Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Background Hepatic resection (HR) and liver transplantation (LT) are potentially curative treatments for Hepatocellular carcinoma (HCC). The aim of this study was to analyze the survival of patients with HCC and indications for surgical treatment (HR or LT) in a high-volume center. Methods This was a retrospective cohort study of consecutive patients with HCC and indications for LT or HR from May 2006 to July 2019. Analysis of overall survival (OS) and disease-free survival (DFS) rates, univariate analysis and construction of a multivariable model to identify risk factors were performed. Results A total of 744 patients with HCC were evaluated, 563 (75.6%) of whom were enrolled in waiting list for LT and 181 (24.4%) of whom underwent HR. Among the patients enrolled in the waiting list, 362 (64.3%) underwent LT, whereas 201 (35.7%) remained on the waiting list (WL). From the group of 201 patients on the waiting list, 97 (48.2%) were removed from the list due to tumor progression beyond the Milan criteria (MC), and 83 (41.3%) died while waiting for the transplant. In the WL group, 97 (48.2%) patients were removed from the list due to tumor progression beyond the MC, another 83 (41.3%) patients died while waiting for the LT. The OS rates of the LT group were 77.4%, 67.5% and 56.8%, whereas those of the WL + LT (intention-to-treat) group were 59.9%, 47.3%, and 39.9%, and the HRs were 82.8%, 49.3%, and 33.4% at 1, 5 and 10 years, respectively (p = 0.001). Donor age (p = 0.002) and cold ischemia time (p < 0.001) were independent factors related to OS in the LT group, whereas the presence of significant portal hypertension (p < 0.001), alpha-fetoprotein (AFP) value (p < 0.001) and MC (p = 0.002) were independent factors for HR. The DFS rates for HR were 74.9%, 40.0% and 31.0%, and those for LT were 97.9%, 92.0% and 90.9% at 1, 5 and 10 years, respectively (p < 0.001). Higher AFP levels were identified as an independent factor for lower DFS in both groups. Conclusions The present study revealed that the OS of patients listed for LT was greater in the first year than in the second year and that the results were similar to those of the HR in an intention-to-treat analysis. However, patients who achieve LT have better long-term outcomes, especially disease-free survival.

Objectives To comprehensively compare the disease burden among patients with RA, PsA and AS using Patient-Reported Outcome Measurement Information System (PROMIS) scores and to identify distinct patient clusters based on comorbidity profiles and PROMIS outcomes. Methods Data from the global COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 e-survey were analysed. Patients with RA, PsA or AS undergoing treatment with DMARDs were included. PROMIS scores (global physical health, global mental health, fatigue 4a and physical function short form 10a), comorbidities and other variables were compared among the three groups, stratified by disease activity status. Unsupervised hierarchical clustering with eXtreme Gradient Boosting feature importance analysis was performed to identify patient subgroups based on comorbidity profiles and PROMIS outcomes. Results The study included 2561 patients (1907 RA, 311 PsA, 343 AS). After adjusting for demographic factors, no significant differences in PROMIS scores were observed among the three groups, regardless of disease activity status. Clustering analysis identified four distinct patient groups: low burden, comorbid PsA/AS, low burden with depression and high-burden RA. Feature importance analysis revealed PROMIS global physical health as the strongest determinant of cluster assignment, followed by depression and diagnosis. The comorbid PsA/AS and high-burden RA clusters showed a higher prevalence of comorbidities (56.47% and 69.7%, respectively) and depression (41.18% and 41.67%, respectively), along with poorer PROMIS outcomes. Conclusion Disease burden in inflammatory arthritis is determined by a complex interplay of factors, with physical health status and depression playing crucial roles. The identification of distinct patient clusters suggests the need for a paradigm shift towards more integrated care approaches that equally emphasize physical and mental health, regardless of the underlying diagnosis.

The term “feeding difficulties” (FD) encompasses a range of phenotypes characterized by inadequate food intake and/or inappropriate eating habits for a given age. Eosinophilic esophagitis (EoE) is a chronic, immune‐mediated condition often affecting children. It leads to esophageal dysmotility, potentially impacting feeding/eating. However, little is known regarding the true prevalence of feeding/eating difficulties in children with EoE. The main objective of this systematic review was to address this knowledge gap and determine the impact of FD in children with EoE. We searched eight international databases for all published studies from inception until March 2024. All publications were screened against pre‐defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta‐analyses, so a narrative synthesis of quantitative data was performed. A total of 3442 abstracts were assessed, 29 underwent full‐text screening. Ten studies met eligibility criteria and were analyzed. Across these, 18 different terms to define FD and 6 diagnostic tools were used. All included papers reported quantitative data on the FD prevalence in children with EoE, ranging from 13% to 75.3%. Concomitant IgE food sensitization/allergy was common (26.2%–88%) but its impact on FD occurrence was unclear. The current literature suggests that FD is prevalent among children with EoE, particularly those with associated IgE‐mediated food allergies. However, the heterogeneity of terminologies and diagnostic tools makes drawing conclusions challenging, as it might have impacted outcomes. Further research and guidance on the diagnosis and management of FD in children with EoE are needed to appropriately identify and manage such patients.

