SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer.

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Safety and effectiveness of abatacept in juvenile idiopathic arthritis: results from the PRINTO/PRCSG registry.

OBJECTIVE: To report the interim 5-year safety and effectiveness of abatacept in patients with juvenile idiopathic arthritis (JIA) in the PRINTO/PRCSG registry. METHODS: The Abatacept JIA Registry (NCT01357668) is an ongoing observational study of children with JIA receiving abatacept; enrolment started in January 2013. Clinical sites enrolled patients with JIA starting or currently receiving abatacept. Eligible patients were assessed for safety (primary end point) and effectiveness over 10 years. Effectiveness was measured by clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10) in patients with JIA over 5 years. As-observed analysis is presented according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: As of 31 March 2020, 587 patients were enrolled; 569 are included in this analysis (including 134 new users) with 1214.6 patient-years of safety data available. Over 5 years, the incidence rate (IR) per 100 patient-years of follow-up of serious adverse events was 5.52 (95% confidence interval [CI]: 4.27, 7.01) and of events of special interest was 3.62 (95% CI: 2.63, 4.86), with 18 serious infections (IR 1.48 [95% CI: 0.88, 2.34]). As early as month 3, 55.9% of patients achieved cJADAS10 low disease activity and inactive disease (20.3%, 72/354 and 35.6%, 126/354, respectively), sustained over 5 years. Disease activity measures improved over 5 years across JIA categories. CONCLUSION: Abatacept was well tolerated in patients with JIA, with no new safety signals identified and with well-controlled disease activity, including some patients achieving inactive disease or remission. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01357668.

Assessment of foot impairment in systemic sclerosis: a cross-sectional study.

OBJECTIVES: To assess foot function in Systemic Sclerosis (SSc) and its association with sociodemographic and clinical factors. To evaluate mobility, foot alterations, foot pain, and foot care in these patients. METHODS: Consecutive SSc patients underwent structured interviews and physical examinations. Disability was assessed using Health Assessment Questionnaire (HAQ) and Scleroderma Health Assessment Questionnaire. (SHAQ). Foot function was measured using Foot Function Index (FFI), foot pain using a numeric pain scale (NPS), and mobility using Timed-UP-Go test (TUG). RESULTS: 101 patients were included. Forefoot pain was observed in 50.5%, hindfoot pain in 31.7%, foot ulcers in 6.9%, foot plantar callosities in 38.6%, foot arthritis in 2.97%, hallux valgus in 9.9%, claw toes in 5%, and valgus ankle in 3% of patients. The mean FFI was 3.54 (±2.6), NPS was 6.08 (±3.58), and TUG test was 10.52 (±6.5) seconds. Higher FFI scores, increased NPS, and prolonged TUG were associated with Raynaud's phenomenon severity, SHAQ, and HAQ. 36.6% of patients reported never having their feet examined, and only 32.7% had their feet examined within the past year. CONCLUSION: Foot dysfunction and pain are common in SSc. Higher FFI scores, increased pain, and prolonged TUG duration were linked to disability (HAQ and SHAQ). These analyses should be considered exploratory and require confirmation in external cohorts. Routine foot examinations were lacking in clinical practice. Improved attention for evaluating and caring for the feet in SSc patients is needed.

The Influence of Time on the Epidemiology and Clinical Manifestations of Behçet's Disease in Brazil.

