for malignancies” and “increased risk for cardiovascular disease” were the least acceptable side effects. Despite suboptimal control, advanced therapies were only used in a minority of patients, and DMARD switches were planned for only half of the patients.Conclusion: Suboptimal disease control negatively impacts treatment satisfaction, work ability, QoL, and HRU. Data collected on patient perspectives may inform shared decision-making and optimize treat-to-target strategies for improving patient outcomes in RA.Keywords: adherence, digital health literacy, patient preference, rheumatoid arthritis, treatment satisfaction

Purpose: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This study aimed to assess the impact of implementing a clinical care pathway algorithm on reducing the time to treatment for ICI-P., Methods: Patients with lung cancer and suspected ICI-P were enrolled, and a multimodal intervention promoting algorithm use was implemented in two phases. Pre- and post-intervention analyses were conducted to evaluate the primary outcome of time from ICI-P diagnosis to treatment initiation., Results: Of the 82 patients admitted with suspected ICI-P, 73.17% were confirmed to have ICI-P, predominantly associated with non-small cell lung cancer (91.67%) and stage IV disease (95%). Pembrolizumab was the most commonly used immune checkpoint inhibitor (55%). The mean times to treatment were 2.37 days in the pre-intervention phase, 3.07 days (p = 0.46), and 1.27 days (p = 0.40) in the post-intervention phases 1 and 2, respectively. Utilization of the immunotoxicity order set significantly increased from 0 to 27.27% (p = 0.04) after phase 2. While there were no significant changes in ICU admissions or inpatient mortality, outpatient pulmonology follow-ups increased statistically significantly, demonstrating enhanced continuity of care. The overall mortality for patients with ICI-P was 22%, underscoring the urgency of optimizing management strategies. Notably, all patients discharged on high-dose corticosteroids received appropriate gastrointestinal prophylaxis and prophylaxis against Pneumocystis jirovecii pneumonia infections at the end of phase 2., Conclusion: Implementing a clinical care pathway algorithm for managing severe ICI-P in hospitalized lung cancer patients standardizes practices, reducing variability in management., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Communication failures are among the most common causes of harmful medical errors. At one Comprehensive Cancer Center, patient handoffs varied among services. The authors describe the implementation and results of an organization-wide project to improve handoffs and implement an evidence-based handoff tool across all inpatient services., Methods: The research team created a task force composed of members from 22 hospital services-advanced practice providers (APPs), trainees, some faculty members, electronic health record (EHR) staff, education and training specialists, and nocturnal providers. Over two years, the task force expanded to include consulting services and Anesthesiology. Factors contributing to ineffective handoffs were identified and organized into categories. The EHR I-PASS tool was used to standardize handoff documentation. Training was provided to staff on its use, and compliance was monitored using a customized dashboard. I-PASS champions in each service were responsible for the rollout of I-PASS in their respective services. The data were reported quarterly to the Quality Assessment and Performance Improvement (QAPI) governing committee. Provider handoff perception was assessed through the biennial Institution-wide safety culture survey., Results: All fellows, residents, APPs, and physician assistants were trained in the use of I-PASS, either online or in person. Adherence to the I-PASS written tool improved from 41.6% in 2019 to 70.5% in 2022 (p < 0.05), with improvements seen in most services. The frequency of updating I-PASS elements and the action list in the handoff tool also increased over time. The handoff favorability score on the safety culture survey improved from 38% in 2018 to 59% in 2022., Conclusion: The implementation approach developed by the Provider Handoff Task Force led to increased use of the I-PASS EHR tool and improved safety culture survey handoff favorability., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Banana ( Musa acuminata ) is the most important crop in the Canary Islands (38.9% of the total cultivated area). The main pathogen affecting this crop is the soil fungal Fusarium oxysporum f. sp. cubense subtropical race 4 ( Foc -STR4), for which there is no effective control method under field conditions. Therefore, the use of native biological control agents may be an effective and sustainable alternative. This study aims to: (i) investigate the diversity and distribution of Trichoderma species in the rhizosphere of different banana agroecosystems affected by Foc -STR4 in Tenerife (the island with the greatest bioclimatic diversity and cultivated area), (ii) develop and preserve a culture collection of native Trichoderma species, and (iii) evaluate the influence of soil chemical properties on the Trichoderma community. A total of 131 Trichoderma isolates were obtained from 84 soil samples collected from 14 farms located in different agroecosystems on the northern (cooler and wetter) and southern (warmer and drier) slopes of Tenerife. Ten Trichoderma species, including T. afroharzianum, T. asperellum, T. atrobrunneum, T. gamsii, T. guizhouense, T. hamatum, T. harzianum, T. hirsutum, T. longibrachiatum , and T. virens , and two putative novel species, named T . aff. harzianum and T . aff. hortense , were identified based on the tef1-α sequences. Trichoderma virens (35.89% relative abundance) and T. aff. harzianum (27.48%) were the most abundant and dominant species on both slopes, while other species were observed only on one slope (north or south). Biodiversity indices (Margalef, Shannon, Simpson, and Pielou) showed that species diversity and evenness were highest in the healthy soils of the northern slope. The Spearman analysis showed significant correlations between Trichoderma species and soil chemistry parameters (mainly with phosphorus and soil pH). To the best of our knowledge, six species are reported for the first time in the Canary Islands ( T. afroharzianum, T. asperellum, T. atrobrunneum, T. guizhouense, T. hamatum, T. hirsutum ) and in the rhizosphere of banana soils ( T. afroharzianum, T. atrobrunneum, T. gamsii, T. guizhouense, T. hirsutum , T. virens ). This study provides essential information on the diversity/distribution of native Trichoderma species for the benefit of future applications in the control of Foc -STR4., 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 Correa-Delgado, Brito-López, Jaizme Vega and Laich.)

