Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE.

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8+GZMH+ cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.

A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection.

The notion that neutrophils exist as a homogeneous population is being replaced with the knowledge that neutrophils adopt different functional states. Neutrophils can have a pro-inflammatory phenotype or an anti-inflammatory state, but how these states are regulated remains unclear. Here, we demonstrated that the neutrophil-expressed G-protein-coupled receptor (GPCR) Mrgpra1 is a negative regulator of neutrophil bactericidal functions. Mrgpra1-mediated signaling was driven by its ligand, neuropeptide FF (NPFF), which dictated the balance between pro- and anti-inflammatory programming. Specifically, the Mrgpra1-NPFF axis counter-regulated interferon (IFN) γ-mediated neutrophil polarization during acute lung infection by favoring an alternative-like polarization, suggesting that it may act to balance overzealous neutrophilic responses. Distinct, cross-regulated populations of neutrophils were the primary source of NPFF and IFNγ during infection. As a subset of neutrophils at steady state expressed NPFF, these findings could have broad implications in various infectious and inflammatory diseases. Therefore, a neutrophil-intrinsic pathway determines their cellular fate, function, and magnitude of infection.

Anti-Gephyrin Antibodies: A Novel Specificity in Patients With Systemic Sclerosis and Lower Bowel Dysfunction.

OBJECTIVE: Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction. METHODS: Serum from a patient with SSc with GI dysfunction but without defined SSc-associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry. RESULTS: We identified gephyrin as a novel SSc autoantigen. Anti-gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti-gephyrin antibody-positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15%, P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti-gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00; P = 0.001) and severe distention and bloating (0.03 vs 0.004; P = 0.010). Severe constipation was associated with anti-gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility. CONCLUSION: Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti-gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.

The Brazilian Toxoplasma gondii strain BRI caused greater inflammation and impairment in anxiogenic behavior in mice, which was reverted by rosuvastatin treatment.

This study aimed to investigate the effect of rosuvastatin treatment on anxiety-related behavior and short- and long-term memory impairment in mice infected with acute RH and BRI strains of Toxoplasma gondii. Balb/C mice were infected intraperitoneally and after 2 h, oral treatment with rosuvastatin (40 mg/kg/day) was initiated for 4 days. Behaviors related to anxiety and locomotion were evaluated in the open field (OF), and short- and long-term memory through the novel object recognition test (NOR). At the end of the experiments, peritoneal fluid, brain, liver, and lung were collected for T. gondii DNA quantification and histopathological analysis. Infection with BRI strain reduced the dwell time and central locomotion in the OF (p < 0.05), indicating anxiogenic type behavior, while treatment with rosuvastatin reversed this response (p < 0.05). RH strain infection did not alter any behavior in the OF (p > 0.05) and both strains impaired short- and long-term memory (NOR test), but with no significant treatment effect (p > 0.05). The BRI strain was shown to be more damaging in relation to anxiogenic type behavior when compared to the RH strain (p < 0.05), whereas rosuvastatin reduced this damaging effect in BRI. The treatment reduced the parasite load in the peritoneal lavage, liver, and lung of animals infected with both acute strains; however, it significantly (p < 0.05) attenuated the inflammatory process only in BRI-infected and treated animals, showing that non-archetypal genotypes are more damaging in rodents. This suggests that rosuvastatin may be a drug with great therapeutic potential against T. gondii mainly to reduce damage from virulent strains.

Application of machine learning models to identify serological predictors of COVID-19 severity and outcomes.

Critically ill people with COVID-19 have greater antibody titers than those with mild to moderate illness, but their association with recovery or death from COVID-19 has not been characterized. In 178 COVID-19 patients, 73 non-hospitalized and 105 hospitalized patients, mucosal swabs and plasma samples were collected at hospital enrollment and up to 3 months post-enrollment (MPE) to measure virus RNA, cytokines/chemokines, binding antibodies, ACE2 binding inhibition, and Fc effector antibody responses against SARS-CoV-2. The association of demographic variables and >20 serological antibody measures with intubation or death due to COVID-19 was determined using machine learning algorithms. Predictive models revealed that IgG binding and ACE2 binding inhibition responses at 1 MPE were positively and C1q complement activity at enrollment was negatively associated with an increased probability of intubation or death from COVID-19 within 3 MPE. Serological antibody measures were more predictive than demographic variables of intubation or death among COVID-19 patients.