Microcirculation contributes significantly to blood flow resistance, with upper airway microcirculation in obstructive sleep apnea (OSA) affected by endothelial activation, perturbed blood flow shear stress, and snoring-induced tissue vibration. The relevance of these mechanisms on microcirculation response and remodeling remains largely unknown but may influence management decisions in OSA. This study analyzed pharyngeal muscle tissue from non-obese, young adult patients with OSA and chronic heavy snoring. We assessed arteriole morphometry and quantified the expression of endothelial activation markers: 8-isoprostane, vascular cell adhesion molecule-1, E-selectin, vascular endothelial growth factor, endothelin-1, and endothelial cell specific molecule-1. Morphometric analysis of 319 arterioles (mean of 8 vessels per patient) revealed thicker walls in severe OSA compared to mild OSA without lumen reduction, indicating outward hypertrophy, and a positive correlation between the apnea–hypopnea index (a measure of OSA severity) and arteriole wall thickness. However, analysis of 1872 arterioles showed no increase in endothelial activation markers with disease severity, either in the arteriole walls or muscle tissue. This suggests that, in young non-obese adults, severe OSA likely leads to adaptive, mechanically driven microcirculation outward hypertrophy, potentially due to perturbed shear stress, with potential implications for OSA management.

OBJECTIVE To evaluate the efficacy and safety of empagliflozin in patients with type 2 diabetes mellitus (T2DM) undergoing elective on-pump coronary artery bypass grafting (CABG). RESEARCH DESIGN AND METHODS Investigator-initiated, pragmatic, single-center, randomized, open-label trial with blinded outcome adjudication conducted in Brazil. A total of 145 patients with T2DM scheduled for elective on-pump CABG were randomized to receive empagliflozin 25 mg daily plus standard care (n = 71) for at least 3 months, which was discontinued 72 h before surgery, or to received standard care alone (n = 74). The primary outcome was postoperative acute kidney injury (AKI) within 7 days of surgery, defined by creatinine-based criteria (namely, Acute Kidney Injury Network; Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease; or Kidney Disease: Improving Global Outcomes). Secondary outcomes included 30-day postoperative atrial fibrillation and type 5 myocardial infarction (MI). Safety outcomes were ketoacidosis, urinary tract infection, hospital-acquired pneumonia, and wound infection within 30 days after CABG. RESULTS AKI occurred in 22.5% of the empagliflozin group vs. 39.1% in the control group (relative risk [RR] 0.57 [95% CI 0.34–0.96]; P = 0.03). Rates of atrial fibrillation (15.4% vs. 13.5%; RR 1.15 [95% CI 0.52–2.53]; P = 0.73) and type 5 MI (1.4% vs. 4.1%; RR 0.35 [95% CI 0.04–3.26]; P = 0.62) were similar between groups. No statistically significant differences between groups were observed for safety events. Three deaths occurred, all in the control group. CONCLUSIONS Empagliflozin use before on-pump CABG in patients with T2DM was associated with a reduced incidence of postoperative AKI without an increase in safety events. These findings warrant confirmation in larger clinical trials.

Resumo Fundamento A edoxabana é um anticoagulante oral que se mostrou segura e eficaz na prevenção de acidente vascular cerebral em pacientes com fibrilação atrial (FA). Dada a ampla utilização da edoxabana desde sua aprovação, é crucial avaliar seu desempenho no contexto clínico brasileiro. Objetivos O objetivo do estudo foi descrever a segurança e a efetividade da edoxabana no tratamento de pacientes com FA no Brasil. Métodos O EdoBRA é um estudo multicêntrico, prospectivo, observacional, conduzido em 30 centros de pesquisa no Brasil. Eventos de sangramento foram considerados medidas de segurança, e eventos cardiovasculares foram considerados para medidas de efetividade. Análises descritivas foram realizadas. Curvas de Kaplan-Meier foram geradas para análise do tempo para o evento, e um intervalo de confiança de 95% usado conforme apropriado. Resultados Entre os 705 pacientes recrutados, 590 foram incluídos na análise por apresentarem pelo menos um evento relatado ou durante o seguimento. As médias (±DP) dos escores de risco CHA2DS2-VASc e HAS-BLED foram, respectivamente, 3 (3,3 ± 1,6) e 2 (1,8 ± 1,2). Durante o acompanhamento de um ano, foram relatados nove sangramentos maiores, incluindo cinco casos de sangramento gastrointestinal [PI 0,85 (IC95% =0,82; 0,88]). Entre os eventos cardiovasculares registrados (n=68), houve quatro eventos de acidente vascular cerebral [PI 0,68 (IC 95% 0,65; 0,71)], um ataque isquêmico transitório [PI 0,17 (IC 95% 0,16; 0,18)] e um tromboembolismo venoso [PI 0,17 (IC 95% 0,16; 0,18)]. Nenhum evento embólico sistêmico foi relatado. Conclusão Em uma população idosa com várias comorbidades, recebendo edoxabana como tratamento de rotina para FA, as taxas de evento cardiovasculares sangramento maior foram baixas.