Recent advances in cryo-electron microscopy (Cryo-EM) have revolutionized our understanding of the complement C5a/C3a receptors that are crucial in inflammation. A recent report by Yadav et al. has elucidated the activation, ligand binding, selectivity, and signaling bias of these receptors, thereby enhancing structure-guided drug discovery. This paves the way for more effective anti-inflammatory therapies that target these receptors with unprecedented precision., Competing Interests: Declaration of interests F.J.F. is an employee and a shareholder of Abvance Biotech SL. M.C.V. is a founder of Abvance Biotech SL and a member of its scientific advisory board., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Immune checkpoint inhibitors (ICI) have become standard of care for some types of lung cancer. Along with expanding usage comes the emergence of immune-related adverse events (irAEs), including ICI-related pneumonitis (ICI-P). Treatment guidelines for managing irAEs have been developed; however, how clinicians manage irAEs in the real-world setting is less well known. We aimed to describe the outcomes and care patterns of grade ≥ 3 ICI-P in an onco-hospitalist service., Patients and Methods: We included patients with lung cancer treated with ICI who were admitted to an oncology hospitalist service with a suspicion of ICI-P. We described the hospitalization characteristics, treatment patterns, discharge practices, and clinical outcomes of patients with confirmed ICI-P. The primary outcome was time to start treatment for ICI-P., Results: Among 49 patients admitted with a suspicion of ICI-P, 31 patients were confirmed to have ICI-P and subsequently received ICI-P directed treatment. Pulmonology was consulted in 97% of patients. Median time to start treatment for ICI-P was 1 day (IQR 0-3.5 days). All 31 patients received corticosteroids. Inpatient mortality was 32%. Majority of patients discharged with steroids were prescribed prophylaxis for gastritis and opportunistic infections. Thirty-eight percent of patients were seen by pulmonology and 86% were seen by the oncology team post-discharge., Conclusion: Our study confirms prior findings of high mortality among patients with high-grade ICI-P. Early diagnosis and treatment are key to improving clinical outcomes. Understanding the care patterns and adherence to treatment guidelines of clinicians caring for this patient population may help identify ways to further standardize management practices and improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Understanding of immune-related adverse events (irAEs) has evolved rapidly, and management guidelines are continually updated. We explored temporal changes in checkpoint inhibitor-induced irAE management at a tertiary cancer care center to identify areas for improvement. We conducted a single-center retrospective study of patients who developed a gastrointestinal, pulmonary, renal, or cardiac irAE between July and 1 October in 2019 or 2021. We collected patient demographic and clinical information up to 1 year after toxicity. Endoscopic evaluation and specialty follow-up after discharge for patients with gastrointestinal irAEs declined between the 2019 and 2021 periods. Symptom duration and steroid taper attempts also declined. For pulmonary irAEs, rates of specialty consultation, hospital admission and readmission, and mortality improved in 2021 compared with 2019. Follow-up rates after hospital discharge were consistently low (<50%) in both periods. For cardiac irAEs, consultation with a cardiologist was frequent and prompt in both periods. Outpatient treatment and earlier specialty consultation improved outcomes with gastrointestinal irAEs. Our study exploring irAE practice changes over time identified areas to improve management; specifically, timely specialty consultation was associated with better outcomes for gastrointestinal irAEs. These findings can help improve the quality of management algorithms at our institution and may inform policies in other institutions.

X-ray crystallography has for most of the last century been the standard technique to determine the high-resolution structure of biological macromolecules, including multi-subunit protein-protein and protein-nucleic acids as large as the ribosome and viruses. As such, the successful application of X-ray crystallography to many biological problems revolutionized biology and biomedicine by solving the structures of small molecules and vitamins, peptides and proteins, DNA and RNA molecules, and many complexes-affording a detailed knowledge of the structures that clarified biological and chemical mechanisms, conformational changes, interactions, catalysis and the biological processes underlying DNA replication, translation, and protein synthesis. Now reaching well into the first quarter of the twenty-first century, X-ray crystallography shares the structural biology stage with cryo-electron microscopy and other innovative structure determination methods, as relevant and central to our understanding of biological function and structure as ever. In this chapter, we provide an overview of modern X-ray crystallography and how it interfaces with other mainstream structural biology techniques, with an emphasis on macromolecular complexes., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: The objective of this study was to assess the SARS-CoV-2-specific humoral and T cell response after a two-dose regimen of SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA)., Methods: In this observational study, patients with RA who are ≥18 years of age and vaccinated for SARS-CoV-2 according to the Argentine National Health Ministry's vaccination strategy were included. Anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies (ELISA-COVIDAR test), neutralizing activity (cytotoxicity in VERO cells), and specific T cell response (IFN-γ ELISpot Assay) were assessed after the first and second dose., Results: A total of 120 patients with RA were included. Mostly, homologous regimens were used, including Gam-COVID-Vac (27.5%), ChAdOx1 (24.2%), and BBIBP-CorV (22.5%). The most frequent combination was Gam-COVID-Vac/mRNA-1273 (21.7%). After the second dose, 81.7% presented with anti-SARS-CoV-2 antibodies, 70.0% presented with neutralizing activity, and 65.3% presented with specific T cell response. The use of BBIBP-CorV and treatment with abatacept (ABA) and rituximab (RTX) were associated with undetectable antibodies and no neutralizing activity after two doses. BBIBP-CorV was also associated with the absence of T cell response. The total incidence of adverse events was 357.1 events per 1,000 doses, significantly lower with BBIBP-CorV (166.7 events per 1,000 doses, P < 0.02)., Conclusion: In this RA cohort vaccinated with homologous and heterologous regimens against COVID-19, 2 out of 10 patients did not develop anti-SARS-CoV-2 IgG, 70% presented with neutralizing activity, and 65% presented with specific T cell response. The use of BBIBP-CorV was associated with deficient humoral and cellular response, whereas treatment with ABA and RTX resulted in an impaired anti-SARS-CoV-2 IgG formation and neutralizing activity., (© 2023 American College of Rheumatology.)

