A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2).

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Imaging in urethral stricture disease: an educational review of current techniques with a focus on MRI.

Urethral stricture disease refers to narrowing of the urethral lumen obstructing the flow of urine. Urethral strictures can significantly impact daily life due to incontinence, incomplete emptying, hesitancy, and increased risk of urinary tract infections. Imaging is central to the evaluation of suspected urethral stricture, as assessment of stricture length and severity is crucial for guidance of surgical management. The currently employed modalities include radiography, chiefly retrograde urethrography (RUG) and voiding cystourethrography (VCUG); magnetic resonance urethrography (MRU); and sonourethrography (SUG). MRU has become a recent focus of research as it provides high spatial resolution, multiplanar capacity, and soft tissue type differentiation for evaluation of periurethral compartments and concurrent soft tissue defects. The protocol for MRU has evolved over the years to now include dynamic micturition imaging and image reconstruction options. In this review, we discuss each of the imaging modalities used in the diagnosis and evaluation of urethral stricture and provide an overview of literature on MRU over the last decade, including suggested indications that have not yet been incorporated into current guidelines. We delineate scenarios where special diagnostic imaging beyond radiography is beneficial, providing examples from our practice and description of our techniques for each modality.

Chronic kidney disease in patients with childhood-onset systemic lupus erythematosus.

BACKGROUND: Lupus nephritis (LN) is a frequent manifestation of childhood-onset systemic lupus erythematosus (cSLE) with a potential risk for kidney failure and poor outcomes. This study aimed to evaluate stages III, IV, and V of chronic kidney disease (CKD) and investigate risk factors for CKD in cSLE patients. METHODS: We performed a nationwide observational cohort study in 27 pediatric rheumatology centers, including medical charts of 1528 cSLE patients. Data were collected at cSLE diagnosis, during follow-up, and at last visit or death, between September 2016 and May 2019. RESULTS: Of 1077 patients with LN, 59 (5.4%) presented with CKD, 36/59 (61%) needed dialysis, and 7/59 (11.8%) were submitted for kidney transplantation. After Bonferroni's correction for multiple comparisons (p < 0.0013), determinants associated with CKD were higher age at last visit, urinary biomarker abnormalities, neuropsychiatric involvement, higher scores of disease activity at last visit and damage index, and more frequent use of methylprednisolone, cyclosporine, cyclophosphamide, and rituximab. In the regression model analysis, arterial hypertension (HR = 15.42, 95% CI = 6.12-38.83, p ≤ 0.001) and biopsy-proven proliferative nephritis (HR = 2.83, 95%CI = 1.70-4.72, p ≤ 0.001) increased the risk of CKD, while children using antimalarials had 71.0% lower CKD risk ((1.00-0.29) × 100%) than children not using them. The Kaplan-Meier comparison showed lower survival in cSLE patients with biopsy-proven proliferative nephritis (p = 0.02) and CKD (p ≤ 0.001). CONCLUSIONS: A small number of patients manifested CKD; however, frequencies of dialysis and kidney transplantation were relevant. This study reveals that patients with cSLE with hypertension, proliferative nephritis, and absence of use of antimalarials exhibited higher hazard rates of progression to CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Analysis of surgical and histopathological results of robot-assisted partial nephrectomy with use of three or four robotic arms: an early series results

ABSTRACT Objectives: The aim of this study was to evaluate whether criteria exist to guide election between the use the three- or four-arm technique in robotic partial nephrectomy (RPN) instead of just the surgeon's preference. Material and Methods: We performed a retrospective review of 80 patients submitted to RPN from May 2016 to February 2020. The patients were divided into two groups of 40, the first submitted to the surgical procedure with use of three robotic arms and the second with four arms. The group division was performed independently of the complexity of the cases, age or gender of the patients and laterality of the renal lesions. Peri- and postoperative data were analyzed for comparison between the two groups. Results: Both techniques had similar oncological outcomes (positive tumor margins), renal function preservation (warm ischemia time) and hemorrhagic complications (estimated blood loss and renal artery pseudoaneurysm), with a small difference in the need for blood transfusion, favoring the technique with three arms. Conclusions: The two robotic partial nephrectomy techniques had similar oncological and postoperative outcomes, with minimal perioperative complications. The three-arm technique is safe and feasible regardless of the complexity and size of the tumor. Additionally, the use of the three-arm technique reduced surgery costs by US$ 413.00 per patient.

