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O cancro de mama triplo-negativo (TNBC) é um subtipo agressivo de cancro de mama, associado a um mau prognóstico em estadios iniciais e avançados. A quimioterapia continua a ser o tratamento padrão preconizado para estes doentes, apesar de seu benefício limitado. Devido às características agressivas da doença e à falta de terapias dirigidas, várias tentativas foram feitas para investigar novos alvos moleculares. O TNBC é agora conhecido por ser um subtipo de cancro de mama imunogénico. Neste contexto, a imunoterapia surgiu como uma opção promissora de tratamento para esta doença. Durante os últimos anos, os inibidores de checkpoint imunológico (anti-PD1/PD-L1 e anti-CTLA-4 anticorpos monoclonais) foram investigados quer em monoterapia quer em combinação com a terapia convencional nesta neoplasia. Neste artigo apresenta-se uma revisão bibliográfica do papel da imunoterapia no contexto do TNBC, com enfoque no papel dos inibidores de checkpoint imunológico.

A pandemia de COVID-19 é, atualmente, responsável por mais de 526 milhões de infeções e mais de 6,3 milhões de mortes. Como nova doença, é extenso o número de publicações sobre o tema, motivando uma considerável heterogeneidade na sua abordagem. Apesar de existirem terapêuticas com benefício comprovado, continuam a ser propostas novas intervenções e estratégias, algumas das quais carecendo ainda de suporte científico, dificultando assim uma abordagem uniforme e consensual. Este documento tem como objetivo uniformizar, baseando-se na melhor e mais atualizada evidência científica disponível, a prestação de cuidados aos doentes adultos com COVID-19 moderada a crítica, desde o serviço de urgência até à hospitalização, quer em enfermarias gerais, quer em enfermarias de cuidados intensivos de nível 2 e 3. Este protocolo apresenta recomendações para a estratificação da doença COVID-19, critérios de hospitalização, meios complementares de diagnóstico adequados à admissão e durante a hospitalização, medidas terapêuticas gerais e terapêutica farmacológica dirigida, gestão de complicações como pneumonia organizativa e sobreinfeção bacteriana, tromboprofilaxia, considerações especiais na gravidez e amamentação, e possíveis opções terapêuticas futuras.

Despite the extensive information regarding hemophilia’s hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient’s oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.

Aim: Automated external defibrillators (AEDs) use various shock protocols with different characteristics when deployed in pediatric mode. The aim of this study is to assess and compare the safety and efficacy of different AED pediatric protocols using novel experimental approaches. Methods: Two defibrillation protocols (A and B) were assessed across two studies: Protocol A: escalating (50–75–90 J) defibrillation waveform with higher voltage, shorter duration and equal phase durations. Protocol B; non-escalating (50–50–50 J) defibrillation waveform with lower voltage, longer duration and unequal phase durations.Experiment 1: Isolated shock damage was assessed following shocks to 12 anesthetized pigs. Animals were randomized into two groups, receiving three shocks from Protocol A (50–75–90 J) or B (50–50–50 J). Cardiac function, cardiac troponin I (cTnI), creatine phosphokinase (CPK) and histopathology were analyzed. Experiment 2: Defibrillation safety and efficacy were assessed through shock success, ROSC, ST-segment deviation and contractility following 16 randomized shocks from protocol A or B delivered to 10 anesthetized pigs in VF. Results: Experiment 1: No clinically meaningful difference in cTnI, CPK, ST-segment deviation, ejection fraction or histopathological damage was observed following defibrillation with either protocol. No difference was observed between protocols at any timepoint. Experiment 2: all defibrillation types demonstrated shock success and ROSC ≥ 97.5%. Post-ROSC contractility was similar between protocols. Conclusions: There is no evidence that administration of clinically relevant shock sequences, without experimental confounders, result in significant myocardial damage in this model of pediatric resuscitation. Typical variations in AED pediatric mode settings do not affect defibrillation safety and efficacy.

Introduction: Persons with haemophilia (PWH) used to represent a population with a high prevalence of hepatitis C virus (HCV) infection due to the use of contaminated blood products. Although the goals of antiviral therapy are the same as the general population, long real-life follow-up data regarding their outcomes are still scarce. Our aim was to report the outcomes of HCV infection and the results of antiviral therapy in PWH. Methods: A retrospective analysis was performed in a single-centre cohort of PWH with positive HCV antibody. Outcomes registered were rate of spontaneous clearance of HCV, sustained virologic response (SVR) achievement, development of end-stage liver disease, and all-cause and liver-related mortality. Results: Out of 131 PWH, 73 (55.7%) had positive HCV antibody. During a median follow-up time of 22 years, 46 patients (63.9%) developed chronic hepatitis C, of which 16 (34.8%) developed cirrhosis. Treatment was pursued in 34 PWH. Most (n = 32) were first treated with interferon (IFN)-based regimens with SVR rates of 40.6%. Direct-acting antivirals were used in 14 IFN-experienced and 2 naïve patients, with an overall SVR rate of 100%. Overall, 17 patients (23.3%) died during the follow-up, only 4 related to liver disease. Of these, none had achieved SVR. Conclusions: We describe the outcomes of a cohort of Portuguese PWH and hepatitis C exposure after two decades of follow-up, with a lower mortality than previously described. Our response rates to HCV treatment were comparable to those in the general population and stress the importance of early treatment.