The specific kinetics and thermodynamics of protein-protein interactions underlie the molecular mechanisms of cellular functions; hence the characterization of these interaction parameters is central to the quantitative understanding of physiological and pathological processes. Many methods have been developed to study protein-protein interactions, which differ in various features including the interaction detection principle, the sensitivity, whether the method operates in vivo, in vitro, or in silico, the temperature control, the use of labels, immobilization, the amount of sample required, the number of measurements that can be accomplished simultaneously, or the cost. Bio-Layer Interferometry (BLI) is a label-free biophysical method to measure the kinetics of protein-protein interactions. Label-free interaction assays are a broad family of methods that do not require protein modifications (other than immobilization) or labels such as fusions with fluorescent proteins or transactivating domains or chemical modifications like biotinylation or reaction with radionuclides. Besides BLI, other label-free techniques that are widely used for determining protein-protein interactions include surface plasmon resonance (SPR), thermophoresis, and isothermal titration calorimetry (ITC), among others., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The critical enzyme dihydrofolate reductase-thymidylate synthase in Leishmania major ( Lm DHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, a cornerstone of the parasite's reproductive processes. Consequently, the development of inhibitors against Lm DHFR-TS is crucial for the creation of novel anti- Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred in the Asteraceae family. We conducted a combined ligand/structure-based virtual screening to identify potential inhibitors against Lm DHFR-TS. Through consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid ( 237 ), diarctigenin ( 306 ), and isolappaol A ( 308 ), that exhibited a high probability of being inhibitors according to both approaches and were consequently classified as promising hits. Subsequently, we expanded the binding mode examination of these compounds within the active site of the test enzyme through molecular dynamics simulations, revealing a high degree of structural stability and minimal fluctuations in its tertiary structure. The in silico predictions were then validated through in vitro assays to examine the inhibitory capacity of the top-ranked naturally occurring compounds against Lm DHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC 50 values ranging from 6.1 to 10.1 μM. In contrast, other common cinnamic acid derivatives (i.e., flavonoid glycosides) from the Asteraceae family, such as hesperidin, isovitexin 4'- O -glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using Hs DHFR with moderate inhibitory effect. Among these hits, lignans 306 and 308 demonstrated the highest selectivity, displaying superior SI values compared to methotrexate, the reference inhibitor of DHFR-TS. Therefore, continued research into the anti-leishmanial potential of these C6C3-hybrid butyrolactone lignans may offer a brighter outlook for combating this neglected tropical disease.

The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were associated with the subsequent development of organ-specific irAEs. Notably, ACHRG IgM was associated with pneumonitis, anti-cytokeratin 19 IgM with dermatitis, and anti-thyroglobulin IgG with hepatitis. These antibodies merit further investigation as potential biomarkers for identifying high-risk populations for irAEs and/or monitoring irAEs during immunotherapy treatment., Trial Registration: ClinicalTrials.gov identifier: NCT03391869., Competing Interests: Outside of the submitted work MA reports receiving research funding to institution from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and receives consultant and advisor fees from GlaxoSmithKline, Bristol Myers Squibb, Shattuck Lab and AstraZeneca, Speaker fees: AstraZeneca, Nektar Therapeutics, SITC, Participation of Safety review committee for Nanobiotix-MDA alliance, Hengenix outside of the submitted work; NV reports receiving research funding to institution: Mirati, Circulogene and receives consultant fees from Sanofi, Regeneron, Eli Lilly, OncoCyte; JG reports consulting/advisory committee fees from CRISPR Therapeutics, Jounce Therapeutics, Polaris, Seagen, AstraZeneca, Aveo Pharmaceuticals, Infinity Pharmaceuticals, Janssen, Pfizer, and Symphogen; SG reports receiving research funding to institution from Bristol Myers Squibb; MBA reports consulting fees from Astra Zeneca; LB reports receiving research funding to institution AstraZeneca, Amgen, Jazz Pharmaceuticals, reports consulting/advisory committee fees from for AstraZeneca, AbbVie, Arrowhead Pharmaceuticals, Genetech, AbbVie, Merck, Jazz Pharmaceuticals, BeiGene, Chugai Pharmaceuticals, Puma, Amgen, Daiichi Sankyo; JZ reports grants from Merck, grants and personal fees from Johnson and Johnson and Novartis, personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent and Hengrui; JH has served on the scientific advisory boards for AstraZeneca, Biotree, Bristol-Myers Squibb, Boehringer Ingelheim, Catalyst, EMD Serono, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Eli Lilly, Novartis, Seattle Genetics, Spectrum, Synta, Foundation Medicine, Takeda, Mirati Therapeutics, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, and Leads Biolabs. He receives research support from AstraZeneca, Bayer, GlaxoSmithKline, Spectrum, and Takeda, and royalties and licensing fees from Spectrum. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Altan, Li, Wang, Vokes, Sheshadri, Gao, Zhu, Tran, Gandhi, Antonoff, Swisher, Wang, Byers, Abdel-Wahab, Franco-Vega, Wang, Lee, Zhang and Heymach.)

