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Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a mature, peripheral T-cell neoplasm caused by HTLV-1 and its lifetime risk is estimated as 4-7% among HTLV-1 carriers. Acute and lymphoma subtypes are highly aggressive diseases, characterized by shorter survival rates and a high risk of central nervous system involvement (iCNS) compared to other peripheral T-cell lymphomas. Currently, the treatment of ATLL remains a challenging. Our recent study on PTCL epidemiology and outcomes in Latin America (Thais et al. 2023 ASH Meeting) highlighted ATLL (18%) as the second most frequent subtype of PTCL, likely influenced by our distinct viral epidemiology. Objective: It is to assess the prevalence, clinical features, risk factors, and outcomes of iCNS in ATLL in Latin America. Methodology: Patients (pts) aged ≥18 years with newly diagnosed ATLL from GELL (n = 208, 2000-2023, retrospective) and TCBP (n = 83, 2015-2022, ambispective). Overall survival (OS) and progression free survival (PFS) were our endpoints. REDcap Platform (by Vanderbilt) was used to collect and store data, whereas for statistical analysis IBM-SPSS v.24. This trial is registered at Clinical trials (NCT03207789). Results: It was enrolled 291 pts, the prevalence of iCNS in ATLL was 7.9% (23/291), considering only aggressive forms (acute 40% and 60% lymphomatous). Pts'characteristics were similar between those without and with iCNS. There was a high frequency of advanced stage (90% vs 82%); ECOG ≥ 2 (45% vs 43%); B symptoms (74% vs 56%); elevated LDH (84% vs 78%); and IPI ≥3 (82% vs 65%) in the iCNS group. Treatment was heterogeneous including: IFN+AZT (74%) for acute subtypes, and CHOP (52%), CHOEP (26%) and EPOCH (2%), for lymphoma subtypes. Less than 30% of both groups achieved complete response at end of first treatment. Two clinical features were identified as possibly associated to iCNS: median age at diagnosis (55 [20-95] vs 44 [23-65]; p < 0.0001) and extra nodal involvement ≥ 2 (32% vs 65%, p = 0.005). The entire cohort of ATLL had 60- month OS and PFS of 16% [95% CI: 12-20%] and 9% [95% CI: 5-13%]; with median time of OS and PFS of 7 months (6-9) and 5 months (4-6). iCNS did not have an impact on survival outcomes (60 months OS 14% iCNS (n = 23) vs 16% no iCNS (n = 254), p = 0.91; PFS 12% vs 9% no iCNS, p = 0.61;) despite being a devastating complication. Outcomes in pts with lymphoma subtypes were slightly better than acute (60 months OS 19% vs 10%, p < 0.0001; PFS 12% vs 5%, p < 0.0001, respectively). Conclusion: Unlike other lymphoma subtypes, iCNS in ATLL does not appear to significantly impact outcomes. This paradoxical finding underscores the complexity of ATLL and may reflect the limitations of existing treatment options and the absence of standardized therapeutic protocols for this aggressive malignancy. The lack of significant survival difference, despite the severity of iCNS, points to an urgent need for innovative therapies and more effective treatment strategies. Our analysis identified median age at diagnosis and extranodal involvement as potential risk factors for iCNS, suggesting avenues for future prospective studies to further elucidate their role in disease progression. Given the high prevalence of ATLL in Latin America, there is a unique opportunity to advance our understanding of this disease through region-specific research. Collaborative efforts in this region could pave the way for breakthroughs in the management of ATLL and potentially offer insights applicable on a global scale.

Introduction: PTCL accounts for 10-15% of all NHL. As previously demonstrated, Latin America has its own epidemiological distribution, with a high frequency of ATLL and ENKT, likely influenced by distinct genetic profiles and viral epidemiology. 3-year OS is about 40%. Treatment advances have also been limited, except for BV-CHP in some countries. The IPI, which includes extranodal (EN) site as a variable, has been validated for PTCL. However, the specific impact of EN involvement on nodal PTCL (such as PTCL-NOS, AIT, ALCL ALK+/ALK-) and its biological implications remain unclear. Simplification could improve the reproducibility and applicability of these models, especially in low-income countries. Objective: To evaluate number of EN sites in nodal PTCL lymphomas as a risk factors or surrogate for outcomes, as OS and PFS in Latin America cohort. Methodology: Patients (pts) aged ≥18 years with newly diagnosed nodal PTCL-NOS, AITL and ALCL ALK+/ALK-) from GELL (n = 339, 2000-2023, retrospective), TCBP (n = 427, 2015-2022, ambispective). Treatment outcome was determined by OS and PFS. REDcap Platform (by Vanderbilt) was used to collect and store data, whereas statistical analysis the IBM-SPSS v.24. This trial is registered at Clinical trials (NCT03207789). Results: 766 pts [427pts - TCBP and 339 - GELL] diagnosed with nodal PTCL were grouped according to the number of EN: no EN involvement (No EN - 383); one EN involvement (EN1 -168); and 32 (EN2 - 215). Considering all, 61% male; median age 56 y/o; 74% were staged III/IV; 69% IPI 32; 60% was PTCL-NOS, 19% ALCL ALK- and 12% AITL. 61% had B symptoms and 55% elevated LDH. CHOEP was used in 47% and 34% CHOP, and 47% achieved CR after first line; 16% used transplant as consolidation. No EN, EN1 and EN2 were similar regarding clinical characteristics, except, for stage III/IV (58% vs. 79% vs 96%; p < .0001); IPI 32 (58% vs. 59% vs. 99%; p < .0001); ECOG>1 (58% vs. 92% vs. 99%; p < .0001); BMO involvement (16% vs. 24% vs. 63%%; p

Objectives: This study aims to analyze the epidemiology of myelodysplastic syndromes (MDS)-related deaths among Brazilian patients, thereby helping to understand the disorder's behavior and to formulate public health strategies to mitigate its impact. Material and methods: This is a retrospective, observational study with data from the Secretariat of Health Surveillance (SVS). Deaths from January 2014 to December 2023 identified as related to MDS (ICD-10 D46) were included, categorized by sex, age, race, location and calendar year. Statistical analysis was performed considering absolute and relative frequencies. Results: In total, 9,659 deaths related to MDS occurred in Brazil during the period, meaning an average of around 966 deaths per year. Males accounted for 5,082 (52.6%) deaths, while females accounted for 4,576 (47.4%). The number of reported deaths increased with age, from 56 deaths in patients aged 01-09 years old to 2,687 deaths in patients aged 70-79 and 4,045 deaths in patients aged 80+; overall, patients under 60 years old represented 14% of all deaths, while 86% were patients 60+ years old. The white population was the most affected, with 6,498 (63.7%) deaths; 2,284 (23.6%) were brown; 471 (4.9%) were black; and 406 (4.2%) were yellow, indigenous or did not have their race recorded. Regarding location, 5,271 (54.6%) deaths occurred in the Southeast, 1,752 (18.1%) in the South, 1,692 (17.5%) in the Northeast, 592 (6.1%) in the Central-West and 352 (3.6%) in the North. The year with the most deaths was 2023 with 1,120 (15.9% above average), whilst the year with the least was 2015 with 835 (13.6% beneath average). Discussion: The slight male predominance observed, which is greater relative to the Brazilian male/female proportion (48.5/51.5 in 2022 according to IBGE), might be related to genetic and hormonal differences and to environmental exposure to risk factors such as smoking, which may lead to worse survival. The age range reveals that MDS are significantly more prevalent in the elderly, likely due to genetic mutations and age-related changes in bone marrow that are more common with aging. Comorbities and a weakened immune system may as well contribute to a higher death rate in older patients with MDS. The preponderance of reported deaths among whites is possibly due to genetic predisposition or to disparities in socioeconomic backgrounds and access to healthcare services, causing the white population to be more assertively diagnosed, as MDS diagnosis often requires specialized services. This might also explain the regional discrepancies in deaths relative to the population, with proportionally more deaths in the South and Southeast and fewer in the Northeast, North and Central-West, as there is a higher rate of whites and greater access to specialized medical services in the South and Southeast. Yearly mortality remained reasonably stable, with a subtle increase that might be associated with population aging or improved diagnosis capability. Conclusion: The data demonstrates a clear relation between age and mortality, with a significant number of deaths among the elderly population. This highlights the necessity for the development of new treatments that might reduce the risk associated with MDS in older individuals. The higher occurrence of reported deaths in regions and demographics with greater socioeconomic status and access to healthcare exhibits the need for public health strategies to address these disparities.