Uncoupling interferons and the interferon signature explain clinical and transcriptional subsets in SLE.

Interferons (IFN) are thought to be key players in systemic lupus erythematosus (SLE). The unique and interactive roles of the different IFN families in SLE pathogenesis, however, remain poorly understood. Using reporter cells engineered to precisely quantify IFN-I, IFN-II and IFN-III activity levels in serum/plasma, we found that while IFNs play essential role in SLE pathogenesis and disease activity, they are only significant in specific subsets of patients. Interestingly, whereas IFN-I is the main IFN that governs disease activity in SLE, clinical subsets are defined by the co-elevation of IFN-II and IFN-III. Thus, increased IFN-I alone was only associated with cutaneous lupus. In contrast, systemic features, such as nephritis, were linked to co-elevation of IFN-I plus IFN-II and IFN-III, implying a synergistic effect of IFNs in severe SLE. Intriguingly, while increased IFN-I levels were strongly associated with IFN-induced gene expression (93.5%), in up to 64% of cases, the IFN signature was not associated with IFN-I. Importantly, neither IFN-II nor IFN-III explained IFN-induced gene expression in patients with normal IFN-I levels, and not every feature in SLE was associated with elevated IFNs, suggesting IFN-independent subsets in SLE. Together, the data suggest that, unlike the IFN signature, direct quantification of bioactive IFNs can identify pathogenic and clinically relevant SLE subsets amenable for precise anti-IFN therapies. Since IFN-I is only elevated in a subset of SLE patients expressing the IFN signature, this study explains the heterogeneous response in clinical trials targeting IFN-I, where patients were selected based on IFN-induced gene expression rather than IFN-I levels.

Desafios do rastreamento do câncer de mama / Challenges of breast cancer screening

A mamografia é o método de eleição para o rastreamento do câncer de mama, sendo o único que demonstra redução de mortalidade na população de risco habitual. A periodicidade de realização e a idade de início do rastreamento mamográfico são um tema controverso na literatura. Entretanto, dados no nosso país apontam para uma porção significativa de neoplasia de mamas em mulheres abaixo dos 50 anos. A Federação Brasileira das Associações de Ginecologia e Obstetrícia (Febrasgo), a Sociedade Brasileira de Mastologia (SBM) e o Colégio Brasileiro de Radiologia e Diagnóstico por Imagem (CBR) concordam que o rastreamento mamográfico deveria ser realizado, anualmente, por todas as mulheres a partir de 40 anos de idade. No Brasil, há uma distribuição desigual de mamógrafos nas várias regiões. As políticas de rastreamento devem considerar essa desigualdade. A grande maioria dos serviços no Brasil realiza rastreamento oportunístico para o câncer de mama. A implantação de rastreamento organizado por faixa etária e estratificação de risco pode otimizar os custos do sistema público de saúde. Pacientes de alto risco precisam ser rastreadas de forma diferente das pacientes de risco habitual. Essas pacientes precisam ter acesso à ressonância magnética das mamas e também iniciar seu rastreamento em idade mais precoce. O protocolo abreviado da ressonância magnética para rastreamento de pacientes de alto risco para câncer de mama pode melhorar a adesão e o acesso dessas pacientes ao programa de rastreamento. A ultrassonografia das mamas não é método de rastreamento isoladamente. Entretanto, ela tem seu papel como método complementar à mamografia e à ressonância magnética em cenários específicos, bem como em substituição à ressonância magnética em pacientes com contraindicação ao uso desse método. As mamas densas possuem baixa sensibilidade para o rastreamento por mamografia

Long-Term Results of Intraoperative Radiation Therapy for Early Breast Cancer Using a Nondedicated Linear Accelerator.