Objective: To evaluate the association between patients' characteristics and disease activity in an Argentine lupus registry., Methods: Cross-sectional study. Disease activity was stratified into: Remission off-treatment: SLEDAI = 0, without prednisone and immunosuppressive drugs. Low disease activity Toronto Cohort (LDA-TC): SLEDAI ≤2, without prednisone or immunosuppressive drugs. Modified lupus low disease activity (mLLDAS): SLEDAI score of ≤4, with no activity in major organ systems and no new features, prednisone of ≤10 mg/day and/or immunosuppressive drugs (maintenance dose) and Active disease: SLEDAI score of >4 and prednisone >10 mg/day and immunosuppressive drugs. A descriptive analysis and logistic regression model were performed., Results: A total of 1346 patients were included. Of them, 1.6% achieved remission off steroids, 0.8% LDA-TC, 12.1% mLLDAS and the remaining 85.4% had active disease. Active disease was associated with younger age ( p ≤ 0.001), a shorter time to diagnosis ( p ≤ 0.001), higher frequency of hospitalizations ( p ≤ 0.001), seizures ( p = 0.022), serosal disease ( p ≤ 0.001), nephritis ( p ≤ 0.001), higher SDI ( p ≤ 0.001), greater use of immunosuppressive therapies and higher doses of prednisone compared to those on mLLDAS. In the multivariable analysis, the variables associated with active disease were the presence of pleuritis (OR 2.1, 95% CI 1.2-3.9; p = 0.007), persistent proteinuria (OR 2.5, 95% CI 1.2-5.5; p ≤ 0.011), nephritis (OR 2.5, 95% CI 1.2-5.6; p = .018) and hospitalizations (OR 8.9, 95% CI 5.3-16.0; p ≤ 0.001) whereas age at entry into the registry was negatively associated with it (OR 0.9, 95% CI 0.9-1.0; p = 0.029)., Conclusion: Active disease was associated with shorter time to diagnosis, worse outcomes (SDI and hospitalizations) and renal, neurological and serosal disease., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: Pneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival., Materials and Methods: We conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality., Results: The median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03-1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3-11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0-6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0-23.0, P < 0.001) were associated with higher all-cause mortality., Conclusions: Risk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Lack of consistent and standardised handoffs is a leading cause of patient harm. With increased census in our hospital medicine (HM) service, failure to handoff using a standardised method has the potential to cause significant patient harm. We used a quality improvement methodology to standardise an existing and validated handoff tool within our HM team to improve handoff communication among providers and improve patient safety., Methods: A quality improvement team was charged with studying handoff communication among HM teams and between day and night shift providers at a tertiary oncology hospital. Multiple plan-do-study-act cycles were conducted, and process flow maps, root cause analysis and an affinity diagram were developed based on feedback from the HM team. The quality improvement team developed a plan to implement I-PASS (Illness severity, Patient summary, Action list, Situation awareness and contingency plan, and Synthesis by receiver) as the standardised handoff tool to be used among the providers in HM at the end of shift and for handoff to the nocturnal covering service. Rates of I-PASS use were collected before and after several educational interventions to encourage use of I-PASS and were displayed in a control chart. After the I-PASS interventions, HM providers were surveyed twice to evaluate the secondary outcomes: the tool's impact on workflow, perceptions of patient safety, ease of use and satisfaction with I-PASS. Survey results were compared using Fisher exact tests., Results: The HM team's rate of use of I-PASS handoffs increased from 23% to 72%, an improvement of 68%. By the end of the quality improvement project, I-PASS use had increased to 90%. No significant differences were detected in the reported duration of handoffs after I-PASS implementation (on average <5 min per patient, p=0.205). Provider perceptions of handoff quality, efficiency, communication errors and the I-PASS tool's effectiveness were satisfactory., Conclusion: We used a quality improvement methodology to encourage the HM team's adoption of a validated handoff tool. Adherence to the standardised handoff tool significantly improved workflows and facilitated communication between the day and night shift teams., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The complement system plays crucial roles in a wide breadth of immune and inflammatory processes and is frequently cited as an etiological or aggravating factor in many human diseases, from asthma to cancer. Complement receptors encompass at least eight proteins from four structural classes, orchestrating complement-mediated humoral and cellular effector responses and coordinating the complex cross-talk between innate and adaptive immunity. The progressive increase in understanding of the structural features of the main complement factors, activated proteolytic fragments, and their assemblies have spurred a renewed interest in deciphering their receptor complexes. In this review, we describe what is currently known about the structural biology of the complement receptors and their complexes with natural agonists and pharmacological antagonists. We highlight the fundamental concepts and the gray areas where issues and problems have been identified, including current research gaps. We seek to offer guidance into the structural biology of the complement system as structural information underlies fundamental and therapeutic research endeavors. Finally, we also indicate what we believe are potential developments in the field., Competing Interests: Abvance Biotech SL provided salaries for KdlP and FJF. The remaining 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 © 2023 Santos-López, de la Paz, Fernández and Vega.)

Objective: The aim of this study was to provide an evidence-based framework to guide health care professionals treating patients under glucocorticoid (GC) therapy and develop guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in postmenopausal women and men aged ≥50 years., Methods: An expert panel on bone diseases designed a series of clinically meaningful questions following the PICO (Population, Intervention, Comparator, and Outcome) structure. Using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, we made a systematic literature review, extracted and summarized the effect estimates, and graded the quality of the evidence. The expert panel voted each PICO question and made recommendations after reaching an agreement of at least 70%., Results: Seventeen recommendations (9 strong and 8 conditional) and 8 general principles were developed for postmenopausal women and men aged ≥50 years under GC treatment. Bone mineral density (BMD), occurrence of fragility fractures, probability of fracture at 10 years by Fracture Risk Assessment Tool, and other screening factors for low BMD are recommended for patient evaluation and stratification according to fragility fracture risk. The treatment of patients under GC therapy should include counseling on lifestyle habits and strict control of comorbidities. The goal of GIO treatment is the nonoccurrence of new fragility fractures as well as to increase or maintain BMD in certain clinical situations. This was considered for the therapeutic approach in different clinical scenarios., Conclusions: This GIO guideline provides evidence-based guidance for health care providers treating patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The circulating form of human endoglin (sEng) is a cleavage product of membrane-bound endoglin present on endothelial cells. Because sEng encompasses an RGD motif involved in integrin binding, we hypothesized that sEng would be able to bind integrin αIIbβ3, thereby compromising platelet binding to fibrinogen and thrombus stability., Methods: In vitro human platelet aggregation, thrombus retraction, and secretion-competition assays were performed in the presence of sEng. Surface plasmon resonance (SPR) binding and computational (docking) analyses were carried out to evaluate protein-protein interactions. A transgenic mouse overexpressing human sEng (hsEng + ) was used to measure bleeding/rebleeding, prothrombin time (PT), blood stream, and embolus formation after FeCl 3 -induced injury of the carotid artery., Results: Under flow conditions, supplementation of human whole blood with sEng led to a smaller thrombus size. sEng inhibited platelet aggregation and thrombus retraction, interfering with fibrinogen binding, but did not affect platelet activation. SPR binding studies demonstrated that the specific interaction between αIIbβ3 and sEng and molecular modeling showed a good fitting between αIIbβ3 and sEng structures involving the endoglin RGD motif, suggesting the possible formation of a highly stable αIIbβ3/sEng. hsEng + mice showed increased bleeding time and number of rebleedings compared to wild-type mice. No differences in PT were denoted between genotypes. After FeCl 3 injury, the number of released emboli in hsEng + mice was higher and the occlusion was slower compared to controls., Conclusions: Our results demonstrate that sEng interferes with thrombus formation and stabilization, likely via its binding to platelet αIIbβ3, suggesting its involvement in primary hemostasis control., Competing Interests: Declaration of competing interest A patent titled “Methods and pharmaceutical composition for treating thrombotic disorders” (EP22305156) related to soluble endoglin and supported by INSERM Transfert (Institut National de la Santé et de la Recherche Médicale) has been granted to E.R. A review on “Novel vascular roles of endoglin” was presented in the “State-of-the-art” session by E.R. at the 30th Congress of the International Society on Thrombosis and Haemostasis (ISTH) in London, UK (July 9, 2022, to July 13, 2022)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Leptospirosis is a neglected worldwide zoonosis involving farm animals and domestic pets caused by the Gram-negative spirochete Leptospira interrogans . This bacterium deploys a variety of immune evasive mechanisms, some of them targeted at the complement system of the host's innate immunity. In this work, we have solved the X-ray crystallographic structure of L. interrogans glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to 2.37-Å resolution, a glycolytic enzyme that has been shown to exhibit moonlighting functions that potentiate infectivity and immune evasion in various pathogenic organisms. Besides, we have characterized the enzyme's kinetic parameters toward the cognate substrates and have proven that the two natural products anacardic acid and curcumin are able to inhibit L. interrogans GAPDH at micromolar concentration through a noncompetitive inhibition modality. Furthermore, we have established that L. interrogans GAPDH can interact with the anaphylatoxin C5a of human innate immunity in vitro using bio-layer interferometry and a short-range cross-linking reagent that tethers free thiol groups in protein complexes. To shed light into the interaction between L. interrogans GAPDH and C5a, we have also carried out cross-link guided protein-protein docking. These results suggest that L. interrogans could be placed in the growing list of bacterial pathogens that exploit glycolytic enzymes as extracellular immune evasive factors. Analysis of the docking results indicates a low affinity interaction that is consistent with previous evidence, including known binding modes of other α-helical proteins with GAPDH. These findings allow us to propose L. interrogans GAPDH as a potential immune evasive factor targeting the complement system., Competing Interests: Abvance Biotech slr provided salaries for KdlP, JQG and FJF. The remaining 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 © 2023 Navas-Yuste, de la Paz, Querol-García, Gómez-Quevedo, Rodríguez de Córdoba, Fernández and Vega.)