Objetivo: As neoplasias mieloproliferativas BCR::ABL1-negativas clássicas (NMP), policitemia vera (PV), trombocitemia essencial (TE) e mielofibrose primária (MFP) são caracterizadas por expansão clonal de um progenitor hematopoiético. O metabolismo mitocondrial tem sido recentemente relacionado a uma maior taxa de expansão clonal e resistência a quimioterapia intensiva em leucemia mieloide aguda (LMA). A quantificação do número de cópias do DNA mitocondrial (mtDNAc) está diretamente associada a um maior metabolismo mitocondrial em LMA. O objetivo do estudo é investigar o impacto clínico de mtDNAc em uma coorte de pacientes com NMP BCR::ABL1-negativas clássicas. Material e métodos: A coorte incluiu 242 pacientes adultos com NMP BCR::ABL1-negativas clássicas, em seguimento em uma única instituição, no período de 2006 a 2022. Dados demográficos, laboratoriais e de desfechos foram coletados a partir dos prontuários físicos ou informatizados. Amostras de DNA coletadas para fins de pesquisa de mutação JAK2V617F foram utilizadas para análise de mtDNAc. Níveis de expressão gênica do gene de interesse CYTB e do gene endógeno PK foram quantificados por qPCR e os resultados foram normalizados e expressos como mudança de expressão relativa em relação a um DNA de referência. Os grupos foram estratificados com base na mediana e quartis de mtDNAc. A sobrevida global (SG) foi calculada a partir da data do diagnóstico até a data da última avaliação ou óbito, e analisada utilizando o teste de Log-rank. Resultados e discussão: A coorte incluiu 242 pacientes com NMP, (PV = 75, TE = 53, MFP = 114), 121 do sexo masculino (50%), mediana de idade de 63 anos (17-87 anos). Mutações JAK2V617F, MPL e CALR foram observadas em 64%, 2% e 14% dos pacientes com NMP, respectivamente. Pacientes de sexo feminino apresentaram maior nível de mtDNAc do que os pacientes do sexo masculino (mediana 0.83 versus 0.62, p < 0.05). No grupo de pacientes com PV e mutação JAK2V617F, observamos um menor nível de mtDNAc (mediana 0.59) comparado aos pacientes com TE (mediana 0.83) e MFP (mediana 0.72, p < 0.05). Nos pacientes com NMP, a estratificacao dos pacientes com base nos níveis de mtDNAc (divisão em quartis de expressão) revelou que baixos níveis de mtDNAc associados com o aumento nos índices hematimétricos de hemoglobina (Hb), hematócrito (Ht) e contagem de glóbulos vermelhos, enquanto alto mtDNAc esteve associado com alto níveis de plaquetas (p < 0.05). Nos pacientes com MFP o mtDNAc não esteve associado com o grau da fibrose medular. Dos 242 pacientes, 6 progrediram para LMA (2 PV, 2 TE e 2 MFP), e 57 (23,5%) pacientes evoluíram para óbito. Não observamos nenhuma relação com o nível de mtDNAc com a progressão para LMA ou com a SG. Entretanto, analisando a SG nos pacientes com PV, TE e MFP, os pacientes com MFP que apresentaram os mais altos (24 pacientes, SG 29%) e mais baixos níveis de mtDNAc (16 pacientes, SG 33%) apresentaram uma pior SG quando comparados com os pacientes com níveis intermediários de mtDNAc (45 pacientes, SG 58%). Conclusão: Os níveis de mtDNAc variam significativamente entre os diferentes subtipos e entre os sexos. Esses achados sugerem que o mtDNAc pode ter um papel prognóstico em pacientes com MFP, mas não em pacientes com PV ou TE. Futuros estudos são necessários para elucidar os mecanismos biológicos subjacentes a essas associações e para determinar o potencial do mtDNAc como biomarcador clínico em NMP.

Introdução: A coleta de células tronco de fonte periférica (CTP) para transplante de medula óssea (TMO) autólogo é um procedimento essencial na oncohematologia pediátrica, embora seja desafiador. Objetivos: Relatar o caso de duas pacientes pediátricas submetidas à leucoaférese para coleta de CTP com cateter venoso central (CVC) de 5 French . Relato de caso 1: Menina, 3 meses, com peso de 4,89 kg, com indicação de 3 TMO autólogos para tratamento de tumor teratoide rabdoide. Foi submetida ao procedimento de leucoaférese com CVC femoral duplo lúmen 5fr. Utilizada máquina Spectra Optia , feito prime com 1 unidade de concentrado de hemácias (CH) e iniciado soroterapia com reposição de eletrólitos. Iniciado com taxa de infusão de anticoagulante 1.2, velocidade de entrada 10 ml/min, foi aberta a porta de coleta e aumentada para 1.0 (estava em 0.5). Foi otimizada a proporção de anticoagulante do sistema para 15 e elevada a taxa de infusão de anticoagulante até 2.2, alcançando a velocidade de entrada 12.6ml/min, que foi mantida até o fim do procedimento. Optado por reinfundir 100 ml de hemácias. O Balanço hídrico ao final da coleta foi de +84 ml. Processadas as 6 volemias. Finalizada a coleta com CD34 coletado de 19/kg/receptor. Relato de caso 2: Menina, 11 meses, peso 7,5 kg, com diagnóstico de tumor teratoide rabdoide, com indicação de 3 TMO autólogos. Estava com CVC 5fr em veia jugular interna direita. Utilizada máquina Spectra Optia , realizado prime com 1 unidade de CH e iniciado soroterapia com reposição de eletrólitos. Iniciado o procedimento de coleta, com porta de 0.5 e proporção de anticoagulante 0.8, aumentada porta de coleta para 1.0 e otimizada proporção de anticoagulante até chegar em 1.9, alcançando velocidade de entrada 18.9 ml/min, que foi mantida até o final do procedimento. Não realizado reinfusão. O balanço hídrico ao final foi de +58ml. Processadas as 6 volemias. Coletado CD34 de 18,84 Kg/receptor. Discussão: Os principais riscos associados ao procedimento de aférese em pacientes pediátricos são: complicações do CVC, ocorrência de hipocalcemia e risco de descompensação hemodinâmica. A obtenção do acesso vascular periférico para aférese em crianças pequenas é desafiadora. As veias são menores e podem colapsar sob pressão negativa e não é viável utilizar agulhas de grande calibre para manutenção do fluxo. Conclusão: Apesar das experiências positivas com aféreses de alto volume em pacientes pediátricos de baixo peso e com CVC de menor calibre, o ideal é que seja utilizado cateteres com calibre maior ou igual a 7fr para garantia de êxito no processamento. Nos casos citados, não foi viável a passagem de cateter com calibre superior a 5r devido às limitações técnicas relacionadas ao tamanho das pacientes. Pelo baixo número de relatos de sucesso na literatura com cateteres de calibre inferior a 7fr, não é possível determinar a segurança da aférese neste cenário, fazendo-se necessário novos estudos sobre esta população.

