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Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

Since the first descriptions of superior canal dehiscence (SCD) syndrome, it has been widely demonstrated how a bony defect overlying the superior semicircular canal (SSC) can result in a low-imped...

Few data from randomized clinical trials (RCTs) investigating the efficacy of post-induction strategies after the first-line treatment with anti-Epidermal Growth Factor Receptor (EGFR) in patients with metastatic colorectal cancer (mCRC) are available. A systematic review and metanalysis might therefore be useful to highlight and even strengthen these data. A literature search in Pubmed, Embase, American Society of Clinical Oncology (ASCO) Annual Meetings, ASCO Gastrointestinal Symposia, and European Society for Medical Oncology (ESMO) Congresses was performed. The search included RCTs of patients with mCRC treated with an initial period of cytotoxic chemotherapy (CT) in association with anti-EGFR (ie, panitumumab or cetuximab) as first-line regimen, and then switched to one of the following strategies: observation; maintenance with anti-EGFR, fluoropyrimidine (FP), or both; or continuing the induction regimen until disease progression or unacceptable toxicity. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the Mantel-Haenszel method fixed-effect model or the DerSimonian-Laird method random-effect model according to heterogeneity (I

The authors describe and compare two complementary techniques that are habitually used to image ferromagnetic and ferroelectric materials with sub‐micron spatial resolutions (typically 50 nm, at best 10 nm). The first technique is variable‐temperature photoemission electron microscopy with magnetic/antiferromagnetic/polar contrast from circularly/linearly polarized incident X‐rays (XPEEM). The second technique is magnetic force microscopy (MFM). Focusing mainly on the authors’ own work, but not exclusively, published/unpublished XPEEM and MFM images of ferroic domains and complex magnetic textures (involving vortices and phase separation) are presented. Highlights include the use of two XPEEM images to create 2D vector maps of in‐plane (IP) magnetization, and the use of imaging to detect electrically driven local reversals of magnetization. The brief and simple descriptions of XPEEM and MFM should be useful for beginners seeking to employ these techniques in order to understand and harness ferroic materials.

Background In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes. Methods Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed. Results Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6–6.1 versus 3.0–3.8 months (hazard ratios, 0.47–0.88), median progression-free survival was 1.9–2.3 versus 1.7–1.8 months (hazard ratios, 0.49–0.67), and median time to ECOG PS ≥ 2 was 4.0–4.7 versus 1.9–2.5 months (hazard ratios, 0.56–0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0–6.1 and 2.1–2.3 months, respectively) than in those who previously received these agents (4.6–5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted. Conclusions In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type. Clinical trials registration clinicaltrials.gov NCT02500043.

Purpose: No evidence exists as to whether type 2 diabetes (T2DM) impairs clinical outcome from Immune Checkpoint Inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose lowering medications (GLM) for T2DM had shorter OS and PFS. We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment of patients with/without diabetes. Results: A total of 1395 patients were included. Primary tumors included NSCLC (54.7%), melanoma (24.7%), renal cell (15.0%) and other carcinomas (5.6%). Following multivariable analysis, patients on GLM (n=226, 16.2%) displayed an increased risk of death (HR 1.29, 95%CI:1.07-1.56) and disease progression/death (HR 1.21, 95%CI:1.03-1.43) independent of number of GLM received. We matched 92 metformin exposed with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM was associated with an increased risk of death (HR 1.53, 95%CI:1.16-2.03) and disease progression/death (HR 1.34, 95%CI:1.04-1.72). T2DM patients with higher pre-treatment glycaemia had higher neutrophil-to-lymphocyte ratio (p=0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n=22) revealed differential regulation of innate and adaptive immune pathways in T2DM patients. Conclusions: In this study patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a pre-existing diagnosis of T2DM in influencing poorer outcomes in this population.

Background Body weight loss (BWL) is a negative prognostic factor in metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). In the phase III TAGS study, trifluridine/tipiracil improved survival versus placebo in third- or later-line mGC/GEJC. These retrospective analyses examined the association of early BWL with survival outcomes in TAGS. Methods Efficacy and safety were assessed in patients who experienced Results Body weight data were available for 451 of 507 (89%) patients in TAGS. In the trifluridine/tipiracil and placebo arms, respectively, 74% (224/304) and 65% (95/147) experienced P P = 0.0003) for OS. Similar results were obtained for progression-free survival. Any-cause grade ≥ 3 adverse events were reported in 77% and 82% of trifluridine/tipiracil-treated and 45% and 67% of placebo-treated patients with Conclusions In TAGS, early BWL was a strong negative prognostic factor for OS in patients with mGC/GEJC receiving third- or later-line treatment.