OBJECTIVE: Modifications in the severity and clinical expression of Behçet's disease (BD) have been described in some areas that are considered endemic for the disease. This study aims to evaluate the chronological changes in epidemiology and clinical characteristics of BD patients in a referral center in Brazil, which is considered a non-endemic area for the disease. METHODS: A descriptive and cross-sectional study involving BD patients divided into two groups: group 1 patients were diagnosed and followed between 1988 and 2010, and group 2 were diagnosed and followed between 2011 and 2022. RESULTS: No significant differences were found regarding gender and age at onset of symptoms between groups. We found a significant decrease in the frequency of bilateral ocular involvement, posterior uveitis, and retinal vasculitis. CONCLUSION: The demographic dates of this group of Brazilian BD patients remained similar over the last decade. Our study supports the notion that BD is becoming lighter in some regions. BD is a severe blinding disorder, and we found a lower frequency of ocular involvement over time. These findings may be attributed to a higher level of education of patients and a growing awareness of the disease. Newer immunomodulating and biologic agents may offer an improved prognosis in patients with BD with severe manifestations.

Factor-inhibiting HIF (FIH) promotes lung cancer progression.

Factor-inhibiting HIF (FIH) is an asparagine hydroxylase that acts on hypoxia-inducible factors (HIFs) to control cellular adaptation to hypoxia. FIH is expressed in several tumor types, but its impact in tumor progression remains largely unexplored. We observed that FIH was expressed on human lung cancer tissue. Deletion of FIH in mouse and human lung cancer cells resulted in an increased glycolytic metabolism, consistent with increased HIF activity. FIH-deficient lung cancer cells exhibited decreased proliferation. Analysis of RNA-Seq data confirmed changes in the cell cycle and survival and revealed molecular pathways that were dysregulated in the absence of FIH, including the upregulation of angiomotin (Amot), a key component of the Hippo tumor suppressor pathway. We show that FIH-deficient tumors were characterized by higher immune infiltration of NK and T cells compared with FIH competent tumor cells. In vivo studies demonstrate that FIH deletion resulted in reduced tumor growth and metastatic capacity. Moreover, high FIH expression correlated with poor overall survival in non-small cell lung cancer (NSCLC). Our data unravel FIH as a therapeutic target for the treatment of lung cancer.

Abordagem à pessoa nos Serviço de Urgência e Unidade de Cuidados Intensivos após a pandemia COVID-19: scoping review / Approach to the person in emergency and intensive care after the pandemic covid-19: scoping review

Objetivo: Perceber quais as alterações que ocorreram na abordagem à pessoa em situação crítica no Serviço de Urgência e Unidade de Cuidados Intensivos após início da pandemia COVID-19. Método: A estratégia de pesquisa para a scopingreview foi realizada nas bases de dados Medline via PubMed, EBSCO Host, BioMed Central, ScienceDirect, BVS e Scielo através da utilização de descritores MeSH e DeCS, artigos com fulltext gratuito, publicados em língua portuguesa, inglesa e espanhola, com datas de publicação entre 2019 e 2021, implementados critérios de inclusão e exclusão.Resultados: Foram identificados 4 estudos elegíveis para análise, publicados em 2020, nenhum dos estudos em Português. Conclusão: As principais alterações estão relacionadas com a utilização de equipamento de proteção individual, colocando o enfoque na segurança dos profissionais de saúde.(AU)

Aim: To understand the changes that occurred in the approach to critically ill patients in the Emergency Department and Intensive Care Unit after the beginning of the COVID-19 pandemic. Method: The search strategy for the scoping review was conducted in Medline databases via PubMed, EBSCO Host, BioMed Central, ScienceDirect, BVS and Scielo by using MeSH and DeCS descriptors, articles with free full text, published in Portuguese, English and Spanish language, with publication dates between 2019 and 2021, implemented inclusion and exclusion criteria.Results: Four eligible studies were identified for analysis, published in 2020, and none of the studies was in Portuguese. Conclusion: The main changes are related to the use of personal protective equipment, focusing on the safety of health professionals.(AU)