Background/objective: This study describes the impact of immunomodulatory and/or immunosuppressive (IM/IS) drugs in the outcomes of COVID-19 infection in a cohort of patients with immune-mediated inflammatory diseases (IMIDs)., Methods: Adult patients with IMIDs with a confirmed SARS-CoV-2 infection were included. Data were reported by the treating physician between August 13, 2020 and July 31, 2021. Sociodemographic data, comorbidities, and DMARDs, as well as clinical characteristics, complications, and treatment of the SARS-CoV-2 infection, were recorded. Descriptive analysis and multivariable logistic regression models were carried out., Results: A total of 1672 patients with IMIDs were included, of whom 1402 were treated with IM/IS drugs. The most frequent diseases were rheumatoid arthritis (47.7%) and systemic lupus erythematosus (18.4%). COVID-19 symptoms were present in 95.2% of the patients. A total of 461 (27.6%) patients were hospitalized, 8.2% were admitted to the intensive care unit, and 4.4% died due to COVID-19.Patients without IM/IS treatment used glucocorticoids less frequently but at higher doses, had higher levels of disease activity, were significantly older, were more frequently hospitalized, admitted to the intensive care unit, and died due to COVID-19. After adjusting for these factors, treatment with IM/IS drugs was not associated with a worse COVID-19 outcome (World Health Organization-Ordinal Scale ≥5) (odds ratio, 1.24; 95% confidence interval, 0.73-2.06)., Conclusions: SAR-COVID is the first multicenter Argentine registry collecting data from patients with rheumatic diseases and SARS-CoV-2 infection. After adjusting for relevant covariates, treatment with IM/IS drugs was not associated with severe COVID-19 in patients with IMIDs., Study Registration: This study has been registered in ClinicalTrials.gov under the number NCT04568421., Competing Interests: Conflicts of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SAR-COVID is a multisponsor registry, where Pfizer, Abbvie, and Elea Phoenix had provided unrestricted grants. None of them has participated or influenced the development of the project, data collection, analysis, and interpretation, or the drafting of this report. They do not have access to the information collected in the database., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background/objective: This study aims to describe the course and to identify poor prognostic factors of SARS-CoV-2 infection in patients with rheumatic diseases., Methods: Patients ≥ 18 years of age, with a rheumatic disease, who had confirmed SARS-CoV-2 infection were consecutively included by major rheumatology centers from Argentina, in the national, observational SAR-COVID registry between August 13, 2020 and July 31, 2021. Hospitalization, oxygen requirement, and death were considered poor COVID-19 outcomes., Results: A total of 1915 patients were included. The most frequent rheumatic diseases were rheumatoid arthritis (42%) and systemic lupus erythematosus (16%). Comorbidities were reported in half of them (48%). Symptoms were reported by 95% of the patients, 28% were hospitalized, 8% were admitted to the intensive care unit (ICU), and 4% died due to COVID-19. During hospitalization, 9% required non-invasive mechanical ventilation (NIMV) or high flow oxygen devices and 17% invasive mechanical ventilation (IMV). In multivariate analysis models, using poor COVID-19 outcomes as dependent variables, older age, male gender, higher disease activity, treatment with glucocorticoids or rituximab, and the presence of at least one comorbidity and a greater number of them were associated with worse prognosis. In addition, patients with public health insurance and Mestizos were more likely to require hospitalization., Conclusions: In addition to the known poor prognostic factors, in this cohort of patients with rheumatic diseases, high disease activity, and treatment with glucocorticoids and rituximab were associated with worse COVID-19 outcomes. Furthermore, patients with public health insurance and Mestizos were 44% and 39% more likely to be hospitalized, respectively., Study Registration: This study has been registered in ClinicalTrials.gov under the number NCT04568421. Key Points • High disease activity, and treatment with glucocorticoids and rituximab were associated with poor COVID-19 outcome in patients with rheumatic diseases. • Some socioeconomic factors related to social inequality, including non-Caucasian ethnicity and public health insurance, were associated with hospitalization due to COVID-19., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Cystic fibrosis (CF) disease is characterized by an intense airway inflammatory response mediated by neutrophils and chronic respiratory infections caused by P. aeruginosa . High levels of the complement component C5a, the strongest neutrophil chemoattractant molecule, are commonly found in the CF lung and have been associated with a worsening of the disease. In this study, we investigated how the isolates from CF patients modulate the levels of C5a and identified the bacterial factors involved. We demonstrated that most isolates from airway chronic infections induce the production and accumulation of C5a, an effect attributable to the loss of C5a cleavage by the exoproteases alkaline protease (AprA) and elastase B (LasB). Furthermore, we found that lack of the bacterial protease-dependent C5a degradation is due to mutations in the master regulator LasR. Thus, complementation of a non-C5a-cleaving CF isolate with a functional wild-type LasR restored its ability to express both proteases, cleave C5a and reduce neutrophil recruitment in vitro. These findings suggest that the non-cleaving C5a phenotype acquired by the LasR variants frequently isolated in CF patients may account for the strong neutrophilia and general neutrophil dysfunction predisposing toward increased inflammation and reduced bacterial clearance described in CF patients.