Currently, the standard treatment for gastric and gastroesophageal junction (GEJ) adenocarcinoma, including distal esophagus, consists of perioperative chemotherapy (CT) according to FLOT schedule (5FU/leucovorin/oxaliplatin and docetaxel), or of concomitant chemoradiotherapy (CTRT) based on CROSS regimen. However, due to the relatively lack of direct comparisons between perioperative CT and neoadjuvant CTRT, the effectiveness of these new combinations is unknown. Therefore, we performed a network meta-analysis (NMA) to compare the efficacy of different neoadjuvant treatments for gastric and GEJ adenocarcinoma in terms of overall and disease-free survival (OS and DFS).We searched MEDLINE, Embase, and Cochrane from database inception until February 1st 2022 for randomized clinical trials that enrolled adults with gastric and GEJ carcinomas and provided data about OS and/or DFS. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Surface under the cumulative rank (SUCRA) curve plots were produced. The primary outcome was OS, secondary endpoint DFS.A total of 1247 citations were screened; 14 randomized clinical trials were included. In Bayesian comparisons, FLOT-based CT ranked as one of the better regimens with a probability of 41%, both with induction CT followed by CTRT (P = 0.45). For DFS analysis, the FLOT regimen was the preferred option (P = 0.62).In conclusion, this NMA adds further evidence to the optimization of treatment strategies for gastric and GEJ adenocarcinomas and confirms that incorporation of perioperative triplet-based CT improved both OS and DFS compared to surgery alone and other preoperative strategies.

Il ruolo della tracheotomia nei pazienti affetti da disfunzione moderata o severa delle vie aeree inferiori.Durante la pandemia di COVID-19 la necessità di eseguire una tracheotomia nei pazienti con insufficienza respiratoria prolungata è drammaticamente aumentata, poiché i pazienti contagiati dal virus SARS-CoV-2 manifestano una sindrome da distress respiratorio acuto grave che spesso necessita di un’intubazione prolungata. La tracheotomia offre diversi vantaggi rispetto all’intubazione translaringea prolungata: un migliore comfort del paziente può infatti consentire una riduzione della somministrazione di analgesici e sedativi, può migliorare la mobilità con particolare riguardo ai muscoli respiratori e i pazienti possono raggiungere un’autonomia più precocemente. Tuttavia in letteratura è ancora aperto un dibattito su quale sia, nell’esecuzione della tracheotomia, la tempistica ottimale e la tecnica chirurgica più appropriate, così come se sia più indicate la tecnica a cielo aperto (ST) rispetto alla dilatazione percutanea (PDT). In generale, in terapia intensiva, la PDT in elezione è più comunemente usata; la ST può essere preferita a seconda dell’esperienza del medico e delle caratteristiche del paziente. La tempistica di esecuzione deve essere individualizzata sulle condizioni del paziente e l’indicazione deve considerare i problemi legati all’intubazione prolungata e il rischio di complicanze legate alla procedura chirurgica.Patients affected by severe acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have a high likelihood of needing prolonged intubation. As observed worldwide during the Coronavirus Disease 2019 (COVID-19) pandemic, the need for tracheotomy in patients with prolonged respiratory failure has dramatically increased. Tracheotomy in these patients offers several advantages over prolonged translaryngeal intubation: improved patient comfort may allow a reduction in intravenous administration of analgesics, sedatives and muscle relaxant drugs, enhance mobility with particular regard to respiratory muscles, and patients may achieve autonomy earlier. However, there is still debate about the optimal timing and surgical technique of tracheotomy. Similarly, debate is still open regarding the relative merits of open surgical tracheotomy (ST)