Objetivo: Conocer qué cambios se han producido en el abordaje a los pacientes críticos en el Servicio de Urgencia y enUnidades de Cuidados Intensivos tras el inicio de la pandemia COVID-19.Método: La estrategia de búsqueda para la revisión se realizó en las bases de datos Medline e PubMed, EBSCO Host, BioMed Central, ScienceDirect, BVS y Scielo con el uso de descriptores MeSH y DeCS, artículos con libre acceso a texto completo, publicados en portugués, inglés y español, entre el 2019 y 2021, usando criterios de inclusión y exclusión.Resultados: Identificamos 4 estudios elegibles para el análisis, todos publicados en 2020, e ninguno en portugués.Conclusión: Los principales cambios están relacionados con el uso de equipamientos de protección personal, conel enfoque en la seguridad de los profesionales de salud.(AU)

Information Delay of Significant Bloodstream Isolates and Patient Mortality: A Retrospective Analysis of 6225 Adult Patients With Bloodstream Infections.

BACKGROUND: Our aim in this study was to evaluate the clinical and prognostic impact of communicating microbiological information in real time for adult patients with bloodstream infections (BSIs). METHODS: We retrospectively reviewed 6225 clinical episodes of bacteremia in a teaching hospital from January 2013 to December 2019. Bacteremia-associated mortality was compared when blood culture results were relayed to the infectious diseases specialist (IDS) in real time and periods when results were relayed the following morning. The impact of information availability using mortality at 30 days was used as the main outcome of the study. RESULTS: The initial analysis (all microorganisms included) did not show an association of mortality and information delay to the IDS (odds ratio [OR], 1.18; 95% confidence interval [CI], .99-1.42). However, information delay of BSIs caused by fast-growing microorganisms such as Enterobacterales was associated with a significant increase in the odds of death at 30 days both in the univariate (OR, 1.76; 95% CI, 1.30-2.38) and multivariate analysis (OR, 2.22; 95% CI, 1.50-3.30). Similar results were found with mortality at 14 days and 7 days in the univariate (OR, 1.54; 95% CI, 1.08-2.20 and OR, 1.56; 95% CI, 1.03-2.37, respectively) and the multivariate analysis (OR, 2.05; 95% CI, 1.27-3.32 and OR, 1.92; 95% CI, 1.09-3.40, respectively). CONCLUSIONS: Information delivered in real time has prognostic relevance and is likely to improve survival of patients with documented BSIs. Future studies should address the prognostic impact of adequate resource allocation (microbiologist/IDS with 24/7 coverage) in BSIs.

Real-Life Data on the Effectiveness and Safety of Cefiderocol in Severely Infected Patients: A Case Series.

INTRODUCTION: Real-life data about cefiderocol use to treat extensively drug-resistant bacteria are scarce. We aim to report our early experience in patients with difficult-to-treat infections and limited therapeutic options. METHODS: Patients treated with cefiderocol from March 2018 to April 2022 in a tertiary-care hospital in Spain were included. Demographic, clinical, and microbiological data were collected up to 90 days after the end of treatment or until death. Survival status was recorded at 30 and 90 days. RESULTS: Ten patients were included, seven of them critically ill. Ventilator-associated pneumonia (40%) and bacteremia (40%) were the main infections. Multidrug-resistant or extensively drug-resistant P. aeruginosa was the most frequently isolated pathogen (70%, of which six patients were infected with bacteria with difficult-to-treat resistance), followed by A. baumannii, E. coli, and A. xylosoxidans (10% each). Seven patients received combination therapy. Clinical and microbiological cures were achieved in 90% and 80% of patients, respectively. Two previously susceptible strains (20%) developed resistance to cefiderocol. Overall, 30-day and 90-day mortality rates were 10% and 50%, respectively, although two out of five patients died due to the infection. No serious adverse events were reported, except for one patient who developed thrombocytopenia. CONCLUSION: Cefiderocol seems to be an effective and safe rescue therapy for patients infected with difficult-to-treat pathogens, although there is a definite risk of the emergence of resistance.

Midwifery learning and forecasting: Predicting content demand with user-generated logs.