Patients with Coronavirus disease 2019 (COVID-19) are at increased risk of venous thromboembolism (VTE); however, data on arterial thromboembolism (ATE) is still limited. We report a case series of thromboembolic events (TE) in 290 COVID-19 patients admitted between October and December 2020 to a Portuguese hospital. Admission levels of various laboratory parameters were evaluated and compared between COVID-19 patients with (TE) and without thrombotic events (non-TE). The overall incidence of isolated ATE was 5.52%, isolated VTE was 2.41% and multiple mixed events was 0.7%. A total of 68% events were detected upon admission to the hospital with 76% corresponding to ATE. Admissions to the Intensive Care Unit were higher in patients with TE, when comparing with the non-TE group (44% vs. 27.2%; p = 0.003). Patients with ATE presented significantly lower levels of CRP (p = 0.007), ferritin (p = 0.045), LDH (p = 0.037), fibrinogen (p = 0.010) and higher monocyte counts (p = 0.033) comparatively to the non-TE patients. These results point to an early occurrence of TE and an increased incidence of ATE over VTE. The less prominent inflammation markers in patients with TE and the early presence of TE in patients with otherwise no reason for hospitalization, may suggest a direct role of SARS-CoV-2 in the thrombotic process.

Após a generalização da vacinação contra a COVID-19, foram relatados efeitos adversos como trombose, hemorragia e trombocitopenia. Recentemente, após vacinação, foi reconhecido um síndrome raro e com mortalidade elevada, caraterizado por uma combinação não usual de trombocitopenia e trombose, em particular trombose dos seios venosos cerebrais, com muitas semelhanças com a trombocitopenia induzida pela heparina. Foram desenvolvidas diferentes recomendações na definição, diagnóstico e tratamento destas raras complicações. Apresentamos aqui, um protocolo de atuação baseado na evidência atual.

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G>A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G>A (hypomorphic allele) and a novel pathogenic variant, c.343-2A>G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.

O artigo discute aspectos do processo de patrimonialização das “timbila chopes” de Moçambique que culminou com sua proclamação pelo Programa das Obras-Primas do Patrimônio Oral e Imaterial da Humanidade da Unesco em 2005. Inspirada em análises sobre processos de objetificação e redução semântica implicados no reconhecimento oficial de expressões como patrimônio cultural, abordo elementos da trajetória histórica e social das timbila para compreender seu lugar no imaginário nacional e sua escolha como o primeiro bem cultural imaterial em Moçambique consagrado em arenas internacionais. Enfatizei no decorrer do texto diversos elementos que localizam esse país africano no âmbito das suas relações internacionais; por um lado, discuto algumas das dinâmicas perpetuadas pelo colonialismo, as quais possibilitaram a divulgação das timbila para além do território colonizado e, por outro, reflito sobre a relação de Moçambique com a Unesco, à luz da história política do país e de sua recepção em relação a certos critérios e entendimentos desse organismo internacional no que tange ao patrimônio imaterial. Por fim, destaco as interpretações dadas pelo Estado moçambicano aos ideais de participação social da Unesco e mostro como o dossiê produzido pelo governo moçambicano utilizou o critério de autenticidade em voga naquele momento para descrever e justificar a escolha das timbila.

At the height of international visibility for #metoo, a crowdsourced list was published on Facebook that contained the names of prestigious Indian academics, accusing them of sexual harassment. The list was controversial not only in that it became a viral phenomenon (and resulted in immediate questioning of the legitimacy of internet culture for politics) but also in that these accusations did not contain information on the circumstances of the alleged crimes, so as to protect the victims’ anonymity. The list was quickly dubbed “the list of naming and shaming” and was met with its strongest criticism from within the feminist movement itself, as established feminists argued publicly against such methods and against the queer Dalit leaker of the document, Raya Sarkar. This paper examines these conflicts of solidarity as conflicts between transnational and local positionalities and argues for the possibility of digital spaces as environments that invite a queering of identity politics, constructive disagreement, and transformative justice, rather than mere conflict and its resolution through a homogenous feminist identity.

BackgroundRare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia.ObjectivesTo describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes.MethodsWe reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects.ResultsPatients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity.ConclusionsPreviously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

In this article I discuss some aspects of Brazilian international cooperation within educational agreements with Mozambique. I argue how the implantation of large agriculture investments and the diffusion of soap operas play a central role in the execution of these agreements, in promoting attractive images of a richness and full of opportunities Brazil. At the light of the analysis of narratives from two distinct generations of Mozambique students which studied at Brazilian universities and the observation of historical continuities in local labour practices, I discuss how ideas of development, work and modernity are pivotal to understand the effects of so called south-south cooperation.

RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers.

