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BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Abstract Cell death is a fundamental process in health and disease. Emerging research shows the existence of numerous distinct cell death modalities with similar and intertwined signaling pathways, but resulting in different cellular outcomes, raising the need to understand the decision-making steps during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes but eventually is executed by oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases but also strongly impedes their activation upon classical apoptosis induction, thereby shifting apoptosis to necrosis. While APAP intoxication results in massive drop in mitochondrial respiration, low cellular ATP levels could be excluded as an underlying cause of missing apoptosome formation and caspase activation. In contrast, we identified oxidative stress as a key factor in APAP-induced caspase inhibition. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death was reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that cellular redox status is a critical component in the decision-making between apoptotic and necrotic cell death, as it directly affects caspase activity.

Summary: Proper polarization of newly generated neurons is a critical process for neural network formation and brain development. The pan-neurotrophin p75NTR receptor plays a key role in this process localizing asymmetrically in one of the differentiating neurites and specifying its axonal identity in response to neurotrophins. During axonal specification, p75NTR levels are transiently modulated, yet the molecular mechanisms underlying this process are not known. Here, we identified a previously uncharacterized natural antisense transcript, AS-p75, encoded within the p75NGFR mouse gene. Using an in vitro model of polarizing murine neurons, we found that AS-p75 and p75NTR display divergent expression profiles and that p75NTR expression levels increase upon competition or depletion of AS-p75, indicating that AS-p75 is a negative regulator of p75NTR expression. Depletion of AS-p75 also results in altered p75NTR subcellular distribution and affects the polarization process. Overall, our data uncovered AS-p75 as a modulator of p75NTR expression, offering new insights into the regulation of this neurotrophin receptor during in vitro neuronal polarization.

IntroductionGalvanic vestibular stimulation (GVS) is a simple, safe, and noninvasive method of neurostimulation that can be used to improve body balance. Several central nervous system diseases cause alterations in body balance, including HTLV-1-associated myelopathy (HAM).ObjectiveTo test GVS as a balance rehabilitation strategy for HAM.MethodsThis study is a quasi-experimental clinical trial in which postural balance was compared before and after a GVS rehabilitation protocol applied to 20 patients with HAM, 12 women and 8 men, average age of 78 and 79 years, respectively. They were followed for nine months after the end of the GVS protocol, which consisted of one GVS session per week for 12 consecutive weeks. The GVS current intensity was progressively increased from 1.0 milliamperes (mA) to 3.5 mA until the third session and maintained at 3.5 mA until the 12th session. The electrical stimulation time progressively increased from 9 min in the first session to 18 min in the second session and maintained at 30 min from the third session onwards. Postural balance was assessed by Time up and go test (TUG), Berg balance scale (BBS) and posturography that were performed before the beginning of the intervention, during the intervention (6th week), at the end of the intervention (12th week) and after 9 months of follow-up without electrical stimulation.ResultsIn a blind comparison, in the 12th week of stimulation, improvement was observed in all the tests. In TUG, time in seconds changed from 28 before to 18 after GVS (p

ObjectivesThe study aims to evaluate the applicability of the D2T psoriatic arthritis (PsA) definition, adapted from rheumatoid arthritis, within a single-center observational cohort of PsA patients treated with b/tsDMARDs. In addition, we aimed to establish a numerical index defining D2T-PsA based on the ratio of observed to expected failed b/tsDMARDs and to develop a predictive model identifying features associated with the D2T condition.MethodsThe study included 267 consecutive adult PsA patients receiving b/tsDMARDs, collecting demographic, clinical, and clinimetric data. The prevalence of D2T PsA patients was assessed using a proposed definition. We then developed a predictive model to assess treatment difficulty, utilizing PsA-normalized failed b/tsDMARDs. A generalized linear model was applied to identify clinical and demographic features associated with D2T PsA, employing a bagging procedure for robust variable selection, followed by univariate and multivariable analyses.ResultsAmong the 267 patients, only 8 of them (2.9%) met the proposed D2T PsA criteria. In a subset of 177 patients analyzed using the predictive model, 17.2% of them demonstrated higher treatment difficulty. Univariate analysis revealed associations between treatment difficulty and female sex, psoriasis pattern, fibromyalgia, and steroid therapy. Multivariate analysis confirmed significant associations between fibromyalgia, nail and pustular psoriasis, and steroid use.ConclusionAccording to the predictive model, the proposed D2T PsA definition identified a small subset of patients with increased treatment difficulty. These findings highlight the need for refining the criteria to better define D2T PsA patients, providing valuable insights into managing complex treatment challenges in PsA.