Analysis of surgical and histopathological results of robot-assisted partial nephrectomy with use of three or four robotic arms: an early series results.

OBJECTIVES: The aim of this study was to evaluate whether criteria exist to guide election between the use the three- or four-arm technique in robotic partial nephrectomy (RPN) instead of just the surgeon's preference. MATERIAL AND METHODS: We performed a retrospective review of 80 patients submitted to RPN from May 2016 to February 2020. The patients were divided into two groups of 40, the first submitted to the surgical procedure with use of three robotic arms and the second with four arms. The group division was performed independently of the complexity of the cases, age or gender of the patients and laterality of the renal lesions. Peri- and postoperative data were analyzed for comparison between the two groups. RESULTS: Both techniques had similar oncological outcomes (positive tumor margins), renal function preservation (warm ischemia time) and hemorrhagic complications (estimated blood loss and renal artery pseudoaneurysm), with a small difference in the need for blood transfusion, favoring the technique with three arms. CONCLUSIONS: The two robotic partial nephrectomy techniques had similar oncological and postoperative outcomes, with minimal perioperative complications. The three-arm technique is safe and feasible regardless of the complexity and size of the tumor. Additionally, the use of the three-arm technique reduced surgery costs by US$ 413.00 per patient.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): a Brazilian cohort

Abstract Background: Paediatric inflammatory multisystem syndrome (PIMS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described since mid-April 2020 with the first reports coming from Europe. Our objective was to describe the characteristics of patients among the Brazilian population. Methods: A multicenter retrospective study was conducted with the participation of five pediatric rheumatology centers in Brazil during the period from March to November 2020. Children and adolescents with PIMS temporally associated with SARS-CoV-2 (TS) who met the definition criteria for the disease according to the Royal College of Paediatrics and Child Health were included. Demographic, clinical, laboratory, therapeutic characteristics and molecular and serological diagnosis of SARS-CoV-2 infection were described. Results: Fifty-seven children and adolescents with PIMS-TS were evaluated, 54% female, with a median age of 8 (3-11) years. Most (86%) were previously healthy, with asthma being the main comorbidity, present in 10% of the patients. Fever was the main manifestation, present in all patients, followed by mucocutaneous and gastrointestinal features, present in 89% and 81% of the patients, respectively. Myocarditis occurred in 21% of the patients and in 68% of them required intensive care. The Kawasaki disease phenotype occurred in most patients (77%). All patients had elevated inflammatory markers, with elevated CRP being the most found (98%). Anemia and lymphopenia were present in 79% and 72%, respectively. Laboratory evidence of SARS-CoV-2 was found in 77% of the patients, with 39% positive RT-PCR and 84% positive serology for SARS-CoV-2. An immunomodulatory treatment was performed in 91% of the patients, with 67% receiving intravenous immunoglobulin (IVIG) associated with glucocorticoid, 21% receiving IVIG, and 3.5% receiving glucocorticoid. The median length of hospitalization was 10 days. Conclusions: This study showed a high morbidity of PIMS-TS in Brazilian children, with a prolonged length of hospitalization and a high rate of admission to pediatric intensive care unit. Multicenter prospective studies are needed to assess the morbidity of the disease in the medium and long term.

Findings regarding non-sexual penile fracture in a referral emergency hospital

ABSTRACT Purpose: To describe penile fracture (PF) findings with non-sexual etiology in a referral emergency hospital, with emphasis on demographic data, clinical and intraoperative findings and long-term outcomes. Materials and Methods: Patients with PF of non-sexual cause operated at our institution from January 2014 to January 2019 were submitted to surgical treatment and monitored for at least three months after surgery. Etiology of trauma, epidemiological and clinical presentation data, time to intervention and operative findings were reviewed retrospectively. The evaluation of postoperative erectile function was carried out by filling out the International Index of Erection Function - 5 (IIEF-5). The tool used to assess urinary function was the International Prostate Symptom Score (IPSS) questionnaire. Results: Of a total of 149 patients submitted to surgical treatment for PF, 18 (12%) reported non-sexual etiology. Twelve (66.6%) cases were due to penile manipulation through the act of bending the penis during morning erection, three (16.6%) when rolling over in bed with erect penis, one (5.5%) when embracing the wife during erection, one (5.5%) to laying on the partner with erect penis and the other (5.5%) when sitting on the toilet with an erection. Operative findings were unilateral corpus cavernosum injury in all cases. Only one (5.5%) patient had a partial urethral lesion. Follow-up time varied from 3 to 18 months (mean, 10.1 months). Three (16.6%) patients developed erectile dysfunction six months after surgery. However, all of them responded to treatment with IPDE-5 and reported improvement of erection, with no need for medication, on reevaluation after 18 months. One (5.5%) patient developed penile curvature < 30 degrees. Thirteen (72.2%) patients developed penile nodules. No patient presented voiding complaints during follow-up. Conclusions: PF is a rare urologic emergency, especially with the non-sexual etiology. However, PF should always be considered when the clinical presentation is suggestive, regardless of the etiology. Penile manipulation and roll over in bed were the most common non-sexual causes. These cases are related to low-energy traumas, usually leading to unilateral rupture of corpus cavernosum. Urethral involvement is uncommon but may be present. Early treatment has good long-term clinical outcome, especially when performed in specialized centers with extensive experience in FP.