Objective: To assess all different patterns of associated abnormalities on audiometry, bithermal caloric test (BCT) and cervical/ocular vestibular-evoked myogenic potentials (VEMPs) to air/bone-conduction in patients with selective posterior semicircular canal (PSC) hypofunction and to correlate them with underlying disorders. Study Design: Retrospective review. Setting: Tertiary referral center. Patients: 51 patients (23 men, 28 women, mean age 57.5 yr) with isolated PSC deficit (one bilateral). Interventions: Correlation with instrumental data and underlying diagnoses. Main Outcome Measures: Video-oculographic findings, objective measurements on audiometry, BCT, VEMPs and video-head impulse test (vHIT). Results: Ongoing or previous acute vestibular loss (AVL) was diagnosed in 13 patients (25.5%, 3 inferior vestibular neuritis, 10 AVL with sudden sensorineural hearing loss [SSNHL]), Meniere's disease (MD) in 12 (23.5%), cerebellopontine angle (CPA) lesion in 9 (17.6%), various causes in 7 (13.7%), benign paroxysmal positional vertigo (BPPV) involving the non-ampullary arm of PSC in 5 cases (9.8%) whereas unknown pathology in 5 (9.8%). Involvement of at least one additional receptor besides PSC was seen in 89.8% of cases. Cochlear involvement was diagnosed in 74.5% with pure-tone average significantly greater in patients with AVL+SSNHL (p < 0.05). Overall involvement of labyrinthine receptors or afferents was highest in patients with AVL+SSNHL (p < 0.01), MD and CPA lesions (p < 0.05). Conclusions: Isolated loss of PSC function on vHIT is mostly accompanied by additional labyrinthine deficits that could only be identified through an accurate instrumental evaluation. Assessment of all receptors and afferents should be always pursued to identify the lesion site and better understand the underlying pathophysiological mechanisms.

In this work, we investigate the effect of anti-site disorder on the half-metallic properties of a Mn2FeAl Heusler alloy thin film. The film was grown on TiN-buffered MgO 001 substrates via magnetron sputtering. A detailed structural characterization using x-ray diffraction (XRD) and anomalous XRD showed that the film crystallizes in the partially disordered L21 B structure with 33% disorder between the Mn(B) and Al(D) sites. We measure a positive anisotropic magnetoresistance in the film, which is an indication of non-half metallic behaviour. Our x-ray magnetic circular dichroism sum rules analysis shows that Mn carries the magnetic moment in the film, with a positive Fe moment. Experimentally determined moments correspond most closely with those found by density functional calculated for the L21 B structure with Mn(B) and Al(D) site disorder, matching the experimental structural analysis. We thus attribute the deviation from half-metallic behaviour to the formation of the L21 B structure. To realize a half-metallic Mn2FeAl film it is important that the inverse Heusler XA structure is stabilized with minimal anti-site atomic disorder.

Molecular docking is a key method for structure-based drug design used to predict the conformations assumed by small drug-like ligands when bound to their target. However, the evaluation of molecular docking studies can be hampered by the lack of a free and easy to use platform for the complete analysis of results obtained by the principal docking programs. To this aim, we developed PacDOCK, a freely available and user-friendly web server that comprises a collection of tools for positional distance-based and interaction-based analysis of docking results, which can be provided in several file formats. PacDOCK allows a complete analysis of molecular docking results through root mean square deviation (RMSD) calculation, molecular visualization, and cluster analysis of docked poses. The RMSD calculation compares docked structures with a reference structure, also when atoms are randomly labelled, and their conformational and positional differences can be visualised. In addition, it is possible to visualise a ligand into the target binding pocket and investigate the key receptor–ligand interactions. Moreover, PacDOCK enables the clustering of docking results by identifying a restrained number of clusters from many docked poses. We believe that PacDOCK will contribute to facilitating the analysis of docking results to improve the efficiency of computer-aided drug design.