Middle meningeal artery embolization (MMAE) has gained attention as an innovative approach for chronic subdural hematoma (cSDH). It can be utilized either as a standalone treatment or as an adjunct to surgical evacuation, with the primary goal of reducing the risk of cSDH recurrence. Therefore, we aim to investigate the efficacy and safety of MMAE in cSDH patients. Databases were systematically searched for randomized controlled trials (RCTs) reporting the use of MMAE in cSDH patients. All statistical analyses were performed using Review Manager 5.4.1. We employed risk ratio (RR) and Mean Differences (MD) with 95% confidence intervals (CIs) as the measure of effect size using a random-effects model. We included seven RCTs (1,623 patients; mean age, 72.7 ± 10.9 [MMAE group] and 72.3 ± 11.0 [usual-care group] years; 74.9% [MMAE] and 77.3% [usual-care] were male). MMAE significantly reduced recurrence (RR 0.47, 95% CI: 0.34 to 0.65, p < 0.001). No statistically significant differences were observed in good (RR 1.01, 95% CI: 0.97 to 1.05, p = 0.77) and favorable functional outcome (RR 1.01, 95% CI: 0.96 to 1.07, p = 0.69). Hematoma volume was only significantly reduced in the adjunctive MMAE subgroup analysis (MD -6.49, 95% CI: -12.21 to -0.78, p = 0.03). No statistically significant differences were observed in adverse events (RR 0.97, 95% CI: 0.68 to 1.39, p = 0.885), serious adverse events (RR 0.78, 95% CI: 0.59 to 1.04, p = 0.09), and mortality (RR 0.98, 95% CI: 0.42 to 2.30, p = 0.97). MMAE significantly reduced recurrence risk compared to usual care, with benefits observed in adjunctive MMAE, including lower reoperation rates and reduced hematoma volume at 90 days. Functional outcomes at 90 days were not significantly different between groups. Similarly, adverse events and mortality rates were comparable between groups Clinical trial number: Not applicable.

Background and objectives: Dengue virus (DENV) infection can cause acute encephalitis. Chronic encephalitis with progressive dementia is rarely reported. Methods: We present a case of chronic encephalitis with rapidly progressive dementia, in which a potential DENV brain infection was identified with brain tissue metagenomic next-generation sequencing. Brain pathology and molecular diagnosis are also presented. Results: A 20-year-old man from SP, Brazil, presented with rapidly progressive dementia, speech apraxia, and apathy in June 2022. By January 2023, cognitive testing showed severe global impairment (MMSE score of 18/30). MRI revealed white matter abnormalities and atrophy; CSF analysis disclosed a mild lymphocytic pleocytosis, mildly elevated protein levels, and positive CSF oligoclonal bands. Despite extensive testing ruling out common infectious and inflammatory causes, the patient's condition worsened with executive dysfunction, language impairment, tremors, and myoclonus. In August 2023, a brain biopsy and next-generation sequencing identified DENV-1 genotype V, linked to Brazilian sequences from 2000 to 2022. Discussion: This case highlights a challenging instance of encephalitis with unknown etiology, where metagenomic analysis detected DENV-1 RNA in brain tissue, suggesting a possible cause.

Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma (RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology approaches, we show that functional CDK4 protein is not detectable in cells with CDK4 mutations. Cells display impaired RB phosphorylation in G1, leading to G1/S-phase transition defects and reduced cell proliferation, consistent with complete loss of cellular CDK4 enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell proliferation, human growth, and brain size determination during development.