Findings regarding non-sexual penile fracture in a referral emergency hospital.

PURPOSE: To describe penile fracture (PF) findings with non-sexual etiology in a referral emergency hospital, with emphasis on demographic data, clinical and intraoperative findings and long-term outcomes. MATERIALS AND METHODS: Patients with PF of non-sexual cause operated at our institution from January 2014 to January 2019 were submitted to surgical treatment and monitored for at least three months after surgery. Etiology of trauma, epidemiological and clinical presentation data, time to intervention and operative findings were reviewed retrospectively. The evaluation of postoperative erectile function was carried out by filling out the International Index of Erection Function - 5 (IIEF-5). The tool used to assess urinary function was the International Prostate Symptom Score (IPSS) questionnaire. RESULTS: Of a total of 149 patients submitted to surgical treatment for PF, 18 (12%) reported non-sexual etiology. Twelve (66.6%) cases were due to penile manipulation through the act of bending the penis during morning erection, three (16.6%) when rolling over in bed with erect penis, one (5.5%) when embracing the wife during erection, one (5.5%) to laying on the partner with erect penis and the other (5.5%) when sitting on the toilet with an erection. Operative findings were unilateral corpus cavernosum injury in all cases. Only one (5.5%) patient had a partial urethral lesion. Follow-up time varied from 3 to 18 months (mean, 10.1 months). Three (16.6%) patients developed erectile dysfunction six months after surgery. However, all of them responded to treatment with IPDE-5 and reported improvement of erection, with no need for medication, on reevaluation after 18 months. One (5.5%) patient developed penile curvature < 30 degrees. Thirteen (72.2%) patients developed penile nodules. No patient presented voiding complaints during follow-up. CONCLUSIONS: PF is a rare urologic emergency, especially with the non-sexual etiology. However, PF should always be considered when the clinical presentation is suggestive, regardless of the etiology. Penile manipulation and roll over in bed were the most common non-sexual causes. These cases are related to low-energy traumas, usually leading to unilateral rupture of corpus cavernosum. Urethral involvement is uncommon but may be present. Early treatment has good long-term clinical outcome, especially when performed in specialized centers with extensive experience in FP.

Lessons learned after 20 years' experience with penile fracture

ABSTRACT Objective: To report our experience over the past 20 years in the diagnosis and surgical treatment of penile fracture (PF). Materials and methods: Between January 1997 and January 2017, patients with clinical diagnosis of PF were admitted to our facility and retrospectively assessed. Medical records were reviewed for clinical presentation, etiology and operative findings. Postoperative complications, sexual and urinary function were evaluated. Results: Sexual trauma was the main etiological factor, responsible for 255 cases (88.5%): 110 (43.1%) occurred with the "doggy style" position, 103 (40.3%) with "man on top" position, 31 (12.1%) with the "woman on top" position and 11 (4.3%) in other sexual positions. The most common findings in the clinical presentation were hematoma, in all cases and detumescence in 238 (82.6%). Unilateral corpus cavernosum injuries were found in 199 (69%) patients and bilateral in 89 (31%) patients. Urethral injuries were observed in 54 (18.7%) cases. Nine (14.7%) patients developed erectile dysfunction and eight (13.1%) had penile curvature. Only two (3.7%) patients had complications after urethral reconstruction. Conclusions: PF has typical clinical presentation and no need for additional tests in most cases. Hematoma and immediate penile detumescence are the most common clinical findings. Sexual activity was the most common cause. The 'doggy style' and 'man-on-top' was the most common positions and generally associated with more severe lesions. Concomitant urethral injury should be considered in cases of highenergy trauma. Surgical reconstruction produces satisfactory results, however, it can lead to complications, such as erectile dysfunction and penile curvature.