RESUMO Em indústrias de manufatura, um dos processos de produção consiste em cortar grandes objetos em peças menores. Em pesquisa operacional, o estudo desse processo é conhecido como o problema de corte de estoque (PCE) e, devido à sua dificuldade de resolução, métodos heurísticos vêm sendo desenvolvidos pelos pesquisadores da área. Neste trabalho, propomos utilizar técnicas de análise de decisão multicritério (MCDA) a fim de resolver o PCE de forma eficiente em termos de GAP e tempo computacional. Nossa estratégia consiste em selecionar previamente os melhores padrões de corte com técnicas MCDA e resolver o problema apenas com esses padrões selecionados. Os testes computacionais mostraram que a solução obtida com essa estratégia apresenta um GAP entre 0,25% e 4,25% quando comparada com a solução ótima, dando indícios da qualidade da abordagem proposta. ABSTRACT In manufacturing industries, one of the production processes consists of cutting large objects into smaller pieces. In operational research, this process’s study is known as the cutting stock problem (CSP). Due to its difficulty in resolution, heuristics have been developed by researchers in the area. In this work, we propose to use multicriteria decision analysis (MCDA) techniques to solve the CSP in a reasonable computational time and aiming to obtain solutions very close to the optimum. Our strategy consists of selecting the best cutting patterns using MCDA techniques and solving the problem only with these chosen patterns. The computational tests showed that the solution obtained with this strategy presents a GAP between 0.25% and 4.25% compared to the optimal solution, giving indications that the proposal is promising.

O presente estudo consiste em relatos de experiência dos residentes pedagógicos do Colégio Acreano, os quais foram obtidos a partir dos métodos de observação estruturada, participação nas atividades de classe e conversação. O objetivo deste trabalho foi expressar os limites e desafios enfrentados pelos Residentes Pedagógicos do Colégio Acreano, diante o cenário de pandemia, através dos relatos obtidos e apresentados na seção de resultados do presente trabalho. A partir deles, foi possível notar as diferentes percepções dos residentes acerca do programa em pauta, no que tange ao desenvolver de suas atividades enquanto residentes, ao impacto do modelo de ensino do atual momento em sua prática, e o quão relevante é, os programas de formação inicial para os cursos de licenciatura, em destaque ao PRP.

Human Papillomavirus (HPV) related oropharyngeal carcinoma (OPC) carries a better prognosis compared with HPV-counterparts, thereby pushing the adoption of de-intensification treatment approaches as new strategies to preserve superior oncologic outcomes while minimizing toxicity. We evaluated the effect of treatment de-intensification in terms of overall survival (OS), progression-free survival (PFS), locoregional and distant control (LRC and DM) by selecting prospective or retrospective studies, providing outcome data with reduced intensification versus standard curative treatment in HPV+ OPC patients, with a systematic analysis till September 2020. The primary outcome of interest was OS. Secondary endpoints were PFS, LRC, and DM expressed as HR. A total of 55 studies (from 1393 screened references) were employed for quantitative synthesis for 38 929 patients. Among n = 48 studies with data available, de-intensified treatments reduced OS in HPV+ OPCs (HR = 1.33, 95% CI 1.17-1.52; p 0.01). In de-escalated treatments, PFS was also decreased (HR = 2.11, 95% CI 1.65-2.69; p 0.01). Compared with standard treatments, reduced intensity approaches were associated with reduced locoregional and distant disease control (HR = 2.51, 95% CI 1.75-3.59; p 0.01; and HR = 1.9, 95% CI 1.25-2.9; p 0.01). Chemoradiation improved survival in a definitive curative setting compared with radiotherapy alone (HR = 1.42, 95% CI 1.16-1.75; p 0.01). When adjuvant treatments were compared, standard and de-escalation strategies provided similar OS. In conclusion, in patients with HPV+ OPC, de-escalation treatments should not be widely and agnostically adopted in clinical practice, as therein lies a concrete risk of offering a sub-optimal treatment to patients.