Every day, 800 women and 6700 newborns die from complications related to pregnancy or childbirth. A well-trained midwife can prevent most of these maternal and newborn deaths. Data science models together with logs generated by users of online learning applications for midwives can help improve their learning competencies. In this work, we evaluate various forecasting methods to determine the future interest of users for the different types of content available in the Safe Delivery App, a digital training tool for skilled birth attendants, broken down by profession and region. This first attempt at health content demand forecasting for midwifery learning shows that DeepAR can accurately anticipate content demand in operational settings, and could therefore be used to offer users personalized content and to provide an adaptive learning journey.

A challenging case of granulomatosis with polyangiitis with cardiac involvement: a rare case report.

Background: Granulomatosis with polyangiitis (GPA), a systemic antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, is characterized by inflammation of the small arteries, arterioles, and capillaries classically manifesting with glomerulonephritis and necrotizing granulomatous lesions of the upper and lower respiratory tract. With an incidence of approximately 12 cases per one million individuals per year it is an uncommon diagnosis that typically presents as frequent pulmonary and sinus infections; however, if left without definitive treatment progresses to more severe manifestations specifically hemoptysis and hematuria. Case Description: This case report highlights a 15-year-old woman who had both classic and non-classic findings making the diagnosis challenging. Specifically, her age of presentation, improvement with anti-microbials, and coronary dilation were not classic. Additionally, her lab work was negative for the cytoplasmic subset antineutrophil cytoplasmic autoantibody (c-ANCA), but positive for serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) which further delayed the ultimate diagnosis as this is typically c-ANCA positive. Conclusions: Other systemic vasculitides, such as mucocutaneous lymph node disease, are associated with cardiac pathology necessitating further medical management and follow-up to prevent increased morbidity and mortality. Knowing this, we conclude that further evaluation for cardiac pathology would be prudent as part of the initial workup of patients with a diagnosis of GPA. Included is a brief review of available literature on GPA to emphasize the typical presentation, lab findings, and importance of early diagnosis.

Pseudomonas aeruginosa Bloodstream Infection, Resistance, and Mortality: Do Solid Organ Transplant Recipients Do Better or Worse?

BACKGROUND: The prevalence of antimicrobial resistance of Pseudomonas aeruginosa (P. aeruginosa) in solid organ transplant (SOT) recipients is higher than that of the general population. However, the literature supporting this statement is scarce. Identifying patients at risk of carbapenem resistance (CR) is of great importance, as CR strains more often receive inappropriate empiric antibiotic therapy, which is independently associated with mortality in bloodstream infections (BSIs). METHODS: We prospectively recorded data from all consecutive BSIs from January 1991 to July 2019 using a routine purpose-designed surveillance database. The following variables were included: age, sex, type of transplant, use of vascular and urinary catheters, presence of neutropenia, period of diagnosis, treatment with steroids, origin of BSI, source of bacteremia, septic shock, ICU admission, mechanical ventilation, previous antibiotic treatment, treatment of bacteremia, and 30-day all-cause mortality. RESULTS: We identified 2057 episodes of P. aeruginosa BSI. Of these, 265 (13%) episodes corresponded to SOT recipients (130 kidney transplants, 105 liver, 9 hearts, and 21 kidney-pancreas). Hematologic malignancy [OR 2.71 (95% CI 1.33-5.51), p = 0.006] and prior carbapenem therapy [OR 2.37 (95% CI 1.46-3.86), p < 0.001] were associated with a higher risk of having a CR P. aeruginosa BSI. Age [OR 1.03 (95% CI 1.02-1.04) p < 0.001], urinary catheter [OR 2.05 (95% CI 0.37-3.06), p < 0.001], shock at onset [OR 6.57 (95% CI 4.54-9.51) p < 0.001], high-risk source [OR 4.96 (95% CI 3.32-7.43) p < 0.001], and bacteremia caused by CR strains [OR 1.53 (95% CI 1.01-2.29) p = 0.036] were associated with increased mortality. Correct empirical therapy was protective [OR 0.52 (95% CI 0.35-0.75) p = 0.001]. Mortality at 30 days was higher in non-SOT patients (21% vs. 13%, p = 0.002). SOT was not associated with a higher risk of having a CR P. aeruginosa BSI or higher mortality. CONCLUSIONS: In our cohort of 2057 patients with P. aeruginosa BSIs, hematologic malignancies and previous carbapenem therapy were independently associated with a risk of presenting CR P. aeruginosa BSI. Age, urinary catheter, high-risk source, bacteremia caused by carbapenem-resistant strains, and severity of the infection were independently associated with mortality, whereas correct empirical therapy was a protective factor. An increasing trend in the resistance of P. aeruginosa was found, with >30% of the isolates being resistant to carbapenems in the last period. SOT was not associated with a higher risk of carbapenem-resistant BSIs or higher mortality.

