Autologous stem cell transplantation improves cardiopulmonary exercise testing outcomes in systemic sclerosis patients.

OBJECTIVES: Autologous haematopoietic stem cell transplantation (AHSCT) is a disease-modifying treatment for patients with severe SSc. Here, we aimed at assessing cardiopulmonary function outcomes of SSc patients after AHSCT. METHODS: Twenty-seven SSc adult patients treated with AHSCT were included in this retrospective study. Most had the diffuse cutaneous subset (93%) and pulmonary involvement (85%). Before and 12 months after AHSCT, patients underwent cardiopulmonary exercise testing, transthoracic echocardiography, pulmonary function test with diffusing capacity for carbon monoxide (DLCO), 6-min walk test (6MWT) and quality of life evaluations. RESULTS: After AHSCT, the peak VO2 increased from 954 to 1029 ml/min (P = 0.02), the percentage of predicted peak VO2 increased from 48.9 to 53.5 m (P = 0.01), and the distance measured by the 6MWT increased from 445 to 502 m (P = 0.01), compared with baseline. Improvements in peak VO2 correlated positively with improvements in 6MWT distance, and negatively with a decrease in resting heart rate. At baseline, patients with DLCO >70% had higher peak VO2 values than those with DLCO <70% (P = 0.04), but after AHSCT all patients showed improved VO2 values, regardless of baseline DLCO levels. Increases in VO2 levels after AHSCT positively correlated with increases in the physical component scores of the Short Form-36 quality of life questionnaire (r = 0.70; P = 0.0003). CONCLUSION: AHSCT improves the aerobic capacity of SSc patients probably reflecting combined increments in lungs, skeletal muscle and cardiac function.

Diagnostic Agreement Among General Practitioners, Residents, and Senior Rheumatologists for Rheumatic Diseases.

OBJECTIVE: The aim of this study was to evaluate the concordance of the diagnoses made by senior rheumatologists and those made by residents in rheumatology and by general practitioners (GPs). METHODS: In this cohort, 497 patients referred by GPs from August 1, 2018 to December 16, 2019 were evaluated first by a second-year resident in rheumatology. After clinical rounds, the diagnoses by senior rheumatologists were assumed as the criterion standard and defined the prevalence of the rheumatic diseases, divided into 5 groups: rheumatoid arthritis, spondyloarthritis, other connective tissue diseases and vasculitis, nonautoimmune rheumatic diseases, and nonrheumatic diseases. The follow-up ended on November 30, 2020. We calculated sensibility, specificity, positive predictive value, negative predictive value, and κ coefficient of the diagnosis by GPs and residents. RESULTS: The diagnoses were changed for 58% of the referral letters. Diseases of low complexity, such as fibromyalgia and osteoarthritis, accounted for 50% of the diagnoses. Compared with senior rheumatologists, residents in rheumatology had κ > 0.6 for all the groups, whereas GPs had κ < 0.5, with the worst performance for nonautoimmune rheumatic disease (κ = -0.18) and nonrheumatic disease (κ = 0.15). In terms of level of complexity, 46% of the letters were inappropriate. CONCLUSIONS: We found a poor level of diagnostic agreement between GPs and the rheumatology team. General practitioners had difficulties diagnosing and treating rheumatic diseases, referring patients that should be treated in the primary level of health care. One year of training in rheumatology made residents' skills comparable to those of senior rheumatologists.

Autologous haematopoietic stem cell transplantation restores the suppressive capacity of regulatory B cells in systemic sclerosis patients.

OBJECTIVES: The rationale of autologous haematopoietic stem cell transplantation (AHSCT) for autoimmune diseases is that high-dose immunosuppression eradicates autoreactive T and B cells and the infused autologous haematopoietic stem cells promote reconstitution of a naïve and self-tolerant immune system. The aim of this study was to evaluate the reconstitution of different B cell subsets, both quantitatively and functionally, in SSc patients treated with AHSCT. METHODS: Peripheral blood was harvested from 22 SSc patients before transplantation and at 30, 60, 120, 180 and 360 days post-AHSCT. Immunophenotyping of B cell subsets, B cell cytokine production, signalling pathways and suppressive capacity of regulatory B cells (Bregs) were assessed by flow cytometry. RESULTS: Naïve B cell frequencies increased from 60 to 360 days post-AHSCT compared with pre-transplantation. Conversely, memory B cell frequencies decreased during the same period. Plasma cell frequencies transiently decreased at 60 days post-AHSCT. IL-10-producing Bregs CD19+CD24hiCD38hi and CD19+CD24hiCD27+ frequencies increased at 180 days. Moreover, the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase increased in B cells reconstituted post-AHSCT. Notably, CD19+CD24hiCD38hi Bregs recovered their ability to suppress production of Th1 cytokines by CD4+ T cells at 360 days post-AHSCT. Finally, IL-6 and TGF-ß1-producing B cells decreased following AHSCT. CONCLUSION: Taken together, these results suggest improvements in immunoregulatory and anti-fibrotic mechanisms after AHSCT for SSc, which may contribute to re-establishment of self-tolerance and clinical remission.