Selection for tandem stop codons in ciliate species with reassigned stop codons.

The failure of mRNA translation machinery to recognize a stop codon as a termination signal and subsequent translation of the 3' untranslated region (UTR) is referred to as stop codon readthrough, the frequency of which is related to the length, composition, and structure of mRNA sequences downstream of end-of-gene stop codons. Secondary in-frame stop codons within a few positions downstream of the primary stop codons, so-called tandem stop codons (TSCs), serve as backup termination signals, which limit the effects of readthrough: polypeptide product degradation, mislocalization, and aggregation. In this study, ciliate species with UAA and UAG stop codons reassigned to code for glutamine are found to possess statistical excesses of TSCs at the beginning of their 3' UTRs. The overrepresentation of TSCs in these species is greater than that observed in standard code organisms. Though the overall numbers of TSCs are lower in most species with alternative stop codons because they use fewer than three unique stop codons, the relatively great overrepresentation of TSCs in alternative-code ciliate species suggests that there exist stronger selective pressures to maintain TSCs in these organisms compared to standard code organisms.

Linear growth and bone metabolism in pediatric patients with inflammatory bowel disease / Crescimento linear e metabolismo ósseo em pacientes pediátricos com doença inflamatória intestinal

Abstract Objective: To review the pathophysiology and evaluation methods of linear growth and bone mineral density in children and adolescents diagnosed with inflammatory bowel disease. Source of data: Narrative review carried out in the PubMed and Scopus databases through an active search of the terms: inflammatory bowel disease, growth, failure to thrive, bone health, bone mineral density, and children and adolescents, related to the last ten years, searching in the title, abstract, or keyword fields. Synthesis of findings: Inflammatory bowel diseases of childhood onset may present as part of the clinical picture of delayed linear growth in addition to low bone mineral density. The presence of a chronic inflammatory process with elevated serum levels of inflammatory cytokines negatively interferes with the growth rate and bone metabolism regulation, in addition to increasing energy expenditure, compromising nutrient absorption, and favoring intestinal protein losses. Another important factor is the chronic use of glucocorticoids, which decreases the secretion of growth hormone and the gonadotrophin pulses, causing pubertal and growth spurt delay. In addition to these effects, they inhibit the replication of osteoblastic lineage cells and stimulate osteoclastogenesis. Conclusion: Insufficient growth and low bone mineral density in pediatric patients with inflammatory bowel disease are complex problems that result from multiple factors including chronic inflammation, malnutrition, decreased physical activity, late puberty, genetic susceptibility, and immunosuppressive therapies, such as glucocorticoids.

Resumo Objetivo: Revisar a fisiopatologia e os métodos de avaliação do crescimento linear e densidade mineral óssea em crianças e adolescentes com diagnóstico de doença inflamatória intestinal. Fontes dos dados: Revisão narrativa a partir de pesquisa nas bases de dados PubMed e Scopus por meio de busca ativa dos termos inflammatory bowel disease, growth, failure to thrive, bone health, bone mineral density, children e adolescents nos últimos dez anos e com busca nos campos título, resumo ou palavra-chave. Resumo dos achados: As doenças inflamatórias intestinais com início na infância podem apresentar como parte do quadro clínico atraso do crescimento linear, além de baixa densidade mineral óssea. A presença de processo inflamatório crônico com elevados níveis séricos das citocinas inflamatórias interfere negativamente na velocidade do crescimento e na regulação do metabolismo ósseo, além de aumentar o gasto energético, comprometer a absorção de nutrientes e favorecer perdas proteicas intestinais. Outro fator importante é o uso crônico de glicocorticoides, que diminuem a secreção de hormônio do crescimento e dos pulsos das gonadotrofinas e ocasionam atraso puberal e no estirão do crescimento. Além desses efeitos, inibem a reprodução das células da linhagem osteoblástica e estimulam a osteoclastogênese. Conclusão: A insuficiência do crescimento e a baixa densidade mineral óssea em pacientes pediátricos com doença inflamatória intestinal são problemas complexos e que decorrem de múltiplos fatores, inclusive inflamação crônica, desnutrição, diminuição da atividade física, puberdade tardia, suscetibilidade genética a terapias imunossupressoras, como os glicocorticoides.