Intestinal pneumatosis as a manifestation of systemic sclerosis.

A 60-year-old female patient was admitted to the emergency room for a 7-day history of abdominal bloating, nausea, vomiting, constipation, and lack of flatus. She had been diagnosed with systemic sclerosis (SSc) 10 years ago and had been using methotrexate, sildenafil, and prednisone. She did not present any signs of instability, but physical examination showed malnourishment status and abdominal tenderness and distention. Plain abdominal radiography was suggestive of sigmoid volvulus, confirmed and successfully resolved after endoscopic decompression therapy. Eight months later, the patient developed a new episode of abdominal obstruction. Computed Tomography (CT) scan identified a distended sigmoid colon due to its torsion with gas areas within the bowel wall. This time, endoscopic decompression had failed to treat, so exploratory laparotomy was performed. Colonic distention and sigmoid volvulus were identified during the procedure, after which sigmoidectomy followed by primary anastomosis was performed. Neither perforation nor masses were found. Furthermore, the anatomopathological study was inconsistent with vascular, inflammatory, or neoplastic diseases.

Qualitative Subgenomic RNA to Monitor the Response to Remdesivir in Hospitalized Patients With Coronavirus Disease 2019: Impact on the Length of Hospital Stay and Mortality.

BACKGROUND: There is no reliable microbiological marker to guide the indication and the response to antiviral treatment in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the dynamics of subgenomic RNA (sgRNA) in patients with COVID-19 before and after receiving treatment with remdesivir. METHODS: We included consecutive patients admitted for COVID-19 who received remdesivir according to our institutional protocol and accepted to participate in the study. A nasopharyngeal swab for quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was collected at baseline and after 3 and 5 days of treatment with remdesivir. Genomic and sgRNA were analyzed in those samples and main comorbidities and evolution were collected for the analyses. The main outcomes were early discharge (≤10 days) and 30-day mortality. RESULTS: A total of 117 patients were included in the study, of whom 24 had a negative sgRNA at baseline, with 62.5% (15/24) receiving early discharge (≤10 days) and no deaths in this group. From the 93 remaining patients, 62 had a negative sgRNA at day 5 with 37/62 (59.6%) with early discharge and a mortality rate of 4.8% (3/62). In the subgroup of 31 patients with positive sgRNA after 5 days of remdesivir, the early discharge rate was 29% (9/31) and the mortality rate was 16.1% (5/31). In multivariable analyses, the variables associated with early discharge were negative sgRNA at day 3 and not needing treatment with corticosteroids or intensive care unit admission. CONCLUSIONS: Qualitative sgRNA could help in monitoring the virological response in patients who receive remdesivir. Further studies are needed to confirm these findings.

Longer epidermal cells underlie a quantitative source of variation in wheat flag leaf size.