Objective: The aim of this study was to assess the immune response after a third dose of SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA) with undetectable antibody titers after the primary regimen of 2 doses., Methods: Patients with RA with no seroconversion after 2 doses of SARS-CoV-2 vaccine and who received a third dose of either an mRNA or vector-based vaccine were included. Anti-SARS-CoV-2 IgG antibodies, neutralizing activity, and T cell responses were assessed after the third dose., Results: A total of 21 nonresponder patients were included. At the time of vaccination, 29% were receiving glucocorticoids and 85% biologic disease-modifying antirheumatic drugs (including 6 taking abatacept [ABA] and 4 taking rituximab [RTX]). The majority (95%) received the BNT162b2 vaccine and only one of them received the ChAdOx1 nCoV-19 vaccine. After the third dose, 91% of the patients presented detectable anti-SARS-CoV-2 IgG and 76% showed neutralizing activity. Compared to other treatments, ABA and RTX were associated with the absence of neutralizing activity in 4 out of 5 (80%) patients and lower titers of neutralizing antibodies (median 3, IQR 0-20 vs 8, IQR 4-128; P = 0.20). Specific T cell response was detected in 41% of all patients after the second dose, increasing to 71% after the third dose. The use of ABA was associated with a lower frequency of T cell response (33% vs 87%, P = 0.03)., Conclusion: In this RA cohort, 91% of patients who failed to seroconvert after 2 doses of SARS-CoV-2 vaccine presented detectable anti-SARS-CoV-2 IgG after a third dose. The use of ABA was associated with a lower frequency of specific T cell response., (Copyright © 2022 by the Journal of Rheumatology.)

Background/objective: To evaluate the efficacy and safety of SARS-CoV-2 vaccine in patients with rheumatic and immune-mediated inflammatory diseases (IMIDs) in Argentina: the SAR-CoVAC registry., Methods: SAR-CoVAC is a national, multicenter, and observational registry. Adult patients with rheumatic or IMIDs vaccinated for SARS-CoV-2 were consecutively included between June 1 and September 17, 2021. Sociodemographic data, comorbidities, underlying rheumatic or IMIDs, treatments received, their modification prior to vaccination, and history of SARS-CoV-2 infection were recorded. In addition, date and place of vaccination, type of vaccine applied, scheme, adverse events (AE), disease flares, and new immune-mediated manifestations related to the vaccine were analyzed., Results: A total of 1234 patients were included, 79% were female, with a mean age of 57.8 (SD 14.1) years. The most frequent diseases were rheumatoid arthritis (41.2%), osteoarthritis (14.5%), psoriasis (12.7%), and spondyloarthritis (12.3%). Most of them were in remission (28.5%) or low disease activity (41.4%). At the time of vaccination, 21% were receiving glucocorticoid treatment, 35.7% methotrexate, 29.7% biological (b) disease modifying anti-rheumatic drugs (DMARD), and 5.4% JAK inhibitors. In total, 16.9% had SARS-CoV-2 infection before the first vaccine dose. Most patients (51.1%) received Gam-COVID-Vac as the first vaccine dose, followed by ChAdOx1 nCoV-19 (32.8%) and BBIBP-CorV (14.5%). Half of them (48.8%) were fully vaccinated with 2 doses; 12.5% received combined schemes, being the most frequent Gam-COVID-Vac/mRAN-1273. The median time between doses was 51 days (IQR 53). After the first dose, 25.9% of the patients reported at least one AE and 15.9% after the second, being flu-like syndrome and local hypersensitivity the most frequent manifestations. There was one case of anaphylaxis. Regarding efficacy, 63 events of SARS-CoV-2 infection were reported after vaccination, 19% occurred during the first 14 days post-vaccination, 57.1% after the first dose, and 23.8% after the second. Most cases (85.9%) were asymptomatic or mild and 2 died due to COVID-19., Conclusions: In this national cohort of patients, the most common vaccines used were Gam-COVID-Vac and ChAdOx1 nCoV-19. A quarter of the patients presented an AE and 5.1% presented SARS-CoV-2 infection after vaccination, in most cases mild., Study Registration: This study has been registered in ClinicalTrials.gov under the number: NCT04845997. Key Points • This study shows real-world data about efficacy and safety of SARS-CoV-2 vaccination in patients with rheumatic and immune-mediated inflammatory diseases. Interestingly, different types of vaccines were used including vector-based, mRNA, and inactivated vaccines, and mixed regimens were enabled. • A quarter of the patients presented an adverse event. The incidence of adverse events was significantly higher in those receiving mRAN-1273 and ChAdOx1 nCoV-19. • In this cohort, 5.1% presented SARS-CoV-2 infection after vaccination, in most cases mild., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to "reprogram" monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(β-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases., Competing Interests: IS, AL and JA are co-inventors on pending or issued patents involving compounds and methods for immunomodulation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Serrano, Luque, Mitjavila, Blom, Rodríguez de Córdoba, Vega, Torras and Aran.)

Complement activation on cell surfaces leads to the massive deposition of C3b, iC3b, and C3dg, the main complement opsonins. Recognition of iC3b by complement receptor type 3 (CR3) fosters pathogen opsonophagocytosis by macrophages and the stimulation of adaptive immunity by complement-opsonized antigens. Here, we present the crystallographic structure of the complex between human iC3b and the von Willebrand A inserted domain of the α chain of CR3 (αI). The crystal contains two composite interfaces for CR3 αI, encompassing distinct sets of contiguous macroglobulin (MG) domains on the C3c moiety, MG1-MG2 and MG6-MG7 domains. These composite binding sites define two iC3b-CR3 αI complexes characterized by specific rearrangements of the two semi-independent modules, C3c moiety and TED domain. Furthermore, we show the structure of iC3b in a physiologically-relevant extended conformation. Based on previously available data and novel insights reported herein, we propose an integrative model that reconciles conflicting facts about iC3b structure and function and explains the molecular basis for iC3b selective recognition by CR3 on opsonized surfaces., (© 2022. The Author(s).)