The study aimed to: (i) characterize dietary intake and identify disorders eating attitudes in women with SLE, (ii) evaluate possible differences in both dietary intake and disorders eating attitudes in patients with SLE according to nutritional status, (iii) investigate possible associations between eating disorders attitudes, anthropometric characteristics and food consumption. Methods: This cross-sectional study included 46 premenopausal female patients (18-40 years), with inactive disease, using prednisone <10 mg/day and hydroxychloroquine at a stable dose. Patients were allocated into two groups according to their nutritional status by body mass index (BMI): normal weight (BMI between 18.5 and 24.9 kg/m ² ) and excess weight (BMI >25 kg/m ² ). Food consumption was assessed according to the processing level and energy and macronutrient content. The Disordered Eating Attitude Scale (DEAS) was applied. Results: Patients with excess weight had a higher DEAS score when compared to those with normal weight (34 ± 8.7 vs 25 ± 5.9, p = .001). A higher percentage of patients with excess weight demonstrated disturbance in their relationship with food and concerns about food and weight gain versus those with normal weight. DEAS score was positively associated with BMI, abdominal circumference, and fat mass percentage and negatively associated with lipid intake. Conclusion: Disordered eating attitudes differ in SLE patients according to nutritional status, and those with excess weight show higher DEAS scores, which may be related to food and weight gain.

Introduction: Legg-Calvé-Perthes disease is a major cause of hip joint deformities in children. Currently, experimental research is directed at investigating biological therapies, including the use of human dental pulp stem cells (hDPSC), which have not yet been studied for this purpose in swine models. This study aimed to evaluate whether local injection of hDPSC induces bone mineralization in the proximal femoral epiphysis in an experimental model of avascular necrosis of the femoral head in immature pigs. Methods: Ten immature pigs underwent surgery to induce osteonecrosis of the proximal femoral epiphysis on the right side. In the intervention group (IG), hDPSC injections were performed immediately after osteonecrosis induction, and in the control group (CG), no additional procedure was performed. Left hips were used as controls. After 8 weeks, all animals were euthanized, and macroscopic, radiographic, and histological evaluations were performed. Results: Bone mineralization was greater in the right hips of the IG compared to the CG (p = 0.0356), with an average mineralization index increase of 77.78% after hDPSC injection. Radiographic evaluation of the epiphyseal index showed a greater collapse in the right IG hips compared to the right CG hips (p < 0.001) and macroscopic evaluation showed a higher chance of the femoral head being flat (p = 0,049). Conclusion: The injection of hDPSC into the proximal femoral epiphysis with induced osteonecrosis increases bone mineralization in immature pigs, but these treated hips show more deformity compared to the untreated hips. Level of Evidence IV, Case Series . Keywords: Legg-Calvé-Perthes Disease. Ischemia. Models; Animal. Swine. Dental Pulp. Stem Cells. Biological Treatment

Objective: Compare the formation of symptomatic neuromas in patients submitted to digital amputations, with and without nerve conduits (Neurolac® ), and sensitivity return. Methods: Prospective, case-control study, including 14 patients with digital amputations (total of 17 fingers) whose conduits were used on the ulnar or radial side, while the contralateral side was used in the same patients as control. The Tinel test, Semmes-Weinstein monofilament, and two-point discrimination tests were evaluated at one week, two weeks, one month, three months, and six months postoperatively. Results: Using nerve conduits (Neurolac®) in digital nerve amputation stumps had statistical significance (p = 0.04) in preventing pain due to symptomatic neuroma at the end of six months after digital regularization. Conclusion: There is a favorable trend towards using conduits as prophylaxis of symptomatic neuroma formation since the nerves in which they were used showed fewer clinical signs of neuroma formation six months after surgery. Level of evidence II, Prospective comparative study. Keywords: Amputation; Traumatic; Fingers; Neuroma; Nerve Conduit; Sensory Recovery

Objective Self-limited delayed puberty (SLDP) is the most common cause of delayed puberty and exhibits high heritability, although few causal genes have been identified. This study aims to identify potential candidate genes associated with SLDP. Methods Whole-exome sequencing was conducted in 71 children with SLDP, most of whom presented with short stature. Rare coding variants were prioritized through comprehensive bioinformatics analyses and classified as high-impact or moderate-impact based on predicted functional effects. Candidate genes were selected based on the absence of human phenotype data, recurrence within the cohort, intolerance to mutation, and prior identification in genome-wide association studies. Burden tests compared the frequency of rare high-impact variants in these candidate genes between SLDP patients and the gnomAD v2.0 control group. Gene-phenotype associations were further explored using UK Biobank data. Results Fourteen high-impact and seven moderate-impact variants were identified in 19 candidate genes, suggesting a potential role in SLDP. Variants in eight candidate genes (GPS1, INHBB, SP3, NAMPT, ARID3B, NASP, FNBP1, PRDM2) were significantly enriched in cases compared to controls in the burden test analysis. INHBB was additionally linked to delayed menarche in UK Biobank data. Furthermore, three pathogenic variants (CDK13, GDF5, ANRKD11) and six likely pathogenic variants (TYMP, DPF2, KMT2C, TP63, MC3R, GHSR) previously associated with growth or pubertal human disorders were identified. Conclusion These findings suggest that SLDP involves both monogenic and polygenic mechanisms, with novel candidate genes contributing to its genetic basis. The association of INHBB with pubertal timing underscores its potential role in SLDP pathophysiology.