The wheat flag leaf is the main contributor of photosynthetic assimilates to developing grains. Understanding how canopy architecture strategies affect source strength and yield will aid improved crop design. We used an eight-founder population to investigate the genetic architecture of flag leaf area, length, width and angle in European wheat. For the strongest genetic locus identified, we subsequently created a near-isogenic line (NIL) pair for more detailed investigation across seven test environments. Genetic control of traits investigated was highly polygenic, with colocalisation of replicated quantitative trait loci (QTL) for one or more traits identifying 24 loci. For QTL QFll.niab-5A.1 (FLL5A), development of a NIL pair found the FLL5A+ allele commonly conferred a c. 7% increase in flag and second leaf length and a more erect leaf angle, resulting in higher flag and/or second leaf area. Increased FLL5A-mediated flag leaf length was associated with: (1) longer pavement cells and (2) larger stomata at lower density, with a trend for decreased maximum stomatal conductance (Gsmax ) per unit leaf area. For FLL5A, cell size rather than number predominantly determined leaf length. The observed trade-offs between leaf size and stomatal morphology highlight the need for future studies to consider these traits at the whole-leaf level.

A flow cytometry-based neutralization assay for simultaneous evaluation of blocking antibodies against SARS-CoV-2 variants.

Vaccines against SARS-CoV-2 have alleviated infection rates, hospitalization and deaths associated with COVID-19. In order to monitor humoral immunity, several serology tests have been developed, but the recent emergence of variants of concern has revealed the need for assays that predict the neutralizing capacity of antibodies in a fast and adaptable manner. Sensitive and fast neutralization assays would allow a timely evaluation of immunity against emerging variants and support drug and vaccine discovery efforts. Here we describe a simple, fast, and cell-free multiplexed flow cytometry assay to interrogate the ability of antibodies to prevent the interaction of Angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the original Wuhan-1 SARS-CoV-2 strain and emerging variants simultaneously, as a surrogate neutralization assay. Using this method, we demonstrate that serum antibodies collected from representative individuals at different time-points during the pandemic present variable neutralizing activity against emerging variants, such as Omicron BA.1 and South African B.1.351. Importantly, antibodies present in samples collected during 2021, before the third dose of the vaccine was administered, do not confer complete neutralization against Omicron BA.1, as opposed to samples collected in 2022 which show significant neutralizing activity. The proposed approach has a comparable performance to other established surrogate methods such as cell-based assays using pseudotyped lentiviral particles expressing the spike of SARS-CoV-2, as demonstrated by the assessment of the blocking activity of therapeutic antibodies (i.e. Imdevimab) and serum samples. This method offers a scalable, cost effective and adaptable platform for the dynamic evaluation of antibody protection in affected populations against variants of SARS-CoV-2.

Impaired repair properties of endothelial colony-forming cells in patients with granulomatosis with polyangiitis.

In patients with ANCA-associated vasculitis, interactions between neutrophils and endothelial cells cause endothelial damage and imbalance. Endothelial colony-forming cells (ECFCs) represent a cellular population of the endothelial lineage with proliferative capacity and vasoreparative properties. This study aimed to evaluate the angiogenic capacity of ECFCs of patients with granulomatosis with polyangiitis (GPA). The ECFCs of 13 patients with PR3-positive GPA and 14 healthy controls were isolated and characterized using fluorescence-activated cell sorting, capillary tube formation measurement, scratching assays and migration assays with and without plasma stimulation. Furthermore, three patients with active disease underwent post-treatment recollection of ECFCs for longitudinal evaluation. The ECFCs from the patients and controls showed similar capillary structure formation. However, the ECFCs from the patients with inactive GPA exhibited early losses of angiogenic capacity. Impairments in the migration capacities of the ECFCs were also observed in patients with GPA and controls (12th h, p = 0.05). Incubation of ECFCs from patients with GPA in remission with plasma from healthy controls significantly decreased migration capacity (p = 0.0001). Longitudinal analysis revealed that treatment significantly lowered ECFC migration rates. This study revealed that ECFCs from the patients with PR3-positive GPA in remission demonstrated early losses of tube formation and reduced migration capacity compared to those of the healthy controls, suggesting impairment of endothelial function.