Objective: The objective is to describe the main characteristics of patients with systemic lupus erythematosus (SLE) in Argentina and to examine the influence of ethnicity on the expression of the disease., Patients and Methods: RELESSAR is a multicentre register carried out by 106 researchers from 67 rheumatologic Argentine centres. It is a cross-sectional study of SLE (1982/1997 ACR) patients. RELESSAR electronic database includes demographic, cumulative SLE manifestations, SELENA-SLEDAI, SLICC-SDI, Katz's severity and Charlson's comorbidity indexes and treatment patterns., Results: We included 1,610 patients, 91.7% were female with a median age at diagnosis of 28.1 ± 12.8; 96.2% met ≥4 ACR 1982/97 criteria. Frequent manifestations were arthritis (83.5%), malar rash (79.5%), photosensitivity (75.3%), haematological (63.8%) and renal disease (47.4%), antinuclear antibodies (96%), anti-dsDNA (66.5%) and anti-Smith antibodies (29%). The mean Selena-SLEDAI score at last visit was 3.18 (SD 4.3) and mean SDI was 1 (SD 1.3). The accumulated treatments most frequently used were antimalarials (90.4%), corticosteroids (90%), azathioprine (31.8%), intravenous cyclophosphamide (30.2%), mycophenolate mofetil or mycophenolic acid (24.5%), methotrexate (19.3%), belimumab 5.3% and rituximab 5.1%. Refractory lupus was diagnosed in 9.3% of the cases. The main causes of death were lupus activity (25.0%), activity and concomitant infections (25.0%), infections (18.2%), vascular disease (13.6%) and cancer (4.5%). Mortality was associated with higher SLEDAI, Katz, damage indexes and comorbidities. Of the 1610 patients included, 44.6% were Caucasian, 44.5% Mestizo, 8.1% Amerindian and 1.2% Afro-Latin American. Mestizo patients had higher male representation, low socioeconomic status, more inadequate medical coverage, fewer formal years of education and shorter disease duration. Polyadenopathies and Raynaud's phenomenon were more frequent in Caucasians. In the logistic regression analysis higher damage index (OR 1.28, CI 95% 1.02-1.61, p = 0.03) remained associated to mestizo ethnicity., Conclusions: This study represents the largest number of adult patients with SLE studied in Argentina. Caucasian patients were differentiated by having Raynaud's phenomenon and polyadenopathy more frequently, while patients of Mestizo origin had higher damage indexes.

Background: Although domestic infestations by Triatoma infestans have been successfully controlled across Latin America, in areas of the Gran Chaco region, recurrent post-spraying house colonization continues to be a significant challenge, jeopardizing Chagas disease vector control and maintaining active Trypanosoma cruzi transmission., Methodology/principal Findings: To investigate the dynamics of triatomine reinfestation in a rural area of the Paraguayan Chaco, genetic characterization (based on 10 microsatellite loci and cytochrome B sequence polymorphisms) was performed on baseline and reinfestant T. infestans (n = 138) from four indigenous communities and adjacent sylvatic sites. House quality and basic economic activities were assessed across the four communities. Significant genetic differentiation was detected among all baseline triatomine populations. Faster reinfestation was observed in the communities with higher infestation rates pre-spraying. Baseline and reinfestant populations from the same communities were not genetically different, but two potentially distinct processes of reinfestation were evident. In Campo Largo, the reinfestant population was likely founded by domestic survivor foci, with reduced genetic diversity relative to the baseline population. However, in 12 de Junio, reinfestant bugs were likely derived from different sources, including survivors from the pre-spraying population and sympatric sylvatic bugs, indicative of gene-flow between these habitats, likely driven by high human mobility and economic activities in adjacent sylvatic areas., Conclusions/significance: Our results demonstrate that sylvatic T. infestans threatens vector control strategies, either as a reinfestation source or by providing a temporary refuge during insecticide spraying. Passive anthropogenic importation of T. infestans and active human interactions with neighboring forested areas also played a role in recolonization. Optimization of spraying, integrated community development and close monitoring of sylvatic areas should be considered when implementing vector control activities in the Gran Chaco., Competing Interests: The authors have declared that no competing interests exist.

Endoglin (Eng, CD105) is a type I membrane glycoprotein that functions in endothelial cells as an auxiliary receptor for transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP) family members and as an integrin ligand, modulating the vascular pathophysiology. Besides the membrane-bound endoglin, there is a soluble form of endoglin (sEng) that can be generated by the action of the matrix metalloproteinase (MMP)-14 or -12 on the juxtamembrane region of its ectodomain. High levels of sEng have been reported in patients with preeclampsia, hypercholesterolemia, atherosclerosis and cancer. In addition, sEng is a marker of cardiovascular damage in patients with hypertension and diabetes, plays a pathogenic role in preeclampsia, and inhibits angiogenesis and tumor proliferation, migration, and invasion in cancer. However, the mechanisms of action of sEng have not yet been elucidated, and new tools and experimental approaches are necessary to advance in this field. To this end, we aimed to obtain a fluorescent form of sEng as a new tool for biological imaging. Thus, we cloned the extracellular domain of endoglin in the pEGFP-N1 plasmid to generate a fusion protein with green fluorescent protein (GFP), giving rise to pEGFP-N1/Eng.EC. The recombinant fusion protein was characterized by transient and stable transfections in CHO-K1 cells using fluorescence microscopy, SDS-PAGE, immunodetection, and ELISA techniques. Upon transfection with pEGFP-N1/Eng.EC, fluorescence was readily detected in cells, indicating that the GFP contained in the recombinant protein was properly folded into the cytosol. Furthermore, as evidenced by Western blot analysis, the secreted fusion protein yielded the expected molecular mass and displayed a specific fluorescent signal. The fusion protein was also able to bind to BMP9 and BMP10 in vitro. Therefore, the construct described here could be used as a tool for functional in vitro studies of the extracellular domain of endoglin.