Introdução: As citopenias são condições hematológicas frequentes, caracterizadas pela redução das principais linhagens celulares. Essas podem representar um desafio diagnóstico, especialmente quando a avaliação hematológica inicial é inconclusiva. Relato de caso: Paciente feminina, 71 anos, é encaminhada para avaliação hematológica devido à bicitopenia a esclarecer. Em fevereiro de 2024, paciente inicia com quadro de astenia associada ao aparecimento de petéquias difusas e hematomas em membros. Paciente negava febre, perda ponderal ou sangramentos. Em maio de 2024, inicia-se investigação laboratorial, evidenciando anemia severa (Hb 5,3 g/dL) e plaquetopenia (8.000 μl). Paciente recebeu múltiplas reposições de ferro endovenosas e transfusões com concentrado de hemácias e de plaquetas, ainda no hospital de origem, contudo sem melhora. Paciente, então, é encaminhada ao Hospital São Lucas da PUCRS, onde é realizada a biópsia de medula óssea, com resultado normocelular, porém com diminuição das linhagens megacariocítica e eritroide. O resultado também demonstrava presença de hemossiderófagos e a pesquisa de fibrose reticulínica foi negativa. O medulograma demonstrava a tendência à hipocelularidade com predomínio de formas granulocíticas, também com diminuição das séries eritroides e megacariocítica. A imunofenotipagem não identificava população imatura e/ou de imunofenótipo aberrante na amostra. A pesquisa para HPN demonstrou ausência de clone na amostra e o cariótipo normal feminino sem anormalidades. Após os exames, iniciou-se tratamento para o diagnóstico de aplasia medular, com imunossupressão com ciclosporina, pulsoterapia com metilprednisolona e manutenção com prednisona, o que permitiu uma melhora parcial da plaquetopenia. Havia plano de iniciar com eltrombopague, portanto medicação foi solicitada, com liberação por via judicial depois de um mês de processo. Nesse período, a paciente manteve-se internada, ainda bastante plaquetopênica (3.000 a 8.000 μl) e anêmica (Hb 5 a 5,8 g/dL). Ademais, os exames laboratoriais complementares não demonstraram sinais de hemólise, nem perda de função renal ou hepática. As sorologias virais agudas foram negativas, indicando somente infecção prévia por CMV, EBV e toxoplasmose. Paciente não apresentou hepatoesplenomegalias ou linfonodomegalias. Até o momento, a paciente ainda encontra-se internada por investigação hematológica inconclusiva. Discussão: A bicitopenia, caracterizada pela redução de eritrócitos e plaquetas, pode ter diversas etiologias, incluindo incluindo distúrbios medulares, hemólise, infecções, doenças autoimunes e exposição a agentes tóxicos. A avaliação diagnóstica inicial deve incluir um hemograma completo, esfregaço sanguíneo, testes de função hepática e renal, além de exames para detecção de infecções virais e autoimunes. A biópsia da medula óssea é crucial para avaliação de distúrbios medulares, como a aplasia medular. No caso em questão, a avaliação hematológica inconclusiva levanta a suspeita de aplasia medular, uma condição caracterizada pela hipoplasia ou ausência de células hematopoiéticas na medula óssea. O manejo depende da causa na aplasia medular, incluindo transfusões, imunossupressores e transplante de medula. Conclusão: A bicitopenia com avaliação hematológica inconclusiva demanda investigação rigorosa, principalmente com a exclusão de outras causas para o diagnóstico e manejo adequados da condição.

Objetivos: O presente estudo tem como objetivo analisar um caso de linfo-histiocitose hemofagocítica (LHF) secundária à tuberculose miliar disseminada, assim como estudar as relações existentes entre essas duas patologias. Relato de caso: Paciente do sexo masculino, 24 anos, previamente hígido, com histórico de tuberculose hepática tratada há 2 anos. Iniciou há 25 dias quadro de tosse produtiva com hemoptise, dispnéia, febre diária, diaforese noturna e perda ponderal de 13 Kg. Ao exame físico notava-se hepatoesplenomegalia dolorosa a palpação e ausculta pulmonar com roncos difusos. Os exames complementares evidenciaram pancitopenia com hemoglobina 6,1 g/dL, hematocrito 18.4%, plaquetas 7.000/mm3, leucocitos 2.660/mm3 e linfocitos 452/mm³. Desidrogenase láctica de 6.355 U/L, além de elevação de transaminases. A tomografia computadorizada de tórax revelou inúmeros micronódulos pulmonares de distribuição randômica dispersos difusamente no parênquima, com opacidades parenquimatosas no hemitórax esquerdo e lobo médio direito, apresentando escavações de tamanhos variados e alguns com paredes espessadas e opacidades atelectásicas. A tomografia de abdomen apresentou hepatoesplenomegalia com moderada quantidade de líquido livre na pelve e pequena quantidade no abdome superior. As sorologias para HIV, HBsAg, Anti HBs, HTLV, HCV, e VDRL apresentaram-se negativas. A suspeita diagnóstica foi confirmada com a dosagem de triglicerídeos 401 mg/dL e ferritina 33.000 ng/dL associado a citopenias. O tratamento foi iniciado com Levofloxacino, Amicacina e Etambutol. Paciente evoluiu com transferência para hospital especializado para seguimento do tratamento. Discussão: A LHF é uma síndrome de ativação imunológica que pode ser desencadeada por infecções, malignidades ou doenças autoimunes. Neste caso, a LHF foi secundária à tuberculose miliar disseminada, uma condição severa que envolve múltiplos órgãos, como evidenciado pelos micronódulos pulmonares e hepatoesplenomegalia. A relação entre tuberculose e LHF é rara e preocupante, pela severidade das duas condições podendo levar a um quadro clínico mais grave. O diagnóstico de LHF é sustentado pela presença de sintomas como febre persistente, hepatoesplenomegalia e citopenias, além de exames como triglicerídeos elevados e ferritina extremamente alta. Esses achados estavam presentes no paciente, que também apresentou pancitopenia significativa e níveis elevados de LDH. A tuberculose miliar disseminada, confirmada pela cultura positiva para tuberculose, é frequentemente associada a estados de imunossupressão. A coexistência com LHF, embora rara, pode agravar significativamente a condição do paciente, exigindo uma abordagem terapêutica abrangente e agressiva. Este caso destaca a importância de considerar diagnósticos diferenciais e adicionais em pacientes com infecções graves e sintomas hematológicos inexplicados ou atípicos, sendo a identificação precoce da LHF e o início imediato de tratamento são cruciais para melhorar o prognóstico e a sobrevida desses pacientes, especialmente em contextos de infecções graves paralelas. Conclusão: A LHF secundária à tuberculose miliar disseminada é uma condição rara, mas com prognóstico favorável quando o diagnóstico é feito precocemente e o tratamento é adequado. Assim, o relato ressalta a importância de conscientizar a comunidade médica sobre as relações entre essas duas patologias.