Accurate EEG source localization is crucial for mapping resting-state network dynamics and it plays a key role in estimating source-level functional connectivity. However, EEG source estimation techniques encounter numerous methodological challenges, with a key one being the selection of the regularization parameter in minimum norm estimation. This choice is particularly intricate because the optimal amount of regularization for EEG source estimation may not align with the requirements of EEG connectivityanalysis, highlighting a nuanced trade-off. In this study, we employed a methodological approach to determine the optimal regularization coefficient that yields the most effective reconstruction outcomes across all simulations involving varying signal-to-noise ratios for synthetic EEG signals. To this aim, we considered three resting state networks: the Motor Network, the Visual Network, and the Dorsal Attention Network. The performance was assessed using three metrics, at different regularization parameters: the Region Localization Error, source extension, and source fragmentation. The results were validated using real functional connectivity data. We show that the best estimate of functional connectivity is obtained using 10−2, while 10−1 has to be preferred when source localization only is at target.

Objective. To provide a comprehensive overview of peripheral spondyloarthritis (pSpA), focusing specifically on its occurrence and management in patients with inflammatory bowel disease (IBD). Methods. An exhaustive literature search was conducted in PubMed, Embase, Cochrane Database of Systematic Reviews, and Google Scholar to identify relevant studies on pSpA in IBD patients. Titles, abstracts, and full-text articles were screened for relevance. Data on study design, patient characteristics, diagnostic criteria, main findings, and conclusions were extracted from selected articles. Study quality was assessed using appropriate checklists. Information was synthesized narratively to summarize current understanding. Results. pSpA is the most common extraintestinal manifestation in IBD, with a median prevalence of 16%. It worsens quality of life and requires collaboration between gastroenterologists and rheumatologists for optimal diagnosis and treatment. Several “red flags” guide appropriate specialist referral of IBD patients with suspected pSpA. Once the diagnosis is confirmed, the choice of therapy depends on IBD phenotype and patterns of articular/axial involvement. Anti-tumor necrosis factor (TNF) drugs are first-line biologics, with interleukin (IL)-12/23 and IL-23 inhibitors as alternatives for anti-TNF failure. Small molecules like apremilast and Janus kinase inhibitors also have utility. Recommended treatment algorithms exist, but more randomized controlled trials are needed. Conclusions. Early identification of pSpA is crucial in IBD patients to enable timely intervention, prevent structural damage, and minimize disability. A multidisciplinary, holistic approach addressing musculoskeletal and extra-musculoskeletal manifestations is key to optimal patient outcomes.

Purpose: Warming up before competition is universally recognized as an effective way to enhance performance. However, only a few articles have directly investigated different warm-up strategies adopted by triathletes and suggested by coaches. The Olympic-distance triathlon is an endurance competition characterized, at least for the elite, by a fast start with a strong correlation to the final position in the race. Thus, executing a proper warm-up protocol would be beneficial in optimizing performance. The present study aimed to provide an overview of the warm-up protocol adopted/suggested by national-caliber triathletes/coaches before an Olympic-distance triathlon race. Methods: Online surveys were created and shared between national- and international-caliber Italian, French, and Spanish triathletes and coaches. Information about the rationale, structure, and specific exercises adopted/suggested during personal warm-up protocols was collected. Thereafter, triathletes were grouped according to the discipline sequence reported. Results: Seventy-nine triathletes and nineteen coaches completed the survey. The cycle–run–swim was the most reported discipline sequence adopted, with a total time of 90.0 (25.0) minutes, against the 62.5 (25.0) minutes suggested by coaches. Conditioning exercises were performed by only 31.6% of triathletes 20 to 10 minutes before the race start. Conclusions: Triathletes who took part in this survey adopted very long protocols with the specific intention of including all disciplines. These results highlight the need to raise awareness in triathletes and coaches on the correct warm-up procedures and to stimulate researchers to design studies that directly investigate the effects of different warm-up protocols before competitions. [ABSTRACT FROM AUTHOR]

Legionnaires' disease (LD) is a serious type of pneumonia, typically contracted by susceptible people through the inhalation of aerosols contaminated with Legionella pneumophila (Lp). In this report, the first case of coinfection with Lp–Bordetella bronchiseptica (Bb) is described. A possible source of the Lp infection may be the hotel in Paris (France) where the patient had stayed before developing the symptoms. The Bb infection may have been transmitted by the dog with which he had constant contact, although this has not been proven.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.

