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Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet and nitric oxide synthase inhibition, pulmonary fibrosis induced by bleomycin treatment, and liver fibrosis due to a choline-deficient diet. We also observed up-regulation of endothelial SOX9 in cardiac tissue from patients with heart failure. To test whether SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9 , which promoted fibrosis in multiple organs and resulted in signs of heart failure. Endothelial Sox9 deletion prevented fibrosis and organ dysfunction in the two mouse models of heart failure as well as in the lung and liver fibrosis mouse models. Bulk and single-cell RNA sequencing of mouse endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory gene expression, leading to matrix deposition by endothelial cells. Moreover, mouse endothelial cells activated neighboring fibroblasts that then migrated and deposited matrix in response to SOX9, a process partly mediated by the secreted growth factor CCN2, a direct SOX9 target; endothelial cell-specific Sox9 deletion reversed these changes. These findings suggest a role for endothelial SOX9 as a fibrosis-promoting factor in different mouse organs during disease and imply that endothelial cells are an important regulator of fibrosis.

Objective: Kidney shortage for pediatric kidney transplantation (PKT) entails the need to use low-weight and age donors, despite the apprehension. The aim of this study was to analyze the pediatric deceased donor kidney transplantations (pDDKT) outcomes in the first year after the procedure, stratified by donor age., Method: Retrospective cohort of pDDKTs carried out between January 2013, and January 2018, at a PKT reference hospital in Southern Brazil. Donors were divided into group 1 (≤ 6 years), and group 2 (> 6 years); the analysis of the outcomes was carried out in the same period., Results: There were 143 pDDKTs; 51 (35.66%) in group 1; and 92 (64.34%) in group 2. In both groups there were 17 graft losses (11.8%), with vascular thrombosis as the main cause (group 1: 5; group 2: 4). Among the complications, renal artery stenosis (RAS) with indication for angioplasty and stenting was more frequent in group 1 (7.8%; group 2: 2.2%). The 1-year Renal Transplant Recipients' and graft survival did not show significant differences between the groups, (p =  = 0.95). However, the Glomerular Filtration Rate analysis was higher in group 2, reaching, in the 12th month, 79.3 mL/min/1,73m2, compared to 69.7 mL/min/1,73m 2 in group 1(p =  = 0.033)., Conclusions: Small donors can be considered for pDDKTs, as long as there is an expert team to perform the transplantation., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: The aim of this study was to analyze the waiting list for kidney transplantation in our hospital according to candidate's panel reactive antibodies (cPRA) and its outcomes., Methods: One thousand six hundred forty patients who were on the waiting list between 2015 and 2019 were included. For the analysis, hazard ratios (HR) for transplant were estimated by Fine and Gray's regression model according to panel reactivity and HR for graft loss and death after transplantation., Results: The mean age was 45.39 ± 18.22 years. Male gender was predominant (61.2%), but the proportion decreased linearly with the increase in cPRA (p < 0.001). The distribution of patients according to panels were: 0% (n = 390), 1% - 49% (n = 517), 50% - 84% (n = 269), and ≥ 85% (n = 226). Transplantation was achieved in 85.5% of the sample within a median time of 8 months (CI 95%: 6.9 - 9.1). The estimated HRs for transplantation during the follow-up were 2.84 (95% CI: 2.51 - 3.34), 2.41(95%CI: 2.07 - 2.80), and 2.45(95%CI: 2.08 - 2.90) in the cPRA range of 0%, 1%-49%, and 50%-84%, respectively, compared to cPRA ≥ 85 (p < 0.001). After transplantation, the HR for graft loss was similar in the different cPRA groups, but the HR for death (0.46 95% CI 0.24-0.89 p = 0.022) was lower in the 0% cPRA group when adjusted for age, gender, and presence of donor specific antibodies (DSA)., Conclusion: Patients with cPRA below 85% are more than twice as likely to receive a kidney transplantation with a shorter waiting time. The risk of graft loss after transplantation was similar in the different cPRA groups, and the adjusted risk of death was lower in nonsensitized recipients.

Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.