Introduction: Pneumonia is defined as inflammation of the pulmonary parenchyma caused by an infectious agent. Community-acquired Pneumonia (CAP) is a heterogeneous disease with a significant disease burden, morbidity, and mortality. Severe Community-acquired Pneumonia (SCAP) has been proven to be associated with increased Intensive Care Unit (ICU) admission, mechanical ventilation, and mortality. Although several severity assessment tools are available, there is a lack of evidence to support one tool over another in patients with pneumonia. Aim: To compare the ability of pneumonia-specific scores {{Confusion, Urea, Respiratory rate, Blood pressure (CURB)-65 and Expanded CURB-65)}, Sepsis score {quick Sepsis-related Organ Failure Assessment (qSOFA)}, and Generic score {National Early Warning Score (NEWS)} in predicting SCAP patients at the time of hospital admission. Materials and Methods: This was a hospital-based cross-sectional study conducted in the Department of Pulmonary Medicine, Government Hospital for Chest and Communicable Diseases, Andhra Medical College, Visakhapatnam, India, on 100 patients with clinically and radiologically diagnosed CAP over a period of six months from April 2023 to September 2023 after obtaining Institutional ethics clearance and informed consent. All four severity scores (CURB-65, eCURB-65, qSOFA, NEWS) were documented in each patient at the time of admission. Outcomes such as 30-day mortality and ICU admission were measured. Receiver Operating Characteristic (ROC) curve analysis was performed for mortality prediction and ICU admission for all four scoring systems, and statistical analysis was carried out using Statistical Packages for Social Sciences (SPSS) version 24.0. Results: Out of 100 patients, 62 (62%) were males, and the remaining 38 (38%) were females with a mean age of 56±15 years. The number of patients with co-morbidities was 48 (48%). Regarding addictive habits, smoking and alcohol played a significant role at 38% and 33%, respectively. A 30-day mortality was observed in 18 (18%) patients, and 20 (20%) patients received ICU treatment. The frequency of patients with co-morbidities such as Diabetes Mellitus (DM), Hypertension (HTN), Ischaemic Heart Disease (IHD), and Chronic Obstructive Pulmonary Disease (COPD) was 21%, 33%, 5%, and 3%, respectively. For ICU admission as an outcome measure, the Area Under Receiver Operating Characteristics (AUROC) values were as follows: CURB-65: 0.977 (95% CI: 0.949-1.00, p-value

Introduction: In inherited marrow failure, clonal hematopoiesis (CH) are known to compensates for the intrinsic restricted cell fitness caused by a germline mutation (adaptive mechanisms) or associates with maladaptive mechanisms of clonal evolution, typically myelodysplastic syndromes or acute myeloid leukemia (MDS/AML). Here, we characterized for the first time the genomic landscape of telomere biology disorders (TBD), and report clinically significant genotype-phenotype associations that can serve as markers for patients’ diagnosis, clonal evolution, and survival. Methods: Peripheral blood (PB) samples from 207 TBD patients collected at time of first visit were screened for CH in myeloid and telomere-related genes using an error-correcting DNA sequencing panel at minimum allele frequency (VAF) of 0.5%. Patients were seen at the National Institutes of Health and the Medical School of Ribeirao Preto from 1997 onwards. Clonal trajectories were assessed by single-cell proteogenomic sequencing (scDNA). Results: Most patients were symptomatic (83%), particularly having classical dyskeratosis congenita (DC) or marrow failure with lung or liver disease (BMF/PD_LD); 35 were asymptomatic. A germline mutation, found in 92% of patients, correlated with disease onset and inheritance. CH was restricted to symptomatic patients (80/173; 46%), being recurrently found in PPM1D, POT1, TERT promoter (TERT p), and U2AF1S34/Q157R; TP53 mutations were also common (8% of patients). PPM1D, POT1 and TERTp mutations were often at median low VAF (10%. Abnormal karyotype was seen in 14% patients, mostly with chromosomal 1q abnormalities (Chr1q; 9/25). CH frequency increased with aging and associated with patients’ phenotypes and the underlying germline mutation: CH in TERTp, POT1¸ and MDS-associated genes were significantly enriched in TERT, TINF2, and TERC patients, respectively, rarely co-occurring with other germline mutations. CH in TERTp, TP53 and Chr1q associated with poor overall survival (OS) independently from age (p < 0.001). Presence of MDS-related mutations dominated by U2AF1S34/Q157R, TP53 mutations, and Chr1q highly associated with development of MDS/AML, regardless of VAF. The cumulative MDS/AML incidence in the cohort was 8% by age of 40, being higher in DKC1, TERC, and TERT patients with CH. Presence of TP53 mutations in PB and age were independent markers of solid cancer development, with head and neck squamous cell carcinoma predominating (43%). scDNA evidenced distinct clonal trajectories between adaptive (POT1, PPM1D, and TERTp) and maladaptive CH. U2AF1S34/Q157R and Chr1q were key drivers of malignancy due to successive acquisition of other MDS-related mutations in single cells; adaptive CH was only found in independent clones (linear vs. branched trajectories, respectively). In all, CH emerged at the HSC level and associated with a myeloid bias, being also present in up to 11% of lymphoid cells. Conclusion: The clonal signatures of TBD, not found in immune mediated BMF, are molecular markers of the underlying telomere deficiency that can guide diagnosis, particularly for cases with an unknown germline mutation. CH is also important for surveillance as it identifies high-risk TBD patients with lower OS who could benefit of early intervention. Somatic and karyotypic testing is critical as detection of Chr1q and U2AF1S34/Q157R and TP53 mutations, regardless of VAFs, may warrant earlier therapeutic intervention as it is highly associated with malignancies.

A Leucemia Linfoblástica Aguda (LLA) é uma neoplasia de células linfoides imaturas T ou B, sendo a segunda leucemia aguda mais comum no adulto. Acomete cerca de 1 a 5 /100.000 indivíduos por ano nos Estados Unidos e cerca de 66% dos casos são LLA-B. O tratamento da LLA-B consiste em quimio/imunoterapia de alta intensidade, com objetivo primário de restaurar a hematopoese normal. A monitorização de remissão de doença (Doença Residual Mensurável - DRM) é realizada em diferentes etapas do tratamento por citometria de fluxo multiparamétrica (CFMP), sendo a técnica eficaz na detecção de clones leucêmicos pós-tratamento com quimioterapia de alta intensidade. Para pacientes recaídos/refratários a terapia de resgate mais indicada consiste em imunoterapia com agentes específicos, chamados de terapias-alvo (ex: anti-CD3 + anti-CD19 -Blinatumomabe, anti-CD22 -Inotuzumabe + Ozogamicin), e a terapia com células T geneticamente modificadas - CAR-T (do inglês, Chimeric antigen receptor T Cell). Com o surgimento de tais tratamentos surge também a demanda por padronização da monitorização de DRM nos pacientes, visto que terapia pode resultar em perda de expressão de marcadores, o que inviabiliza a análise pelos métodos anteriormente padronizados, enfatizando a possibilidade de recaídas com clones emergentes negativos para a expressão de CD19, por exemplo. Assim, foi objetivo do presente estudo determinar a viabilidade de implantação de novo protocolo para detecção de DRM com base em seleção alternativa de antígenos de células B para pacientes submetidos à terapia convencional ou anti-CD19 por CFMP. Foram analisadas as medulas ósseas de 2 doadores saudáveis, e 2 pacientes LLA-B tratados no Hospital das Clínicas de Ribeirão Preto - FMRP-USP, sendo um submetido à terapia HyperCVAD e 1 paciente refratário, tratado com CAR-T anti-CD19. As amostras foram preparadas de acordo com protocolo Euroflow e avaliadas quanto à expressão dos marcadores (CD45, CD34, CD38, CD81, CD10, CD20, CD19, CD22, CD24, CD66b, CD66c + CD123, CD73) por CFMP em citômetro BD Canto II e analisadas em software Infinicyt por dois observadores diferentes. Os resultados da análise DRM foram expressos como a porcentagem de células nucleadas viáveis que abrigam o fenótipo anormal, sendo a positividade definida quando igual ou maior do que 0,01%. No presente estudo de viabilidade a detecção de células B foi concordante entre os diferentes tubos, independente de marcação de CD19, não havendo diferença nas frequências observadas tanto para amostras de referência como no paciente analisado (p = 0,4478, Kruskal-Wallis). Não foi observada diferença entre as frequências de células anormais detectadas pelos observadores (p = 0,4, Kruskal Wallis) e nossos resultados demonstram reprodutibilidade entre as análises realizadas, com Correlação de Pearson calculada de 0,9995 (IC: 0,9949-0,999, r2 = 0,9989). A análise de Bland-Altman demonstrou não haver divergência entre as metodologias utilizadas. Não houve diferença nas frequências obtidas dos fenótipos caracterizados como DRM+, independente da combinação de marcadores para a gate de células B (CD19xCD22, CD22xCD24, e CD24xCD66b) p = 0,667, Friedman, α=0,05). Em conclusão, nossos dados indicam que o monitoramento da DRM para pacientes com LLA-B tratados com imunoterapia anti-CD19 é possível por CFMP resultando em dados altamente concordantes. O desempenho do resultado preliminar exposto deve garantir resultados comparáveis ao serem avaliados em múltiplos centros, etapa em fase de planejamento, para garantir o avanço da padronização da resposta de DRM por CFMP.