Low-cost, safe, and effective smoke evacuation device for surgical procedures in the COVID-19 age.

BACKGROUND: Smoke is generated by energy-based surgical instruments. The airborne by-products may have potential health implications. METHODS: We developed a simple way to use de conventional surgical evacuator coupled with de electrosurgical pen attached to a 14G bladder catheter for open surgery. It was used in ten prospective patients with breast cancer. RESULTS: We notice a high reduction in surgical smoke during all breast surgery. A questionnaire was used for all participants of the surgery to answer the impression that they had about the device. The subjective impression was that the surgical smoke in contact whit the surgical team was reduced by more than 95%. CONCLUSIONS: Surgical smoke is the gaseous by-product produced by heat-generating devices in various surgical procedures. Surgical smoke may contain chemicals particles, bacteria, and viruses that are harmful and increase the risk of infection for surgeons and all the team in the operation room due to long term exposure of smoke mainly in coronavirus disease 2019 age. The adapted device described is a very simple and cheaper way to use smoke evacuators attached with the monopolar electrosurgical pen to reduce smoke exposure to the surgical team worldwide.

Automatic Quantitative Computed Tomography Evaluation of the Lungs in Patients With Systemic Sclerosis Treated With Autologous Stem Cell Transplantation.

BACKGROUND/OBJECTIVE: Interstitial lung disease stands among the leading causes of death in systemic sclerosis (SSc) patients. Autologous hematopoietic stem cell transplantation (AHSCT) has been proven superior to conventional immunosuppressive therapy in severe and progressive SSc. Here, pulmonary quantitative measurements were obtained in high-resolution computed tomography (HRCT) scans of patients with SSc before and after AHSCT. METHODS: The medical records of thirthy-three patients who underwent AHSCT between 2011 and 2017 were evaluated for clinical and tomographic features at baseline (pre-AHCST) and 18 months after the procedure. Quantitative analysis of HRCT images by a fully automated program calculated lung volumes, densities, attenuation percentiles, and vascular volume. Patients were divided into 2 groups, according to changes in forced vital capacity (FVC). The "best response" group included patients that had an increased FVC of 10% or greater, and the "stable response" group included those who had a decreased or an increased FVC of less than 10%. RESULTS: In the best response group (15 patients), there was reduction (p < 0.05) of mean lung density and density percentile values after AHSCT. In the stable response group (18 patients), there were no significant changes in lung volumes and pulmonary densities after AHSCT. Pulmonary HRCT densities showed moderate/strong correlation with function. CONCLUSIONS: Quantitative HRCT analysis identified significant reduction in pulmonary densities in patients with improved pulmonary function after AHSCT. Lung density, as evaluated by the quantitative HRCT analysis tool, has potential to become a biomarker in the evaluation of interstitial lung disease treatment in patients with SSc.

Hematopoietic Stem Cell Transplantation Improves Functional Outcomes of Systemic Sclerosis Patients.

BACKGROUND/OBJECTIVE: We sought to evaluate if autologous hematopoietic stem cell transplantation (AHSCT) influences the functional status of systemic sclerosis (SSc) patients. METHODS: From 2014 to 2018, a cohort of 27 SSc patients was assessed before, and at 6 and 12 months after AHSCT for modified Rodnan's skin score (mRSS), mouth opening, hand grip strength, range of motion (ROM), functional ability of upper limbs (DASH questionnaire and Cochin hand function scale-CHFS), 6-minute walk test (6MWT), and quality of life (SF-36 questionnaire). Linear regression models with random effects and Spearman's test were used for statistical analysis. RESULTS: At 6 and 12 months after AHSCT, respectively, we observed significant improvement of mRSS (p < 0.01 and p < 0.01), mouth opening (p = 0.02 and p < 0.01), hand function (DASH, p < 0.01 and p < 0.01; CHFS, p < 0.01 and p < 0.01; strength, p < 0.01 and p < 0.01), physical capacity (6MWT, p = 0.02 and p = 0.03) and physical (p < 0.01 and p < 0.01) and mental (ns and p = 0.02) component scores of SF-36. At 12 months after AHSCT, ROM measurements improved (p < 0.05) in five out of six evaluated joints in both hands, compared to baseline. Correlation was significant between physical capacity and quality of life (R = 0.62; p < 0.01), between DASH and quality of life (R = -0.48; p = 0.03), and between skin involvement and wrist ROM measures (dominant hand, R = -0.65, p < 0.01; non-dominant hand, R = -0.59; p < 0.01). CONCLUSIONS: AHSCT enhances the functional status of SSc patients in the first year of follow-up, significantly improving hand function, physical capacity and quality of life. These results are interpreted as positive outcomes of AHSCT for SSc.