Background: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens., Methods: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14., Results: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82)., Conclusions: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access., Competing Interests: Potential conflicts of interest. A. C. P. has received research grants from Gilead, Pfizer, and IMMY (who also provided diagnostic tests for the study); he reports travel support from Pfizer, United Medical, and Merck; participation on a Data Safety Monitoring or Advisory Board for Gilead; and payment or honoraria for talks on behalf of Gilead, United Medical, Pfizer, Merck, Sharp & Dohme (MSD), IMMY, Astra-Zeneca, and Astellas Pharma. D. R. F. has received research grants and consulting fees from Pfizer, MSD, and Gilead Sciences. D. R. F. also reports travel support from Pfizer, United Medical, Janssen, and Merck; participation on Data Safety Monitoring or Advisory Boards for Gilead Sciences, Merck, and GlaxoSmithKline (GSK); has given paid lectures on behalf of United Medical, Pfizer, Janssen, GSK, Merck, Gilead Sciences, Knight Pharmaceuticals, and MSD, and received non-financial research support from IMMY. N. C. B. reports grants from National Institutes of Health (NIH) (grant numbers NINDS K23 NS110470 and NIAID R01 AI170158) and Karyopharm therapeutics (Site PI for 2020 clinical trial; funds paid to institution); and participation as chair of the Data and Safety Monitoring Board (DSMB) for NCT04335123. A. S. reports grants from Astellas and Mayne, and consulting fees from GSK and F2G. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bioimpedance analysis (BIA) has been demonstrated to add accuracy to nutritional and volume status assessments in dialysis (HD) patients., Aim: to describe a sample of dialysis patients from a single center on their demographics and BIA of volume distribution and nutritional status, and mortality during 12-month follow-up., Methods: prospective observational cohort study to evaluate vintage HD patients with single-frequency BIA., Results: we evaluated 82 patients, 29% over 65 years old. Elderly patients had higher ECW/TBW (0.51 vs. 0.44, p < 0.0001), and narrower phase angle (PhA) (4.9 vs. 6.4º, p < 0.0001). Fifteen patients (18.2%) died during follow-up, eight (53%) were elderly. Death was associated with age (62.6 vs. 50.2 years, p = 0.012), post-HD PhA (4.8 vs. 6.2º, p = 0.0001), and post-HD ECW/TBW (0.50 vs. 0.45, p = 0.015). The ROC curve analysis to predict mortality found ECW/TBW ≥ 0.47 and PhA ≤ 5.5º to have the best sensitivity and specificity. One-year patient survival was lower with post-HD ECW/TBW ≥ 0.47 (69.5% vs. 90.6%, p = 0.019), age ≥ 65 years (64.2%, vs. 86.2%, p = 0.029), and PhA ≤ 5.5º (68.2 vs. 91.0%, p = 0.002). Cox regression analysis demonstrated that PhA [HR 5.04 (95%CI 1.60-15.86), p = 0.006] remained associated with death after adjusting for age and ECW/TBW., Conclusion: BIA is useful in assessing volume distribution and nutrition in HD patients, and combined with clinical judgement, may help determine dry weight, especially in elderly patients. Narrower PhA and higher ECW/TBW after HD were associated with poorer one-year survival.

Background: The molecular dynamics is an approach to obtain kinetic and thermodynamic characteristics of biomolecular structures. The molecular dynamics simulation softwares are very useful, however, most of them are used in command line form and continue with the same common implementation difficulties that plague researchers who are not computer specialists., Results: Here, we have developed the VisualDynamics-a WEB tool developed to automate biological simulations performed in Gromacs using a graphical interface to make molecular dynamics simulation user-friendly task. In this new application the researcher can submit a simulation of the protein in the free form or complexed with a ligand. Can also download the graphics analysis and log files at the end of the simulation., Conclusions: VisualDynamics is a tool that will accelerate implementations and learning in the area of molecular dynamics simulation. Freely available at https://visualdynamics.fiocruz.br/login , is supported by all major web browsers. VisualDynamics was developed with Flask, which is a Python-based free and open-source framework for web development. The code is freely available for download at GitHub https://github.com/LABIOQUIM/visualdynamics ., (© 2023. The Author(s).)

Paired box 9 (PAX9) is a transcription factor of the PAX family functioning as both a transcriptional activator and repressor. Its functional roles in the embryonic development of various tissues and organs have been well studied. However, its roles and molecular mechanisms in cancer development are largely unknown. Here, we review the current understanding of PAX9 expression, upstream regulation of PAX9, and PAX9 downstream events in cancer development. Promoter hypermethylation, promoter SNP, microRNA, and inhibition of upstream pathways (e.g., NOTCH) result in PAX9 silencing or downregulation, whereas gene amplification and an epigenetic axis upregulate PAX9 expression. PAX9 may contribute to carcinogenesis through dysregulation of its transcriptional targets and related molecular pathways. In summary, extensive studies on PAX9 in its cellular and tissue contexts are warranted in various cancers, in particular, HNSCC, ESCC, lung cancer, and cervical SCC.

Background: Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab., Methods: This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group)., Results: Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group., Conclusion: The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries., Competing Interests: I declared that the authors Modelli de Andrade LG, Palma LM, and Miranda SMC received fees from Alexion pharmaceutical to Travel grants and honoraria for speaking and participation at meetings. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch., Results: In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9 -/- mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9 -/- mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9 -/- mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9 -/- mice., Conclusions: Msx1 haploinsufficiency mitigates the arch artery defects in Pax9 -/- mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9 -/- mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development., (© 2021. The Author(s).)

Introduction: Cytomegalovirus (CMV) is one of the most common agents of infection in solid organ transplant patients, with significant morbidity and mortality., Objective: This study aimed to establish a threshold for initiation of preemptive treatment. In addition, the study compared the performance of antigenemia with qPCR results., Study Design: This was a prospective cohort study conducted in 2017 in a single kidney transplant center in Brazil. Clinical validation was performed by comparing in-house qPCR results, against standard of care at that time (Pp65 CMV Antigenemia). ROC curve analysis was performed to determine the ideal threshold for initiation of preemptive therapy based on the qPCR test results., Results: Two hundred and thirty two samples from 30 patients were tested with both antigenemia and qPCR, from which 163 (70.26%) were concordant (Kappa coefficient: 0.435, p<0.001; Spearman correlation: 0.663). PCR allowed for early diagnoses. The median number of days for the first positive result was 50 (range, 24-105) for antigenemia and 42 (range, 24-74) for qPCR (p<0.001). ROC curve analysis revealed that at a threshold of 3,430 IU/mL (Log 3.54), qPCR had a sensitivity of 97.06% and a specificity of 74.24% (AUC 0.92617 ± 0.0185, p<0.001), in the prediction of 10 cells/105 leukocytes by antigenemia and physician's decision to treat., Conclusions: CMV Pp65 antigenemia and CMV qPCR showed fair agreement and a moderate correlation in this study. The in-house qPCR was revealed to be an accurate method to determine CMV DNAemia in kidney transplant patients, resulting in positive results weeks before antigenemia.