Objectives: T-cell Brazil project started in April 2017 focusing to collecting epidemiological and clinical data from the most frequent subtypes of PTCL, as an ambispective study collected diagnosis data from January 2015 to December 2022. Our goals were to obtain the frequency of subtypes and the clinical and biology characteristic from five Brazilian regions; besides to have a routine pathological revision and to evaluate the Overall Survival (OS), Progression-Free Survival (PFS) in 5 years of follow-up. Method: After 39 centers were approved by their Ethical Committee, they registered their cases using the REDcap Platform by Vanderbilt, being 63% public centers. Here, It was just analyzed a Prospective Cohort (PC), with diagnosis date from April 2017 to December 2022, a total of 461 cases. Descriptive analyses, Kaplan-Meier method, Log-Rank test to compare groups and Cox Regression to identify risk factor for OS using IBM-SPSS software v.24. Results: The median age was 52 years (18-92); 58% male; Almost 72% had advanced stages, 25% ECOG ≥ 2; the distribution of main subtypes was: 30% PTCL-NOS; 18% ALCL, ALK-; 14% ATL; 13% ENKTL-NT; 10.5% AITL; 5% ALCL, ALK+; 9.5% others. A median of follow up of 22 months (0-73), 55% pts were alive and 24-month PFS and OS were 36% and 49%, respectively. OS by main subtypes was 69% ALCL, ALK+; 61% ALCL, ALK; 50% PTCL-NOS; 44% ENKTL-NT; 41% AITL; 27% ATL. Cox regression showed ATL (HR 1.6, p = 0.008), ECOG ≥ 2 (HR 1.86, p < 0.0001) and Ann Arbor Stage III-IV (HR 2.06, p < 0.0001) as bad prognosis for OS; whereas for PFS were ATL (HR 1.9, p < 0.0001); ECOG≥ 2 (HR 1.53, p = 0.002); Ann Arbor Stage III-IV (HR 1.75, p = 0.001) and B symptoms (HR 1.36, p = 0.02). Discussion: PTCL make up approximately 10-15% of lymphoid malignancies and its frequency varies geographically. In Brazil, mainly due to its vast dimension, data collection has limitations and is subject to bias. This is the first experience cover all over the country, focusing also an educational and of interchanging experience network among the multidisciplinary health team in Brazil. Conclusions: Our initial target of 500 pts exceeded, hence the number of prospective cohort is getting close, because we are in a consistency data phase and probably more cases will be available after that. So, it is possible to make analyzes with PC. ATL and ENKTL-NT subtype presented more frequent of all, different of the Occidental countries, but similar with recent data from American Latin.

Objectives: To evaluate number of extranodal (EN) sites in nodal PTCL lymphomas (PTCL-NOS, TFH and ALCL ALK+/ALK-) and its specific location as a surrogate for overall survival (OS) and progression free survival (PFS). Also generate hypothesis for further molecular analysis. Material and methods: T-cell Brazil project is a national, ambispective study of patients (pts) with histological diagnosis of PTCL diagnosed from January 2015 to December 2022. Approval for the study was obtained at the coordinating center (Samaritano Hospital – São Paulo) and at each participating center. Inclusion criteria was previously untreated patients age ≥ 19 years, with de novo PTCL lymphoma. Clinical information, initial therapy and response, subsequent therapies, along with survival status and cause of death were collected. Treatment outcome was determined by OS and PFS. REDcap Platform (by Vanderbilt) has been used to collect and store data and for analysis the IBM-SPSS v. 24 was applied. Kaplan-Meier method estimated the OS and PFS, whereas Log-Rank tests to compare its curves. This trial is registered at Clinical trials (NCT03207789). Results: Of 621 registered we selected 198 patients (pts) diagnosed with nodal PTCL with at least one EN involvement. Considering all 198 pts, there was a slight male predominance (63%); median age 53 years; 79% were staged III or IV; 81.5 were IPI 2 or more. Most frequently histology was PTCL-NOS (46%), followed by ALCL ALK+ (32%), ALCL ALK- (12.5%) and TFH (9.5%). The majority had B Symptoms (63%); 37.5% had Bone Marrow infiltration. The chemotherapy most frequently chosen were CHOEP (54.5%) followed by CHOP (19.5%); Transplant as consolidation was in 20% of the cases. Almost half of pts achieved complete response after first line (44%), although 38% relapsed. Cohort 1 (E N = 1) and 2 (EN 32) were similar regarding clinical characteristics, except, for stage III-IV (73% vs 96%; p