Introduction. Antibody-drug conjugates (ADCs) represent a new class of molecular-targeted drugs, which are being developed to selectively target tumor cells and minimize toxicities. Three ADCs, namely trastuzumab emtansine (TDM-1), sacituzumab govitecan, and trastuzumab deruxtecan, are currently approved for the treatment of metastatic breast cancer (MBC). Acute gastrointestinal toxicities are relatively frequent with these agents. We performed a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs. Methods. PubMed, Embase, and the Cochrane Library were searched from inception until December 2020 for phase 2 and 3 trials reporting frequency and severity of gastrointestinal AEs in patients treated with ADCs. Data were collected for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were described and expressed as proportions. A pre-specified subgroup analysis according to type of agent was also performed. Results. Ten studies, involving a total of 4020 patients, were included in the analysis. Gastrointestinal AEs were very frequent with sacituzumab govitecan and trastuzumab deruxtecan but were mostly low-grade. These novel ADCs were characterized by a significantly higher incidence of nausea (65.6% with sacituzumab govitecan, 77.2% with trastuzumab deruxtecan), vomiting (43.7% and 46.6%), and diarrhea (59.7% and 30.2%) compared to TDM-1. Diarrhea was the main AEs associated with sacituzumab govitecan (grade 3 in 7.5% of patients). Abdominal pain and constipation were reported less frequently. Conclusions. Gastrointestinal AEs, especially nausea and diarrhea, are common in patients with MBC treated with novel ADCs. Prevention and treatment of these side effects are essential to maintain the dose intensity of ADCs and optimize the treatment compliance of patients. Table. Gastrointestinal toxicities of the different ADCs in MBC patients in the current pooled analysis.Gastrointestinal toxicities Toxicity pooled % (CI 95%)Sacituzumab govitecanTDM-1Trastuzumab deruxtecanp*p**p#NauseaAll gradesG3-G457.8 (46.9-68)2.2 (1-4.9)65.6 (61-70)4.3 (2.2-8.3)38.1 (32-44.5)0.8 (0.5-1.2)77.2 (72-81.6)2.6 (0.2-30.6)< 0.01< 0.01< 0.01< 0.01< 0.010.71DiarrheaAll grades G3-G434 (21.8-48.8)2.4 (1.7-3.3)59.7 (52.4-66.6)7.5 (4.3-12.7)17.5 (11.-25.4)0.9 (0.6-1.6)30.2 (25.3-35.7)2.4 (1.1-4.9)< 0.01< 0.01< 0.010.03< 0.010.015VomitingAll grades G3-G432.5 (23.6-42.8)2.7 (1.4-5)43.7 (33.5-54.5)4.4 (1.7-10.8)18.2 (15.3-21.4)1.3 (0.9-1.8)46.6 (41-52.3)4.4 (2.5-7.4)< 0.01< 0.01< 0.01< 0.01NSNSAbdominal painAll grades G3-G414.8 (9.4-22.5)1.2 (0.7-2.1)20.1 (11.9-31.8)1.3 (0.4-3.9)6.2 (4.2-9)1.2 (0.5-2.9)14.5 (9.8-21)0.9 (0.3-3.1)< 0.01NS< 0.01NSNSNSConstipationAll grades G3-G428.7 (20.4-38.9)0.6 (0.4-0.9)32.2 (18.6-49.6)0.8 (0.3-2.6)18 (12-26.1)0.5 (0.3-0.9)35.9 (30.7-41.5)0.7 (0.2-2.7)< 0.01NS< 0.01°NSNSNS* Statistically significant difference (p < 0.05) among the three ADCs.** Statistically significant difference (p < 0.05) for TDM-1 versus the other two ADCs.# Statistically significant difference (p < 0.05) for sacituzumab govitecan versus trastuzumab deruxtecan.° This value was not significant for T-DM1 versus sacituzumab govitecan comparison.CI, confidence interval; NS, not significant. Citation Format: Pierluigi di Mauro, Rebecca Pedersini, Fausto Petrelli, Antonio Ghidini, Vito Amoroso, Lara Laini, Maria Chiara Parati, Paolo Bossi, Alfredo Berruti. Gastrointestinal toxicity of antibody-drug conjugates (ADCs) in metastatic breast cancer: A pooled analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-15.

O presente trabalho objetiva realizar uma aproximação entre Brasil e Chile no campo educacional. Acredita-se que, por estarem ambos sob influência do ideário neoliberal e apresentarem elementos socioeconômicas similares, é construtivo realizar uma discussão sobre educação de maneira interligada. Ambos os países apresentam, sob influência do neoliberalismo, sistemas de ensino descentralizados e participação do setor privado balizados por meio de avaliações em larga escala cuja eficácia tem sido questionada. Essas características refletiram no aprofundamento da desigualdade em termos de qualidade, diferenciando não apenas as escolas e universidades, mas também os alunos. Evidência disto são as manifestações populares com demandas na área da educação que aconteceram nos últimos anos no Chile e, mais recentemente, no Brasil, algumas das quais com as mesmas reinvindicações. Dessa forma, a aplicação do ideário neoliberal na educação tem ocasionado consequências negativas em ambos os países, como o aumento da desigualdade educacional e a deterioração da qualidade. Por isso, é imperativo que analisemos as experiências já consolidadas no Chile para entendermos as consequências em ebulição no Brasil, considerando o neoliberalismo e sua influência na educação como um fenômeno supranacional.