A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant.

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.

Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis.

BACKGROUND: Follow-up data on patients with 46,XY partial gonadal dysgenesis (PGD) until adulthood are scarce, making information on prognosis difficult. OBJECTIVE: To analyse the long-term outcomes of patients with 46,XY PGD regarding testosterone production, germ cell tumour risk, genotype and psychosexual adaptation. METHODS: A retrospective longitudinal study of 33 patients (20 assigned male and 13 patients assigned female at birth). Molecular diagnosis was performed by Sanger sequencing or by targeted massively parallel sequencing of 63 genes related to disorders of sex development (DSDs). RESULTS: Age at first and last visit ranged from 0.1 to 43 and from 17 to 53 years, respectively. Spontaneous puberty was observed in 57% of the patients. During follow-up, six of them had a gonadectomy (four due to female gender, and two because of a gonadal tumour). At last evaluation, five of six patients had adult male testosterone levels (median 16.7 nmol/L, range 15.3-21.7 nmol/L) and elevated LH and FSH levels. Germ cell tumours were found in two postpubertal patients (one with an abdominal gonad and one patient with Frasier syndrome). Molecular diagnosis was possible in 11 patients (33%). NR5A1 variants were the most prevalent molecular defects (n = 6), and four of five patients harbouring them developed spontaneous puberty. Gender change was observed in four patients, two from each sex assignment group; all patients reported satisfaction with their gender at final evaluation. Sexual intercourse was reported by 81% of both gender and 82% of them reported satisfaction with their sexual lives. CONCLUSION: Spontaneous puberty was observed in 57% of the patients with 46,XY PGD, being NR5A1 defects the most prevalent ones among all the patients and in those with spontaneous puberty. Gender change due to gender dysphoria was reported by 12% of the patients. All the patients reported satisfaction with their final gender, and most of them with their sexual life.

Long-Term Effects of Anterior Thalamic Nucleus Deep Brain Stimulation on Spatial Learning in the Pilocarpine Model of Temporal Lobe Epilepsy.

INTRODUCTION AND OBJECTIVES: Cognitive impairment is a significant comorbidity of temporal lobe epilepsy that is associated with extensive hippocampal cell loss. Deep brain stimulation (DBS) of the anterior thalamic nucleus (ANT) has been used for the treatment of refractory partial seizures. In the pilocarpine model of epilepsy, ANT DBS applied during status epilepticus (SE) reduces hippocampal inflammation and apoptosis. When given to chronic epileptic animals it reduces hippocampal excitability and seizure frequency. Here, we tested whether ANT DBS delivered during SE and the silent phase of the pilocarpine model would reduce cognitive impairment when animals became chronically epileptic. MATERIALS AND METHODS: SE was induced by a systemic pilocarpine injection (320 mg/kg). Immediately after SE onset, rats were assigned to receive DBS during the first six hours of SE (n = 8; DBSa group) or during SE + the silent period (i.e., 6 h/day until the animals developed the first spontaneous recurrent seizure; n = 10; DBSs group). Four months following SE, animals underwent water maze testing and histological evaluation. Nonstimulated chronic epileptic animals (n = 13; PCTL group) and age-matched naïve rats (n = 11, CTL group) were used as controls. Results were analyzed by repeated-measures analyses of variance (RM_ANOVA) and one-way ANOVAs, followed by Newman-Keuls post hoc tests. RESULTS: Although all groups learned the spatial task, epileptic animals with or without DBS spent significantly less time in the platform quadrant, denoting a spatial memory deficit (p < 0.02). Despite these negative behavioral results, we found that animals given DBS had a significantly higher number of cells in the CA1 region and dentate gyrus. Mossy fiber sprouting was similar among all epileptic groups. CONCLUSIONS: Despite lesser hippocampal neuronal loss, ANT DBS delivered either during SE or during SE and the silent phase of the pilocarpine model did not mitigate memory deficits in chronic epileptic rats.

Immature platelet fraction in hypertensive pregnancy.