Background: Clinically evident interstitial lung disease (ILD) affects between 10 and 42% of the patients with rheumatoid arthritis (RA). Airway involvement seems to be even more common. Most of the available evidence comes from studies performed in established RA patients. The aim of our study was to know the prevalence of non-diagnosed lung disease (airway and interstitial involvement) in patients with early RA and look for associated factors., Methods: We designed an observational, multicenter, cross-sectional study, and included patients with RA of less than two years since diagnosis. We performed a structured questionnaire, HRCT and lung functional tests looking for lung disease, together with joint disease evaluation. We analyzed which variables were associated with the presence of lung disease on HRCT., Results: We included 83 patients, 83% females. The median (IQR) of time since RA diagnosis was 3 (1-6) months. In the HRCT, 57 patients had airway compromisea (72%), and 6 had interstitial abnormalities (7.5%). The most common altertion found in lung functional tests was a reduced DLCO (14%). The presence of at least one abnormality in the physical exam was associated with lung involvement on HRCT [13 (21.6%) vs 0 (0%); p = 0.026]. Also, patients with lung involvement presented significantly lower values of FVC% and DLCO%, and higher values of RV/TLC. No variable related to joint involvement was found associated with alterations in HRCT., Conclusion: Our study shows that a large proportion of early RA patients has abnormal findings in HRCT. Further studies are required to confirm these findings., (© 2021. The Author(s).)

Medium-resolution cryo-electron microscopy maps, in particular when they include a significant number of α-helices, may allow the building of partial models that are useful for molecular-replacement searches in large crystallographic structures when the structures of homologs are not available and experimental phasing has failed. Here, as an example, the solution of the structure of a bacteriophage portal using a partial 30% model built into a 7.8 Å resolution cryo-EM map is shown. Inspection of the self-rotation function allowed the correct oligomerization state to be determined, and density-modification procedures using rotation matrices and a mask based on the cryo-EM structure were critical for solving the structure. A workflow is described that may be applicable to similar cases and this strategy is compared with direct use of the cryo-EM map for molecular replacement., (open access.)

Background: Inflammatory pseudotumour has been used to describe an inflammatory or fibrosing tumoral process of an undetermined cause that may involve a variety of organ systems, including the lungs, spleen, liver, lymph nodes, pancreas and extrahepatic bile duct with potential for recurrence and persistent local growth. In this article, we report a patient with a big mass of uncertain nature and behavior., Case Presentation: A 60-year-old woman presented with a 1-week history of abdominal pain, fever and jaundice. Six months before she had had right upper quadrant pain that was interpreted as biliary colic. A contrast-enhanced CT scan showed a big mass of soft tissue with diffuse infiltration of the gallbladder, displacement of the transverse colon, hepatic flexure and duodenum. For diagnostic distinction between a chronic inflammatory disease or a neoplasm, exploratory laparotomy was required. Intraoperative exploration disclosed a big mass of hard texture involving the gallbladder, with multiple concrements, hepatoduodenal ligament, right and transverse mesocolon, stomach and duodenum. Cholecystectomy was performed, preserving adjacent organs with macroscopic desmoplastic reaction. Histopathologic examination of the gallbladder showed a spindle cell proliferation with diffuse chronic inflammatory infiltrate of lymphocytes, plasma cells and hyalinized fibrous stroma. No vascular invasion or cellular atypia were evident., Conclusion: Inflammatory pseudotumour is a rare condition and diagnostic distinction from a chronic inflammatory disease or other neoplasm is only possible by histopathologic examination. There is a limited number of case reports in the literature indicating tumor location in the gallbladder.

Variants in the ANK3 gene encoding ankyrin-G are associated with neurodevelopmental disorders, including intellectual disability, autism, schizophrenia, and bipolar disorder. However, no upstream regulators of ankyrin-G at synapses are known. Here, we show that ankyrin-G interacts with Usp9X, a neurodevelopmental-disorder-associated deubiquitinase (DUB). Usp9X phosphorylation enhances their interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development. In forebrain-specific Usp9X knockout mice (Usp9X -/Y ), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally. However, reduced cortical spine density in knockouts persists into adulthood. Usp9X -/Y mice display increase of ankyrin-G ubiquitination and aggregation and hyperactivity. USP9X mutations in patients with intellectual disability and autism ablate its catalytic activity or ankyrin-G interaction. Our data reveal a DUB-dependent mechanism of ANKRD protein homeostasis, the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To determine the burden of Rheumatoid Arthritis (RA) on patients' work productivity and health related quality of life (HRQoL), and examine the influence of several exposure variables; to analyze the progression of RA over 1 year and its impact on work productivity and HRQoL., Methods: International multicenter prospective survey including patients in 18 centers in Argentina, Brazil, Colombia and Mexico with diagnosis of RA and aged between 21-55 years. The following standard questionnaires were completed at baseline and throughout a 1-year follow-up: WPAI:RA, WALS, WLQ-25, EQ-5D-3 L and SF-36. Clinical and demographic variables were also collected through interview., Results: The study enrolled 290 patients on baseline visit. Overall mean scores at baseline visit were: WPAI:RA (presenteeism) = 29.5% (SD = 28.8%); WPAI:RA (absenteeism) = 9.0% (SD = 23.2%); WPAI:RA (absenteeism and presenteeism) = 8.6% (SD = 22.6%); WALS = 9.0 (SD = 6.1); WLQ-25 = 7.0% (SD = 5.1%); SF-36 Physical Scale = 39.1 (SD = 10.3) and Mental Scale = 45.4 (SD = 11.3); EQ-5D-3 L VAS = 69.8 (SD = 20.4) and EQ-5D-3 L index = 0.67 (SD = 0.23). Higher educational levels were associated with better results in WLQ-25, while previous orthopedic surgeries reduced absenteeism results of WPAI:RA and work limitations in WLQ-25. Higher disease duration was associated with decreased HRQoL. Intensification of disease activity was associated with decreased work productivity and HRQoL, except in WLQ-25. In the longitudinal analysis, worsening in disease activity was associated with a decrease in both work productivity and HRQoL., Conclusions: RA patients are dealing with workplace disabilities and limitations and loss in HRQoL, and multiple factors seems to be associated with this. Worsening of disease activity further decreased work productivity and HRQoL, stressing the importance of disease tight control.