Supplementary Table 1 from Dacarbazine Treatment before Peptide Vaccination Enlarges T-Cell Repertoire Diversity of Melan-A–Specific, Tumor-Reactive CTL in Melanoma Patients

Supplementary Figure Legend from Dacarbazine Treatment before Peptide Vaccination Enlarges T-Cell Repertoire Diversity of Melan-A–Specific, Tumor-Reactive CTL in Melanoma Patients

Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)–specific, tumor-reactive, long-lasting effector-memory CD8+ T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti–Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A–specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse. Cancer Res; 70(18); 7084–92. ©2010 AACR.

Supplementary Methods from Dacarbazine Treatment before Peptide Vaccination Enlarges T-Cell Repertoire Diversity of Melan-A–Specific, Tumor-Reactive CTL in Melanoma Patients

Supplementary Figure 1 from Dacarbazine Treatment before Peptide Vaccination Enlarges T-Cell Repertoire Diversity of Melan-A–Specific, Tumor-Reactive CTL in Melanoma Patients

Sustainability has become a central issue in Italian livestock systems driving food business operators to adopt high standards of production concerning animal husbandry conditions. Meat sector is largely involved in this ecological transition with the introduction of new label claims concerning the defense of animal welfare (AW). These new guarantees referred to AW provision require new tools for the purpose of authenticity and traceability to assure meat supply chain integrity. Over the years, European Union (EU) Regulations, national, and international initiatives proposed provisions and guidelines for assuring AW introducing requirements to be complied with and providing tools based on scoring systems for a proper animal status assessment. However, the comprehensive and objective assessment of the AW status remains challenging. In this regard, phenotypic insights at molecular level may be investigated by metabolomics, one of the most recent high-throughput omics techniques. Recent advances in analytical and bioinformatic technologies have led to the identification of relevant biomarkers involved in complex clinical phenotypes of diverse biological systems suggesting that metabolomics is a key tool for biomarker discovery. In the present review, the Five Domains model has been employed as a vademecum describing AW. Starting from the individual Domains—nutrition (I), environment (II), health (III), behavior (IV), and mental state (V)—applications and advances of metabolomics related to AW setting aimed at investigating phenotypic outcomes on molecular scale and elucidating the biological routes most perturbed from external solicitations, are reviewed. Strengths and weaknesses of the current state-of-art are highlighted, and new frontiers to be explored for AW assessment throughout the metabolomics approach are argued. Moreover, a detailed description of metabolomics workflow is provided to understand dos and don'ts at experimental level to pursue effective results. Combining the demand for new assessment tools and meat market trends, a new cross-strategy is proposed as the promising combo for the future of AW assessment.

Purpose Non-operative treatment (NOT) for pediatric acute appendicitis complicated with intra-abdominal abscess (IAA) has been introduced in the last decade. The study aimed to report our experience with this approach and investigate potential predictors of success. Methods Medical records of patients affected by appendicitis complicated with IAA between January 2013 and December 2020 were reviewed. The interval before delayed appendectomy, rate of re-admission before delayed appendectomy and the rate of delayed appendectomy were the endpoints of NOT. The outcomes were compared between patients treated by NOT and patients who underwent urgent surgery for complicated appendicitis. Results In the study period, twenty-six patients (37%) underwent NOT, and 45 (63%) underwent urgent surgery for complicated appendicitis with IAA. A delayed appendectomy was performed in 24 children (92%). The median time before surgery was 32 days (IQR 20–58 days). Eight children (31%) were re-admitted before delayed appendectomy, and three cases presented a disease relapse. An appendicolith was detected in two of them. Even though the overall hospital stay was longer for NOT (p = 0.0009), all these patients underwent laparoscopic appendectomy, and no conversions were reported (p = 0.0001; p = 0.0006). In addition, no difference in the rate of post-operative complications was found between the two groups (p = 0.62). Conclusions NOT presented a high rate of success. The presence of appendicolith at diagnosis might be considered a negative predictor of success. NOT might increase the success of mini-invasive surgery when compared to urgent surgery.