BACKGROUND: Imbalance in hemostatic mechanisms can occur during pregnancy with a tendency for hypercoagulability and increased thrombosis risk. Pregnant women with hypertensive disorder, especially preeclampsia, show alterations in platelet indexes. Immature platelet fraction (IPF) has been suggested as a sensitive index for monitoring changes in platelet production and destruction. OBJECTIVES: To evaluate the IPF in patients diagnosed with a gestational hypertensive disorder (GHD). PATIENTS AND METHODS: A cross-sectional study was conducted at an University Hospital to estimate maternal blood IPF index in 99 pregnant women, divided into three groups: normotensive pregnancy (NP), preeclampsia syndrome (PES), and non-proteinuric hypertensive pregnancy (nPHP). Following ethical approval and written informed consent, samples were collected from 33 NP, 34 PES, and 32 nPHP women. Platelet indexes were measured by fluorescent flow cytometry. RESULTS: IPF and mean platelet volume (MPV) counts in GHD were significantly higher than in NP (IPF: 3.8, 2.4-5.1%; 8.6, 5.8-10.6%; 7.3, 4.2-10.2%; p < 0.001 and MPV: 10.6 ± 0.9 fL; 12.1 ± 1.0 fL; 11.6 ± 1.0 fL; p < 0.001 for NP, PES, and nPHP, respectively). No difference was detected between PES and nPHP groups. The distribution of patients with an IPF above 6.1%for NP, PES, and nPHP was 9%, 65%, and 43.8%, respectively (p < 0.001). IPF as a test to differentiate GHD from the controls achieved an area under the curve of 0.83 on a receiver operating characteristics curve. CONCLUSION: A distinct profile in platelet indexes was detected in hypertensive pregnancies. It suggests that these markers could be used in daily routine as an additional tool in the management of pregnant women.

Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis.

Autologous haematopoietic stem-cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to 'reboot' the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify, through a robust and unbiased transcriptomic analysis, any changes of gene expression in T-cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T-cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T-cells of MS patients at 2 years post-transplantation, aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy, we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T-cell subsets at all time points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data, a number of significant changes in both the CD4+ and CD8+ T-cells subsets from MS post-transplant. Notably, CD8+ T-cells revealed more extensive changes in the expression of genes involved in effector immune responses.

Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None.

Successful outcome of allogeneic stem cell transplantation in Seckel syndrome.

Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six-yr-old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations.

Oral health in individuals with cystic fibrosis: A cross-sectional study.

Cystic Fibrosis (CF) is an autosomal recessive disease characterized by the production of thick and viscous mucus progressively affecting various organs and systems, with recurrent respiratory infections. The aim of this study was to learn about the oral health characteristics in CF patients. METHODOLOGY: Data, such as sociodemographic, general and oral health, were collected from the medical records of CF patients aged 0 to 18 years old. The number of patients with tooth decay, prevalence of developmental defects of enamel (DDE), classification of dental occlusion, sialometry, salivary pH and oral microbial profile and respiratory secretions evaluations were recorded. RESULTS: Most patients had pancreatic insufficiency (84.2%), malnutrition (60%), respiratory problems (75.4%) and genotyping of the F508del (66.7%). Regarding the medications used, 96.5% used vitamins and electrolyte replacement, 84,02% used pancreatic enzymes, 64.9% used dornase alfa and 47% were using antibiotics. The percentage of patients with tooth decay was 19.3%, 47% had DDE, low salivary flow and basic salivary pH. The most prevalent microorganisms found on tongue biofilm and respiratory secretions were SA and PA. There was a positive association between the presence of bacteria and fungi found on both the tongue and respiratory secretions. The presence of fungi on the tongue biofilm was significantly associated with the use of antibiotics. CONCLUSIONS: These findings underscore the importance of dentists focusing on prevention and on the specific needs of the patient as well.

2023 Brazilian Society of Rheumatology guidelines for the treatment of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc. METHODS: A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed. RESULTS: Six recommendations were elaborated regarding the pharmacological treatment of Raynaud's phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found. CONCLUSION: These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

Cytogenomic Investigation of Syndromic Brazilian Patients with Differences of Sexual Development.

BACKGROUND: Cytogenomic methods have gained space in the clinical investigation of patients with disorders/differences in sexual development (DSD). Here we evaluated the role of the SNP array in achieving a molecular diagnosis in Brazilian patients with syndromic DSD of unknown etiology. METHODS: Twenty-two patients with DSD and syndromic features were included in the study and underwent SNP-array analysis. RESULTS: In two patients, the diagnosis of 46,XX SRY + DSD was established. Additionally, two deletions were revealed (3q29 and Xp22.33), justifying the syndromic phenotype in these patients. Two pathogenic CNVs, a 10q25.3-q26.2 and a 13q33.1 deletion encompassing the FGFR2 and the EFNB2 gene, were associated with genital atypia and syndromic characteristics in two patients with 46,XY DSD. In a third 46,XY DSD patient, we identified a duplication in the 14q11.2-q12 region of 6.5 Mb associated with a deletion in the 21p11.2-q21.3 region of 12.7 Mb. In a 46,XY DSD patient with delayed neuropsychomotor development and congenital cataracts, a 12 Kb deletion on chromosome 10 was found, partially clarifying the syndromic phenotype, but not the genital atypia. CONCLUSIONS: The SNP array is a useful tool for DSD patients, identifying the molecular etiology in 40% (2/5) of patients with 46,XX DSD and 17.6% (3/17) of patients with 46,XY DSD.

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.