Purpose: Knee arthropathy is a frequent complication affecting hemophilic patients, which can cause severe pain and disability. When conservative measures fail, total knee arthroplasty (TKA) may be performed. Methods: Eighteen TKA were performed in 15 patients with hemophilia during a 24-year period in a Hemophilia Comprehensive Care Center. All patients were evaluated by a multidisciplinary team constituted by a hematologist, an orthopedic surgeon, and a physical medicine and rehabilitation physician. Mean follow-up was 11.3 years. Results: Ten-year survival rate with prosthesis removal as end point was 94.3%. At last, follow-up visual analog pain scale score was 3.2 points, knee osteoarthritis outcome scale was 86.7 points, and mean range of motion was 88°. Only two patients required perioperative transfusion. Complication rate was 27.8% and included two infections, two prosthesis stiffness, and one case of recurrent hemarthrosis. Conclusion: After appropriate medical optimization and with prompt rehabilitation, TKA can be performed in hemophilic patients with good clinical results and survivor rates comparable to nonhemophilic patients.

DOI: http://dx.doi.org/10.5902/1984644415857Este artigo tem como objetivo apresentar os resultados do projeto de extensão “Ensino de filosofia em espaços não formais”, explicitando basicamente os processos de sua execução em termos práticos tanto quanto os desdobramentos filosóficos de seu transcorrer. Em princípio a ideia geral do projeto consistiu em criar um espaço dedicado às possibilidades de experiência com o filosofar que produzisse aos participantes um modo de relação com a filosofia diferente daquele estabelecido em ambientes formais como, por exemplo, a instituição escolar. Devido às experiências anteriores no que se refere ao ensino de filosofia demarcado pelas formalidades institucionais, procuramos transbordar esses espaços convertendo o ensino clássico em uma dimensão dialógica de aprendizagem e de criação de novos espaços de pensamento. Respaldados pelas contribuições filosóficas de Gilles Deleuze e Jacques Rancière, procuramos desterritorializar o ensino da filosofia de sua tradição histórica, afirmando-o eventualmente nas potencialidades criativas do pensar, na contingência das afecções, no encontro com os signos. Em síntese, a escrita deste texto nos permite explorar algumas implicações daquilo que projetamos e do que vivenciamos doravante nossa própria construção de sentido acerca do ensinar e do aprender filosofia, principalmente do que significa pensar filosoficamente.

Variants in CACNA1A that encodes the pore-forming α 1 -subunit of human voltage-gated Cav2.1 (P/Q-type) Ca 2+ channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. To identify modifiers of incoordination in movement disorders, we performed a large-scale functional RNAi screen, using the Caenorhabditis elegans strain CB55, which carries a truncating mutation in the unc-2 gene, the worm ortholog for the human CACNA1A . The screen was carried out by the feeding method in 96-well liquid culture format, using the ORFeome v1.1 feeding library, and time-lapse imaging of worms in liquid culture was used to assess changes in thrashing behavior. We looked for genes that, when silenced, either ameliorated the slow and uncoordinated phenotype of unc-2 , or interacted to produce a more severe phenotype. Of the 350 putative hits from the primary screen, 37 genes consistently showed reproducible results. At least 75% of these are specifically expressed in the C. elegans neurons. Functional network analysis and gene ontology revealed overrepresentation of genes involved in development, growth, locomotion, signal transduction, and vesicle-mediated transport. We have expanded the functional network of genes involved in neurodegeneration leading to cerebellar ataxia related to unc-2 / CACNA1A , further confirming the involvement of the transforming growth factor β pathway and adding a novel signaling cascade, the Notch pathway.

Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding.

BACKGROUND: Circulating endothelial cells (CEC) may be a biomarker of vascular injury and pro-thrombotic tendency, while circulating endothelial progenitor cells (CEP) may be an indicator for angiogenesis and vascular remodelling. However, there is not a universally accepted standardized protocol to identify and quantify these cells and its clinical relevancy remains to be established. OBJECTIVES: To quantify CEC and CEP in patients with venous thromboembolism (VTE) and with myeloproliferative neoplasms (MPN), to characterize the CEC for the expression of activation (CD54, CD62E) and procoagulant (CD142) markers and to investigate whether they correlate with other clinical and laboratory data. PATIENTS AND METHODS: Sixteen patients with VTE, 17 patients with MPN and 20 healthy individuals were studied. The CEC and CEP were quantified and characterized in the blood using flow cytometry, and the demographic, clinical and laboratory data were obtained from hospital records. RESULTS: We found the CEC counts were higher in both patient groups as compared to controls, whereas increased numbers of CEP were found only in patients with MPN. In addition, all disease groups had higher numbers of CD62E+ CEC as compared to controls, whereas only patients with VTE had increased numbers of CD142+ and CD54+ CEC. Moreover, the numbers of total and CD62+ CEC correlated positively with the white blood cells (WBC) counts in both groups of patients, while the numbers of CEP correlated positively with the WBC counts only in patients with MPN. In addition, in patients with VTE a positive correlation was found between the numbers of CD54+ CEC and the antithrombin levels, as well as between the CD142+ CEC counts and the number of thrombotic events. CONCLUSIONS: Our study suggests that CEC counts may reveal endothelial injury in patients with VTE and MPN and that CEC may express different activation-related phenotypes depending on the disease status.