Background Janus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. Filgotinib is a Janus kinase 1–preferential inhibitor available in two doses for moderate-to-severe RA. We report the long-term efficacy and safety of filgotinib.Methods In the ongoing long-term extension study FINCH 4 (NCT03025308), patients continue filgotinib 200 mg or 100 mg from FINCH 1, 2 or 3 or receive filgotinib 200 mg or 100 mg de novo. Efficacy assessments up to week 156 include American College of Rheumatology 20% response (ACR20), Disease Activity Score 28 using C-reactive protein of

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Objective. This paper aims to provide an overview of the use of treatments available for axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) during pregnancy and breastfeeding, according to current national recommendations and international guidelines, as well as data on the impact on pregnancy outcomes of paternal exposure to treatment. Methods. We performed a narrative review of national and international recommendations and guidelines on the reproductive health of patients suffering from rheumatic diseases. The last updated recommendations and guidelines were considered source data. Results. We reported updated information regarding the treatment of axSpA and PsA with nonsteroidal anti-inflammatory drugs, intra-articular glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, and targeted synthetic DMARDs during the preconception period, pregnancy, and breastfeeding, as well as data related to paternal exposure. We highlighted any medications that should be discontinued and/or not used in the reproductive age group and also treatments that may be continued, avoiding the withdrawal of drugs that can be used in the different phases, thus preventing the risk of increasing disease activity and flares before, during, and after pregnancy in SpA patients. Conclusions. The best management of pregnancy in patients with SpA is based on knowledge of updated drug recommendations, a careful and wise evaluation of the risks/benefits of starting or continuing treatment from the SpA diagnosis in a woman of childbearing age through pregnancy and lactation, and sharing therapeutic choices with other healthcare providers (in particular, gynecologists/obstetricians) and the patient.

Superhydrophobic materials, known for their exceptional water-repellent properties, have found widespread applications in diverse fields such as self-cleaning surfaces, anti-icing coatings, and water-resistant textiles. In recent years, researchers have explored a sustainable approach by repurposing waste materials to create superhydrophobic surfaces. This eco-friendly approach not only reduces environmental impact but also aligns with circular economy principles, contributing to a more sustainable future. Creating superhydrophobic materials from waste involves a combination of surface modification techniques and hierarchical structuring, with rigorous characterization to ensure the desired properties. These materials showcase their potential in various industries, opening doors to more environmentally friendly technologies. This review delves into the concept of superhydrophobic materials derived from waste and the methods used for their synthesis. It begins by defining superhydrophobicity and highlighting its unique characteristics. It emphasizes the pivotal role played by superhydrophobic materials across industries. The review then explores waste materials’ untapped potential, discussing the advantages of harnessing waste for superhydrophobic material development. Concrete examples of promising waste materials are provided, including agricultural residues and industrial byproducts. The review outlines five key sections that will be further developed to offer a comprehensive understanding of this innovative and sustainable approach to superhydrophobic materials.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.

Epigenetic processes involving long non-coding RNAs regulate endothelial gene expression. However, the underlying regulatory mechanisms causing endothelial dysfunction remain to be elucidated. Enhancer of zeste homolog 2 (EZH2) is an important rheostat of histone H3K27 trimethylation (H3K27me3) that represses endothelial targets, but EZH2 RNA binding capacity and EZH2:RNA functional interactions have not been explored in post-ischemic angiogenesis. We used formaldehyde/UV-assisted crosslinking ligation and sequencing of hybrids and identified a new role for maternally expressed gene 3 (MEG3). MEG3 formed the predominant RNA:RNA hybrid structures in endothelial cells. Moreover, MEG3:EZH2 assists recruitment onto chromatin. By EZH2-chromatin immunoprecipitation, following MEG3 depletion, we demonstrated that MEG3 controls recruitment of EZH2/H3K27me3 onto integrin subunit alpha4 (ITGA4) promoter. Both MEG3 knockdown or EZH2 inhibition (A-395) promoted ITGA4 expression and improved endothelial cell migration and adhesion to fibronectin in vitro. The A-395 inhibitor re-directed MEG3-assisted chromatin remodeling, offering a direct therapeutic benefit by increasing endothelial function and resilience. This approach subsequently increased the expression of ITGA4 in arterioles following ischemic injury in mice, thus promoting arteriogenesis. Our findings show a context-specific role for MEG3 in guiding EZH2 to repress ITGA4. Novel therapeutic strategies could antagonize MEG3:EZH2 interaction for pre-clinical studies.

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it.Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018–2023). Maternal and infant information were collected in a web-based database.Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress.Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.