Objetivo: Relatar um caso de Leucemia de células plasmocitárias (LCP) e realizar breve revisão de literatura sobre o tema. Relato de caso: Mulher, 63 anos, portadora de DRC dialítica e amaurose secundárias a DM, encaminhada por suspeita diagnóstica de leucemia aguda de serviço externo desde março/2023, foi encaminhada para avaliação neste serviço com quadro de dessaturação e hipotensão durante sessão de hemodiálise em 20/07/23. À admissão, paciente apresentava-se em regular estado geral, em uso de cateter de O2 a 2l/min, mantendo saturação de 92%. Ausculta pulmonar abolida até o terço médio bilateralmente. Os exames de admissão evidenciaram Hemoglobina 7,7 g/dL, VCM 93fl, Leucócitos 84020 mm3 (Neutrófilos 4201 mm3, Linfocitos 7561 mm3 e células anômalas 69736 mm3), plaquetas 79 mil/μL, DHL 358 U/L, Albumina 3,3 g/dL, Cálcio corrigido 9,6 mg/dL. Realizadas tomografias em 20/07, demonstrando múltiplas lesões líticas na calota craniana, ossos da face e da base do crânio e nos ossos ilíacos, bem como fratura compressiva de L3; Tórax com moderado derrame pleural bilateral e atelectasia restritiva do parênquima pulmonar. Tendo em vista o quadro atual de paciente, realizado toracocentese de alívio com presença de 40% de plasmócitos no líquido pleural. Esfregaço de sangue periférico demonstrava células com morfologia mais sugestiva de linfoplasmócitos. Entretanto, imunofenotipagem de sangue periférico evidenciou 86% de plasmócitos clonais que expressam os antígenos CD38 de elevada intensidade, CD138 e imunoglobulina de cadeia leve kappa intracitoplasmática, em associação à perda anômala do antígenos CD19 e CD45 e expressão negativa de CD56 e cadeia leve lambda (citop.), compatível com leucemia de plasmócitos. Eletroforese de proteínas com imunofixação revelou a presença de componente monoclonal em cadeia leve Kappa sem correspondência de cadeias pesadas IgG, IgM e IgA, com relação K/L de 3,80; Diante da gravidade do quadro e status performance de paciente (ECOG 4), optado por esquema de quimioterapia paliativa com Ciclofosfamida 450 mg, Dexametasona 20 mg e Bortezomibe 1,3 mg/m2 para controle de sintomas, com início em 21/07/23. Porém, paciente manteve leucometria acima de 80000 mm3 durante toda internação. Evoluiu, 14 dias após, com quadro de insuficiência respiratória, sendo priorizado conforto e alívio de dispneia, com evolução para óbito na mesma data. Discussão: A LCP é uma variante rara e agressiva do mieloma múltiplo (MM), podendo se apresentar como manifestação inicial da doença, sendo denominada LCP primária, que corresponde a 60% dos casos, ou uma progressão do MM previamente diagnosticado - LCP secundária. Representa cerca de 3 a 5% de todas as neoplasias plasmocitárias no mundo e 1,7% no Brasil. Possui sobrevida média de 6 meses com quimioterapia padrão VAD e 15 meses com uso de Bortezomib e Talidomida. Os critérios diagnósticos atuais incluem número absoluto de Plasmócitos circulantes superiores a 2,0×10/L e/ou plasmocitose >5% da contagem diferencial de leucócitos no sangue periférico. Conclusão: O caso em questão ilustra uma forma rara de doença monoclonal de plasmócitos, que deve ser lembrada como possível causa de leucocitose, já que se trata de uma apresentação muito agressiva da neoplasia maligna de plasmócitos e o retardo no seu reconhecimento pode impactar na dificuldade de realização de quimioterapia adequada pela perda de condição clínica do paciente.

Objectives: To estimate the social return of investment (SROI) of gene therapy (Tx) for hemophilia A and B in Brazil, and to discuss a framework for measuring social and long-term value of advanced therapy medicinal products (ATMPs). Methods: SROI forecast analysis. A conceptual logical model was developed as a first step by a multi-disciplinary team to map (i) main stakeholders; (ii) inputs and outputs expected along the implementation of gene Tx for hemophilia in the Brazilian public health system; and (iii) short-, medium-, and long-term outcomes. This conceptualization is the foundation of the Theory of Change that will underpin the SROI analysis. Patients, family members, and health care professionals (HCPs) were mapped as main stakeholders. Study protocol will be submitted to an Institutional Research Board and participation will be voluntary and conditioned to informed consent. Patients and family members will be enrolled from patients’ associations. One-to-one semi-structured interviews will be carried out using an online platform. Forty stakeholder interviews are planned, with participation of at least 20 patients. Family members and HCPs will account for the other 20 interviews. Theoretical saturation will be assessed through a saturation table and a pre-defined codebook. Questions will address the impact of disease and its treatment on the ability of performing daily life activities and social interactions. The impact of gene Tx on the number of bleedings will be derived from pivotal randomized controlled trials and extrapolated over time. Reduction of health care expenditures related to prophylaxis and complication management will be estimated, as well as the reduction of social security expenditures. Financial proxies will be applied for valuing intangible outcomes. Social value will be calculated by the amount of tangible and intangible earnings multiplied by the respective financial values, with adjustments for attribution, deadweight, and drop off. SROI per dollar invested will be presented as the main study outcome. Results: Results are expected to be obtained and presented in scientific Journals by the end of 2024. Discussion: There are challenges for valuing ATMPs, including lack of definition and valuation of cure for chronic diseases, approach for qualifying cost-savings compared with current treatments, and choice of perspective. Some frameworks have been developed to address limitations of traditional health technology assessments (HTA) methods, considering the specificities of ATMPs and the limitations of using quality-adjusted life years (QALYs) in some situations. The ISPOR Value Flower accounts for novel value elements, such as severity of illness, value of insurance, value of hope. The generalized risk-adjusted cost-effectiveness (GRACE) approach was developed to account for the adjustment of a willingness-to-pay threshold to untreated illness severity or pre-existing permanent disability, and the differentiation between life expectancy and quality of life across health states. SROI is a comprehensive, well-described method of cost-benefit analysis that considers tangible and intangible outcomes, allowing for the measurement of long-term value from the societal perspective Conclusion: This study will provide evidence on the social value of gene Tx for hemophilia, advancing the methods for valuing ATMPs. Results may support future HTA, along with cost-effectiveness analysis and budget impact analysis.

Introduction: Gene therapies for hemophilias present a new reality for patients and their families. Gaining a better understanding of patient perceptions regarding these therapies may provide insights regarding their willingness to accept them. Moreover, as gene therapies will likely be soon available for hemophilias, health technology assessment decision-making needs to be tailored towards patients'preferences and needs. Objectives: To describe a study protocol aimed at understanding patient preferences among people with hemophilias, and their opinions and concerns regarding gene therapies. Methods: The protocol for this qualitative study was designed following the general steps described in the PAVING Study (Patient Preferences to Assess Value IN Gene Therapies in Hemophilia). The protocol consisted of (i) a target literature review and (ii) patient relevant information needs and (treatment) attributes identification and ranking. A target literature review of attributes and previous published preference studies will be performed. Participants will be recruited through purposive sampling. Relevance of attributes will be investigated in online one-to one interviews with up to 20 people with hemophilia A and B. An interview guide for semi-structured interviews was designed. Prior to any questions about gene therapy, participants will receive information regarding the disease, standard of care and gene therapy using an educational tool validated in previous studies to ensure comprehension of the attributes and the gene therapy context. We will translate the educational tool and pilot them with Brazilian participants. Interviews will also cover opinions and concerns of people with hemophilias regarding gene therapies. The selected attributes (from the literature review and interviews) will be included in an exercise, in which participants will rank their top six attributes. Data from answers to open questions will be organized using NVivo and analyzed following framework analysis. Data saturation will be assessed by a saturation table and a documented codebook. Details on the methods and results of the interviews will be reported according to the consolidated criteria for reporting qualitative research (COREQ) checklist. Results: Results are expected to be obtained and presented in conferences and scientific peer-reviewed journals by the end of 2024. Discussion: This protocol describes the methodological steps to qualitatively elicit and study patient preferences and perspectives in hemophilias. These findings will inform future quantitative patient preference studies (discrete choice and best-worst scaling experiments). Conclusion: Results will provide evidence on patient preferences regarding alternatives of care for hemophilias in Brazil. Patient preferences should be considered for decision making related to individual care and to reimbursement and coverage decisions in health systems, along with traditional cost-effectiveness and budget impact analysis. Acknowledgements: All authors contributed to the abstract conception and design. All authors read and approved the final manuscript.