Purpose: To present the long-term results of intraoperative radiation therapy (IORT) for early breast cancer using a nondedicated linear accelerator. Methods and Materials: The eligibility criteria were biopsy-proven invasive carcinoma, age ≥40 years, tumor size ≤3 cm, and N0M0. We excluded multifocal lesions and sentinel lymph node involvement. All patients had previously undergone breast magnetic resonance imaging. Breast-conserving surgery with margins and sentinel lymph node evaluation using frozen sections were performed in all cases. If there were no margins or involved sentinel lymph nodes, the patient was transferred from the operative suite to the linear accelerator room, where IORT was delivered (21 Gy). Results: A total of 209 patients who were followed up for ≥1.5 years from 2004 to 2019 were included. The median age was 60.3 years (range, 40-88.6), and the mean pT was 1.3 cm (range, 0.2-4). There were 90.5% pN0 cases (7.2% of micrometastases and 1.9% of macrometastases). Ninety-seven percent of the cases were margin free. The rate of lymphovascular invasion was 10.6%. Twelve patients were negative for hormonal receptors, and 28 patients were HER2 positive. The median Ki-67 index was 29% (range, 0.1-85). Intrinsic subtype stratification was as follows: luminal A, 62.7% (n = 131); luminal B, 19.1% (n = 40); HER2 enriched 13.4% (n = 28); and triple negative, 4.8% (n = 10). Within the median follow-up of 145 months (range, 12.8-187.1), the 5-year, 10-year, and 15-year overall survival rates were 98%, 94.7%, and 88%, respectively. The 5-year, 10-year, and 15-year disease-free rates were 96.3%, 90%, and 75.6%, respectively. The 15-year local recurrence-free rate was 76%. Fifteen local recurrences (7.2%) occurred throughout the follow-up period. The mean time to local recurrence was 145 months (range, 12.8-187.1). As a first event, 3 cases of lymph node recurrence, 3 cases of distant metastasis, and 2 cancer-related deaths were recorded. Tumor size >1 cm, grade III, and lymphovascular invasion were identified as risk factors. Conclusions: Despite approximately 7% of recurrences, we may infer that IORT may still be a reasonable option for selected cases. However, these patients require a longer follow-up as recurrences may occur after 10 years.

Comparison of Hemodynamic Effects of Dobutamine and Ephedrine Infusions in Isoflurane-Anesthetized Horses.

The objective of this study was to compare the hemodynamic effects of dobutamine and ephedrine during the management of anesthesia-related hypotension in healthy horses. Thirteen horses underwent general anesthesia with isoflurane and were randomly divided into two different groups, one of which received a dobutamine constant rate infusion (CRI) (1 µg/kg bwt/min) and the other received an ephedrine CRI (20 µg/kg bwt/min) when hypotension (<60 mmHg) was identified, following up to 15 min after the blood pressure reached 70 mmHg. All horses were equipped with a pulmonary artery catheter and a peripheral artery catheter, and multiparameter monitoring commenced as soon as they were under mechanical ventilation. Hemodynamic parameters were recorded, while tissue perfusion markers (peripheral oxygen saturation, arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial plasma bicarbonate concentration, arterial oxygen saturation, mixed venous oxygen saturation, mixed venous oxygen content, arterial oxygen content, arteriovenous oxygen difference, oxygen delivery index, oxygen consumption index, and oxygen extraction ratio), serum lactate concentration, and troponin I concentrations were analyzed before the start of infusions (T0), when the blood pressure reached 70 mmHg (T1), and 15 min after T1 (T2). The time to restore the arterial pressure was similar in both groups (p > 0.05); however, the heart rate was higher in the ephedrine group (p = 0.0098), and sinus bradyarrhythmia occurred in the dobutamine group. Furthermore, both experimental protocols increased cardiac output (p = 0.0012), cardiac index (p = 0.0013), systemic vascular resistance (p = 0.008), systemic vascular resistance index (p < 0.001), and ameliorated perfusion markers. In the dobutamine group, the pulmonary artery wedge pressure (p < 0.001) and systolic index (p = 0.003) were elevated, while the arteriovenous oxygen difference was reduced in the ephedrine group (p = 0.02). Troponin I was used as a myocardial injury indicator, and did not differ between moments or between groups (p > 0.05). We concluded that both drugs were effective and safe to treat anesthetic hypotension under the conditions of this study.