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study.

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose. Funding: Partly funded by the Institute of Health Carlos-III and COVID-19 Fund, co-financed by the European Regional Development Fund (FEDER) "A way to make Europe".

C-reactive protein cut-off for early tocilizumab and dexamethasone prescription in hospitalized patients with COVID-19.

Dexamethasone and tocilizumab have been associated with reduction in mortality, however, the beneficial effect is not for all patients and the impact on viral replication is not well defined. We hypostatized that C-reactive protein (CRP) could help in the identification of patients requiring anti-inflammatory therapy. Patients admitted for > 48 h in our hospital for a confirmed or suspected infection by SARS-CoV-2 from February 2020 to February 2021 were retrospectively evaluated. The primary outcome was mortality at 30 days. Demographics and the most relevant variables related with the outcome were included. CRP was stratified by percentiles. Univariate and multivariate analysis were performed. A total of 3218 patients were included with a median (IQR) age of 66 (74-78) years and 58.9% were males. The rate of intensive care unit admission was 24.4% and the 30-day mortality rate was 11.8%. Within the first 5 days from admission, 1018 (31.7%) patients received dexamethasone and 549 tocilizumab (17.1%). The crude analysis showed a mortality reduction in patients receiving dexamethasone when CRP was > 13.75 mg/dL and > 3.5 mg/dL for those receiving tocilizumab. Multivariate analysis identified the interaction of CRP > 13.75 mg/dL with dexamethasone (OR 0.57; CI 95% 0.37-0.89, P = 0014) and CRP > 3.5 mg/dL with tocilizumab (0.65; CI95%:0.44-0.95, P = 0.029) as independent predictors of mortality. Our results suggest that dexamethasone and tocilizumab are associated with a reduction in mortality when prescribed to patients with a certain inflammatory activity assessed by C-reactive protein.

Severity and mortality of COVID-19 in patients with systemic sclerosis: a Brazilian multicenter study.

INTRODUCTION: COVID-19 may be associated with greater severity and mortality in patients with systemic sclerosis (SSc). The present study aimed to evaluate the prevalence, severity and mortality of COVID-19 in a Brazilian cohort of SSc patients. METHODS: This multicenter, retrospective, observational study included 1,042 SSc patients followed in four centers of São Paulo between March 2020 and June 2021. Diagnosis of COVID-19 was established by proper positive RT-PCR testing or by highly suspicious infection. Patients were grouped into mild (outpatient setting treatment and no need for oxygen support) and moderate-to-severe (hospitalization and/or need for oxygen support) COVID-19. RESULTS: Of the 1,042 SSc patients, 118 patients were diagnosed with COVID-19. Interstitial lung disease (SSc-ILD) was present in 65.6% of the total cohort and in 46.3% of SSc patients with COVID-19. There were 78 (66.1%) cases of mild COVID-19, and 40 (33.9%) cases of moderate-to-severe disease, with 6 (5.1%) deaths. By univariate analysis, pulmonary arterial hypertension (OR 9.50, p=0.006), SSc-ILD (OR 3.90, p=0.007), FVC <80% (OR 2.90, p=0.01), cardiac involvement (OR 5.53, p=0.003), and use of rituximab (OR 3.92, p=0.039), but not age, gender, comorbidities or use of corticosteroids, were predictors of worse outcome for COVID-19. Using multivariate analysis, only SSc-ILD was significantly associated to a higher risk of moderate-to-severe COVID-19 (OR 2.73, 95% CI 1.12-6.69, p=0.02). Forty percent of the patients remained with symptoms after presenting COVID-19, predominantly dyspnea and/or cough (17%). CONCLUSION: In this cohort of patients with SSc, those with SSc-ILD were highly impacted by COVID-19, with a higher risk of moderate-to-severe COVID-19 infection and death.