IntroductionPredicting hearing outcome in sudden sensorineural hearing loss (SSNHL) is challenging, as well as detecting the underlying pathomechanisms. SSNHL could be associated with vestibular damage since cochleo-vestibular structures share the same vascularization, along with being in close anatomical proximity. Whereas viral inflammations and autoimmune/vascular disorders most likely represent the involved aetiologies, early-stage Menière's disease (MD) can also present with SSNHL. Since an early treatment could beneficially influence hearing outcome, understanding the possible etiology plays a pivotal role in orienting the most appropriate treatment. We aimed to evaluate the extent of vestibular damage in patients presenting with SSNHL with or without vertigo, investigate the prognostic role of vestibular dysfunctions on hearing recovery and detect specific lesion patterns related to the underlying pathomechanisms.MethodsWe prospectively evaluated 86 patients with SSNHL. Audio-vestibular investigation included pure-tone/speech/impedance audiometry, cervical/ocular-VEMPs, vHIT and video-Frenzel examination. White matter lesions (WML) were evaluated on brain-MRI. Patients were followed-up and divided into “SSNHL-no-vertigo,” “SSNHL+vertigo” and “MD” subgroups.ResultsHearing was more impaired in “SSNHL+vertigo” patients who exhibited either down-sloping or flat-type audiograms, and was less impaired in “MD” where low frequencies were mostly impaired (p < 0.001). Otolith receptors were more frequently involved than semicircular canals (SCs). Although the “SSNHL-no-vertigo” subgroup exhibited the lowest vestibular impairment (p < 0.001), 52% of patients developed otolith dysfunctions and 72% developed nystagmus. Only “MD” subjects showed anterior SC impairment and upbeating spontaneous/positional nystagmus. They more frequently exhibited cervical-VEMPs frequency tuning (p = 0.036) and ipsilesional spontaneous nystagmus (p < 0.001). “SSNHL+vertigo” subjects presented with more frequently impaired cervical-VEMPs and posterior SC and with higher number of impaired receptors (p < 0.001). They mainly exhibited contralesional spontaneous and vibration-induced nystagmus (p < 0.05) and only they showed the highest WML score and “vascular” lesion patterns (p < 0.001). Concerning the outcomes, hearing was better in “MD” and worse in “SSNHL+vertigo” (p < 0.001). Hearing recovery was mostly affected by cervical-VEMPs impairment and the number of involved receptors (p < 0.05). Patients with “vascular” lesion patterns presented with the highest HL degree and WML score (p ≤ 0.001), while none of them exhibited a complete hearing recovery (p = 0.026).ConclusionsOur data suggest that vestibular evaluation in SSNHL can provide useful information on hearing recovery and underlying aetiologies.

Introduction Glans dehiscence (GD) is reportedly a common complication after proximal hypospadias repairs. However, the need for surgical correction is controversial. The aim of this study was to assess awareness, risk factors, and outcome of GD in post-pubertal patients. The agreement with surgeon assessment was also evaluated. Methods The design was retrospective. All consecutive patients treated for proximal hypospadias between 2000 and 2011 were included. The presence of GD was self-reported, and the participants could optionally upload a photograph for surgeon assessment. Cosmetic and functional outcomes were assessed by validated questionnaires (HOSE, PPPS, KINDL®, IIEF-5). Results were compared between patients with and without GD. Results Of 219 patients, 34 (16%) participated. Fourteen of them (41%) self-reported GD. Eighteen patients (8%) also uploaded a photograph and, in ten of them (56%), the surgeon noted the presence of GD with poor agreement [k = − 0.444 (95 CI − 0.856 to − 0.033)] with patient report. Patients self-reporting GD had had more frequently a penile curvature at diagnosis (12/14 = 86%, p = 0.01), and had undergone a single-staged repair (100% vs. 65%, p = 0.03). No difference was found in cosmetic and functional outcomes. Results were similar also comparing groups with and without GD as assessed by the surgeon. Conclusion GD was a common finding after severe hypospadias repair. It was more common in case of surgeon assessment with poor agreement between patients and surgeons. GD did not prove to have clear clinical implications. Therefore, in our opinion, surgical repair of GD should be recommended only on patients request.