Objetivo: Relatar caso de paciente com anti-LW, enfatizando a importância da técnica da Monocamada de Monócitos (MMA) na tomada de decisões. Materiais e métodos: Foram utilizados cartões de gel Bio-Rad® para testes imuno-hematológicos e técnica do MMA para avaliação hemolítica do anticorpo. Resultados: Paciente feminina, 64 anos, portadora de múltiplas comorbidades: SIDA, diabetes mellitus, hipertensão arterial sistêmica e doença renal crônica em hemodiálise. História pregressa G4 P2 A2 e transfusão de um concentrado de hemácias há 10 anos. Internação atual por anemia sintomática, tendo sido solicitada transfusão de concentrado de hemácias. Os exames pré-transfusionais mostraram: tipagem sanguínea grupo “A” R1R1; Pesquisa de Anticorpos Irregulares reagente com células de triagem; Teste direto da antiglobulina reagente (IgG 3+). Painel de identificação de anticorpos com padrão de reatividade somente em células RhD+ e autocontrole reagente, compatível com presença de anti-D. Ao painel com hemácias papainizadas, reatividade com todas as 11 células testadas. Uma vez que a formação de autoanti-D não é esperada e pelo padrão de reatividade do teste enzimático, foi aventada a hipótese de autoanticorpo anti-LW. Hipótese ratificada pela prova de compatibilidade do soro da paciente com hemácias de cordão umbilical RhD negativas com resultado reagente e pelo desaparecimento da reatividade após tratamento das hemácias RhD+ com DTT. Nos deparamos, então, com cenário desafiador: realizar transfusões de hemácias incompatíveis, sendo o anti-LW não hemolítico, respeitando o fenótipo R1R1 da paciente ou utilizar hemácias compatíveis RhD negativas com alto risco de aloimunização principalmente contra o antígeno c (RH4). Para a acertada tomada de decisão, foi realizada a técnica MMA, com ausência de fagocitose dessas pelos macrófagos, sugerindo não haver significado clínico dos anticorpos da paciente. Após sete transfusões sorologicamente incompatíveis com hemácias fenótipo R1R1, a paciente seguiu com bom aproveitamento transfusional, sem apresentar reações transfusionais imediatas ou formação de novos aloanticorpos. Discussão: Os antígenos de Landsteiner-Wiener (LW) são antígenos de alta frequência descritos na década de 1940, e por dependerem da interação com proteínas da família RH para sua expressão, somente duas décadas depois foram identificados como um sistema diferente. Embora raramente identificado e, em geral, sem significado clínico, o anti-LW pode mimetizar sorologicamente o anti-D, por conta da sua maior expressão nas células D+. No entanto, a diferenciação é possível pois o comportamento dos antígenos difere nos tratamentos enzimáticos e na expressão nas hemácias de cordão. No caso descrito, todos os testes realizados confirmaram a hipótese diagnóstica da presença do autoanticorpo anti-LW em indivíduo RhD positivo e o MMA reforçou o provável padrão não-hemolítico do anticorpo, o que foi confirmado após os atendimentos transfusionais mesmo com prova cruzada incompatível. Conclusão: O caso ilustra a importância da utilização das diversas ferramentas disponíveis para o diagnóstico imunohematológico, do conhecimento das peculiaridades e do comportamento clínico dos anticorpos eritrocitários identificados e da utilização do MMA como suporte à decisão de seguir com transfusões que apresentem incompatibilidade in vitro por ser excelente teste preditor de hemólise clinicamente significativa in vivo.

Introdução: O linfoma folicular é uma forma comum de câncer do sistema linfático que se origina preferencialmente nas células B do sistema imunológico. Existe, ainda, uma rara associação vista entre essa neoplasia com o sarcoma de Kaposi, tumor maligno incomum de origem vascular. Contudo, a relação que essas duas doenças possuem permanece incerta. Relato de caso: Paciente masculino, 52 anos, hipertensão arterial em uso de captopril, queixa-se de massas com aumento de volume na região cervical. Realiza-se um PET-SCAN que evicenciou um hipermetabolismo glicolítico de padrão anômalo em linfonodos cervicais e abdominais e em pilares amigdalinos, compatível com distúrbio linfoproliferativo em atividade. Biopsia dos linfonodos apresenta histologia de células fusiformes proliferativas e espaços vasculares em forma de fenda, o que sugere diagnóstico sistêmico de sarcoma de Kaposi e de linfoma folicular de alto grau, e descobre-se também a soro positividade do paciente para HIV. Primeira internação (10/2021) com objetivo de quimioterapia seguindo protocolo DA-EPOCH R. Iniciado antibioticoterapia profilática com bactrim e filgrastima, por neutropenia afebril até a alta. Nova internação (01/2022) para terceiro ciclo de quimioterapia, marcado por dor epigástrica persistente,apesar do uso de pantoprazol. Grande intercorrência, contudo, foi leucopenia grave, com sepse de foco abdominal, iniciando-se piperacilina-tazobactam na UTI. Escalonamento de antibiótico para meropenem, vancomicina e fluconazol, porém evoluiu para encefalopatia séptica, ainda sem germe isolado em culturas. Melhora do quadro clínico e aumento da contagem de leucócitos permite encaminhamento para enfermaria. Paciente indicado para acompanhamento ambulatorial. Discussão: Pertencente ao grupo de linfomas não Hodgkin, o linfoma folicular costuma apresentar crescimento lento, porém nesse paciente a neoplasia apresentava-se com alto grau de desenvolvimento. Sua morfologia mais proeminente são células pequenas frequentemente “clivadas”, conhecidas como foliculares, misturadas a células grandes. Do ponto de vista clínico, costuma ser heterogêneo, podendo o indivíduo permanecer assintomático por longos períodos, principalmente precocemente. Os sintomas, porém, relatados são linfonodomegalia, como foi o caso do paciente; esplenomegalia; astenia; sintomas B; e citopenias. Do ponto de vista diagnóstico, a confirmação deve ser feita por meio de biópsia excisional, com avaliação imuno-histoquímica da massa linfática, havendo expressão de CD10+ e de BCL2+. Haverá ainda alterações de cariótipo com t(14;18) em alguns casos. Normalmente, o esquema quimioterápico costumas ser usado como fonte primária de tratamento, porém o uso do protocolo DA-EPOCH R não costuma ser a escolha, já que sua indicação é para linfomas de alto grau. Já o sarcoma de Kaposi, costuma estar intimamente conectado com infecção por HIV, manifestando-se como lesões cutâneas em forma de mancha ou nódulo violáceos isolados ou em grupo. O diagnóstico é clínico, baseado na aparência característica das lesões, no entanto a confirmação requer uma biópsia, onde o exame histopatológico demonstrará os sinais típicos de proliferação vascular, além da presença de células átipicas. Nos casos mais graves ou com envolvimento sistêmico, são utilizadas terapias sistêmicas, como quimioterapia e imunoterapia, embora a resposta ao tratamento varie significativamente entre os pacientes. Conclusão: Portanto, é visto a importância do diagnóstico e conduta terapêutica em pacientes com ambas neoplasias. Buscando uma melhor compreensão da fisiopatologia dessas doenças e com relevância da avaliação criteriosa dos fatores de risco e da imunossupressão nos pacientes acometidos por essa combinação neoplásica.