Diagnóstico de precisão das lesões mamárias / Accurate diagnosis of breast lesions

PONTOS-CHAVE As lesões mamárias compreendem uma ampla variedade de diagnósticos que apresentam comportamentos diversos. As lesões mamárias podem ser classificadas como lesões benignas, de potencial de malignidade indeterminado (B3), carcinoma in situ e carcinoma invasor. Na era da medicina personalizada, individualizar e obter um diagnóstico preciso faz grande diferença no desfecho final da paciente, principalmente no caso do câncer de mama. Exames de imagem direcionados e de qualidade, métodos de biópsia adequadamente selecionados e análises de anatomopatologia convencional, imuno-histoquímica e até molecular são determinantes no diagnóstico e no manejo das pacientes.

Advances in preventive vaccine development against HTLV-1 infection: A systematic review of the last 35 years.

Introduction: The Human T-lymphotropic virus type 1 (HTLV-1) was the first described human retrovirus. It is currently estimated that around 5 to 10 million people worldwide are infected with this virus. Despite its high prevalence, there is still no preventive vaccine against the HTLV-1 infection. It is known that vaccine development and large-scale immunization play an important role in global public health. To understand the advances in this field we performed a systematic review regarding the current progress in the development of a preventive vaccine against the HTLV-1 infection. Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA®) guidelines and was registered at the International Prospective Register of Systematic Reviews (PROSPERO). The search for articles was performed in PubMed, Lilacs, Embase and SciELO databases. From the 2,485 articles identified, 25 were selected according to the inclusion and exclusion criteria. Results: The analysis of these articles indicated that potential vaccine designs in development are available, although there is still a paucity of studies in the human clinical trial phase. Discussion: Although HTLV-1 was discovered almost 40 years ago, it remains a great challenge and a worldwide neglected threat. The scarcity of funding contributes decisively to the inconclusiveness of the vaccine development. The data summarized here intends to highlight the necessity to improve the current knowledge of this neglected retrovirus, encouraging for more studies on vaccine development aiming the to eliminate this human threat. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42021270412).

Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus.

Anti-dsDNA antibodies are pathogenically heterogeneous, implying distinct origins and antigenic properties. Unexpectedly, during the clinical and molecular characterization of autoantibodies to the endonuclease DNase1L3 in patients with systemic lupus erythematosus (SLE), we identified a subset of neutralizing anti-DNase1L3 antibodies previously catalogued as anti-dsDNA. Based on their variable heavy-chain (VH) gene usage, these antibodies can be divided in two groups. One group is encoded by the inherently autoreactive VH4-34 gene segment, derives from anti-DNase1L3 germline-encoded precursors, and gains cross-reactivity to dsDNA - and some additionally to cardiolipin - following somatic hypermutation. The second group, originally defined as nephritogenic anti-dsDNA antibodies, is encoded by diverse VH gene segments. Although affinity maturation results in dual reactivity to DNase1L3 and dsDNA, their binding efficiencies favor DNase1L3 as the primary antigen. Clinical, transcriptional and monoclonal antibody data support that cross-reactive anti-DNase1L3/dsDNA antibodies are more pathogenic than single reactive anti-dsDNA antibodies. These findings point to DNase1L3 as the primary target of a subset of antibodies classified as anti-dsDNA, shedding light on the origin and pathogenic heterogeneity of antibodies reactive to dsDNA in SLE.

One year follow-up on a randomized study investigating serratus anterior muscle and pectoral nerves type I block to reduced neuropathic pain descriptors after mastectomy.