Prescriptive Process Monitoring is a prominent problem in Process Mining, which consists in identifying a set of actions to be recommended with the goal of optimising a target measure of interest or Key Performance Indicator (KPI). One challenge that makes this problem difficult is the need to provide Prescriptive Process Monitoring techniques only based on temporally annotated (process) execution data, stored in, so-called execution logs, due to the lack of well crafted and human validated explicit models. In this paper we aim at proposing an AI based approach that learns, by means of Reinforcement Learning (RL), an optimal policy (almost) only from the observation of past executions and recommends the best activities to carry on for optimizing a KPI of interest. This is achieved first by learning a Markov Decision Process for the specific KPIs from data, and then by using RL training to learn the optimal policy. The approach is validated on real and synthetic datasets and compared with off-policy Deep RL approaches. The ability of our approach to compare with, and often overcome, Deep RL approaches provides a contribution towards the exploitation of white box RL techniques in scenarios where only temporal execution data are available., Comment: 10 pages, 5 figures

BACKGROUND The majority of patients with coronavirus disease 2019 (COVID-19) have good prognoses, but some develop a critical illness that can lead to death. Evidence shows severe acute respiratory syndrome is closely related to the induced cytokine storm. Interleukin-6 is a key player; its role in systemic inflammation is well known. AIM To evaluate the effect of tocilizumab (TCZ), an interleukin-6 receptor antagonist, on the outcomes for patients with COVID-19 pneumonia. METHODS PubMed, EMBASE, SCOPUS, Web of Science, MedRxiv, Science Direct, and the Cochrane Library were searched from inception to 9th June 2020 for observational or prospective studies reporting results of hospitalized adult patients with COVID-19 infection treated with TCZ. Effect sizes were reported as odds ratios (ORs) with 95% confidence intervals (CIs), and an OR less than 1 was associated with a better outcome in those treated with TCZ. RESULTS Overall 13476 patients (33 studies; n = 3264 received TCZ) with COVID-19 pneumonia and various degree of severity were included. Outcome was improved with TCZ. In the primary analysis (n = 19 studies reporting data), mortality was reduced in patients treated with TCZ (OR = 0.64, 95%CI: 0.47-0.87; P < 0.01). In 9 studies where risk of death with TCZ use was controlled for other variables mortality was reduced by 57% (OR = 0.43, 95%CI: 0.27-0.7; P < 0.01). Intensive care need (mechanical ventilation) was also reduced (OR = 0.36, 95%CI: 0.14-0.89; P = 0.02). CONCLUSION In COVID-19-infected patients treated with TCZ, outcome may be improved compared to those not treated with TCZ.

Background: Foreign bodies in the upper aerodigestive tract represent an uncommon cause of visits to emergency departments. In the majority of cases, foreign bodies do not go beyond the pharynx. They cause dyspnoea or pneumonia if they reach the tracheobronchial tree. If ingested, they will pass spontaneously through the gastrointestinal canal in the majority of cases. Nevertheless, especially in the case of sharp-pointed or large objects, the foreign bodies can stop in the oesophagus. In case of dysphagia, stinging sensation and/or odynophagia occurring after eating a meal, a foreign body in the upper aerodigestive tract should be suspected. If not clinically visible, imaging is required. Case presentation: A 72-year-old woman presented to the Emergency Department with pharyngodynia, odynophagia, stinging, dysphagia, and sialorrhea for 12 hours. Her symptoms started after eating a meal involving meat. The patient underwent a standard two-projection radiogram of the neck. The antero-posterior projection radiogram was unremarkable. The lateral projection radiogram showed 16 millimetres in maximum length radiopaque foreign body within the cervical oesophagus. The patient underwent transoral flexible oesophagoscopy under general anaesthesia, which resulted in successful removal of the foreign body (bony fragment). Her symptoms improved rapidly after the procedure, and the patient was discharged after 48 hours in good health. Conclusion: A foreign body in the cervical oesophagus may lead to visceral perforation. Once suspected, every effort should be made to identify and remove the foreign body to avoid potentially catastrophic consequences. In some cases, imaging could be necessary to detect the foreign body.