Breast cancer is the second most common diagnosed type of cancer in women. Chronic neuropathic pain after mastectomy occurs frequently and is a serious health problem. In our previous single-center, prospective, randomized controlled clinical study, we demonstrated that the combination of serratus anterior plane block (SAM) and pectoral nerve block type I (PECS I) with general anesthesia reduced acute postoperative pain. The present report describes a prospective follow-up study of this published study to investigate the development of chronic neuropathic pain 12 months after mastectomy by comparing the use of general anesthesia alone and general anesthesia with SAM + PECS I. Additionally, the use of analgesic medication, quality of life, depressive symptoms, and possible correlations between plasma levels of interleukin (IL)-1 beta, IL-6, and IL-10 collected before and 24 h after surgery as predictors of pain and depression were evaluated. The results showed that the use of SAM + PECS I with general anesthesia reduced numbness, hypoesthesia to touch, the incidence of patients with chronic pain in other body regions and depressive symptoms, however, did not significantly reduce the incidence of chronic neuropathic pain after mastectomy. Additionally, there was no difference in the consumption of analgesic medication and quality of life. Furthermore, no correlation was observed between IL-1 beta, IL-6, and IL-10 levels and pain and depression. The combination of general anesthesia with SAM + PECS I reduced the occurrence of specific neuropathic pain descriptors and depressive symptoms. These results could promote the use of SAM + PECS I blocks for the prevention of specific neuropathic pain symptoms after mastectomy.Registration of clinical trial: The Research Ethics Board of the Hospital Sirio-Libanes/Brazil approved the study (CAAE 48721715.0.0000.5461). This study is registered at Registro Brasileiro de Ensaios Clinicos (ReBEC), and ClinicalTrials.gov, Identifier: NCT02647385.

Using machine learning pipeline to predict entry into the attack zone in football.

Sports sciences are increasingly data-intensive nowadays since computational tools can extract information from large amounts of data and derive insights from athlete performances during the competition. This paper addresses a performance prediction problem in soccer, a popular collective sport modality played by two teams competing against each other in the same field. In a soccer game, teams score points by placing the ball into the opponent's goal and the winner is the team with the highest count of goals. Retaining possession of the ball is one key to success, but it is not enough since a team needs to score to achieve victory, which requires an offensive toward the opponent's goal. The focus of this work is to determine if analyzing the first five seconds after the control of the ball is taken by one of the teams provides enough information to determine whether the ball will reach the final quarter of the soccer field, therefore creating a goal-scoring chance. By doing so, we can further investigate which conditions increase strategic leverage. Our approach comprises modeling players' interactions as graph structures and extracting metrics from these structures. These metrics, when combined, form time series that we encode in two-dimensional representations of visual rhythms, allowing feature extraction through deep convolutional networks, coupled with a classifier to predict the outcome (whether the final quarter of the field is reached). The results indicate that offensive play near the adversary penalty area can be predicted by looking at the first five seconds. Finally, the explainability of our models reveals the main metrics along with its contributions for the final inference result, which corroborates other studies found in the literature for soccer match analysis.

An update on autoantibodies in systemic lupus erythematosus.

PURPOSE OF REVIEW: Autoantibodies are cornerstone biomarkers in systemic lupus erythematosus (SLE), an autoimmune disease characterized by autoantibody-mediated tissue damage. Autoantibodies can inform about disease susceptibility, clinical course, outcomes and the cause of SLE. Identifying pathogenic autoantibodies in SLE, however, remains a significant challenge. This review summarizes recent advances in the field of autoantibodies in SLE. RECENT FINDINGS: High-throughput technologies and innovative hypothesis have been applied to identify autoantibodies linked to pathogenic pathways in SLE. This work has led to the discovery of functional autoantibodies targeting key components is SLE pathogenesis (e.g. DNase1L3, cytokines, extracellular immunoregulatory receptors), as well as the identification of endogenous retroelements and interferon-induced proteins as sources of autoantigens in SLE. Others have reinvigorated the study of mitochondria, which has antigenic parallels with bacteria, as a trigger of autoantibodies in SLE, and identified faecal IgA to nuclear antigens as potential biomarkers linking gut permeability and microbial translocation in SLE pathogenesis. Recent studies showed that levels of autoantibodies against dsDNA, C1q, chromatin, Sm and ribosomal P may serve as biomarkers of proliferative lupus nephritis, and identified novel autoantibodies to several unique species of Ro52 overexpressed by SLE neutrophils. SUMMARY: Autoantibodies hold promise as biomarkers of pathogenic mechanisms in SLE.