Abstract Background The use of musculoskeletal ultrasound (MSKUS) for point-of-care (POC) evaluation of hemophilic arthropathy is growing rapidly. However, the extent to which MSKUS influences clinical treatment decisions is unknown. Methods We conducted a three-year, prospective, multi-center study at three hemophilia treatment centers in the United States to evaluate the utilization of POC-MSKUS for routine clinical decision-making in adult persons with hemophilic arthropathy. Bilateral elbows, knees and ankles were assessed clinically [Hemophilia Joint Health Score (HJHS)] and with POC-MSKUS by the Joint TissueActivity and Damage Exam (JADE) protocol at baseline and approximately annually for two additional times. Treatment decisions, including physical therapy (PT) and “medical” (joint injections/aspirations, referrals to orthopedics, changes/adjustments of hemostatic plans, and use of oral anti-inflammatory medications) were recorded in relation to POC-MSKUS. Results Forty-four persons [median age 37 years (IQR 29, 51)], mostly with severe Hemophilia A on clotting factor prophylaxis, completed 129 visits, yielding 792 joint exams by POC-MSKUS and HJHS [median at baseline 27 (IQR 18, 42)] over a median follow up of 584 days (range: 363 to 1072). Among 157 management decisions, 70% were related to PT plans (n = 110) and 30% were “medical”. Point-of-care MSKUS influenced 47/110 (43%) PT plans, mostly informing treatment of specific arthropathic joints (45/47 plans) in patients with high HJHS. Physical therapy plans influenced by POC-MSKUS directed more manual therapy/therapeutic exercises, while plans based on physical exam were focused more on global exercises and wellness. Treatment decisions were mostly based on the identification of specific musculoskeletal abnormalities visualized by POC-MSKUS. Of note 20/47 (43%) POC-MSKUS plans included de-escalation strategies, thereby reducing exercise intensity, mostly for joint instability and subclinical hemarthroses. Point-of-care MSKUS also informed 68% (32/47) of “medical” decisions, surprisingly mostly for injections/aspirations and referrals to orthopedics, and not for adjustments of hemostatic treatment. Although not formally studied, ultrasound images were used frequently for patient education. Conclusion Routine joint evaluations with POC-MSKUS resulted in few changes regarding medical management decisions but had a profound effect on the formulation of PT plans. Based on these findings, new studies are essential to determine the benefit of MSKUS-informed management plans on joint health outcomes.

Abstract Background The generic 36-item Short-Form Health Survey (SF-36v2) has been used to assess health related quality of life in adult patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) even though it has not yet been validated for use in this specific disease. Objective This study aims to validate the SF-36v2 for use in adult patients with C1-INH-HAE. Results There was a very low item non-response rate (1–3.4%), with a high ceiling effect in 25/35 items and a low floor effect in 3/35 items. A moderate ceiling effect was observed in 5/8 dimensions of the SF-36v2, whereas no floor effect was noticed in any of the dimensions. Internal consistency was good to excellent with Cronbach's alpha coefficient ranging between 0.82 and 0.93 for the different dimensions. Construct validity was good: seven out of the 8 hypotheses defined on clinical criteria were confirmed, discriminant validity assessment showed significant differences among patients with different C1-INH-HAE severity, convergent validity showed a good correlation among the physical and mental component summaries of the SF-36v2 and the HAE-QoL total score (0.45 and 0.64 respectively, P

Sea otters Enhydra lutris have been absent from Oregon, USA, following their extirpation over a century ago. Stakeholder groups and native tribes are advocating for reintroduction to restore historic populations. We investigated the potential for successful reintroduction by: (1) estimating expected equilibrium sea otter densities as a function of habitat variables to assess sea otter habitat in Oregon; and (2) spatially relating areas of high expected densities to human activities (e.g. fisheries, recreation, vessel activity, protected areas) to anticipate potential disturbance or fishery resource competition. We estimated that 4538 (1742-8976; 95% CI) sea otters could exist in Oregon, with higher expected abundance (N = 1551) and densities (x¯ = 2.45 km-2) within the southern region. Most core habitat areas (97%), representing clusters of high expected densities, overlapped with some form of human activity. While commercial shipping and tow lanes overlapped little (1%) with core habitat areas, recreational activities (58%) and fisheries (76%) had a higher degree of overlap, posing higher disturbance risk. We anticipate higher resource competition potential with the commercial red sea urchin fishery (67% of harvest areas) than the commercial Dungeness crab fishery (9% of high-catch crabbing grounds). Our study presents the first published carrying capacity estimate for sea otters in Oregon and can provide population recovery targets, focus attention on ecological and socioeconomic considerations, and help to inform a recovery plan for a resident sea otter population. Our findings suggest current available habitat may be sufficient to support a sea otter population, but resource managers may need to further investigate and consider whether current human activities might conflict with reestablishment in Oregon, if plans for a reintroduction continue.

Plasmodium falciparum infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has become even more challenging to control and eliminate the disease. Multiomics studies of the parasite have started to provide a glimpse into the confounding genetics and mechanisms of artemisinin resistance and identified mutations in Kelch13 (K13) as a molecular marker of resistance. Over the years, thousands of genomes and transcriptomes of artemisinin-resistant/sensitive isolates have been documented, supplementing the search for new genes/pathways to target artemisinin-resistant isolates. This meta-analysis seeks to recap the genetic landscape and the transcriptional deregulation that demarcate artemisinin resistance in the field. To explore the genetic territory of artemisinin resistance, we use genomic single-nucleotide polymorphism (SNP) datasets from 2,517 isolates from 15 countries from the MalariaGEN Network (The Pf3K project, pilot data release 4, 2015) to dissect the prevalence, geographical distribution, and co-existing patterns of genetic markers associated with/enabling artemisinin resistance. We have identified several mutations which co-exist with the established markers of artemisinin resistance. Interestingly, K13-resistant parasites harbor α-ß hydrolase and putative HECT domain–containing protein genes with the maximum number of SNPs. We have also explored the multiple, publicly available transcriptomic datasets to identify genes from key biological pathways whose consistent deregulation may be contributing to the biology of resistant parasites. Surprisingly, glycolytic and pentose phosphate pathways were consistently downregulated in artemisinin-resistant parasites. Thus, this meta-analysis highlights the genetic and transcriptomic features of resistant parasites to propel further exploratory studies in the community to tackle artemisinin resistance.

Objetivo: A osteonecrose (ON) é uma importante manifestação óssea da doença falciforme (DF), a qual traz grande morbidade para pacientes. Sua fisiopatologia está relacionada à vaso-oclusão decorrente do aumento da adesão entre as hemácias falciformes e outros componentes do sangue, como também da própria hemólise. Esse agravo acomete principalmente homens e o principal sítio anatômico é a cabeça do fêmur. Assim, o objetivo deste relato de casos é apresentar manifestações atípicas de ON em pacientes com DF. Material e métodos: Análise retrospectiva de prontuários de pacientes com DF que apresentaram ON com apresentações incomuns. Foram incluídos dois prontuários, com manifestações do agravo no úmero. Resultados: O primeiro caso foi de uma paciente do gênero feminino, 30 anos, HbSS, com diagnóstico de ON de úmero direito após quadro de dor em cotovelo direito com irradiação para braço e mão. À época, exames laboratoriais mostravam Hb de 9,0 g/dL, leucócitos de 8.280/mm3 e plaquetas de 467.000/mm3. O segundo caso foi uma paciente do gênero feminino de 35 anos, HbSS, com ON prévia de cabeça de fêmur, a qual necessitou de artroplastia total de quadril. Iniciou quadro de dor em ombro esquerdo, de forte intensidade e difícil tratamento, cujo diagnóstico foi ON em úmero esquerdo, quando exames apontavam Hb de 11 g/dL, leucócitos de 4.370/mm3 e plaquetas de 236.000/mm3. Ambas as pacientes faziam uso de hidroxiureia em dose terapêutica e, após o diagnóstico, passaram por tratamento conservador. Discussão: A ON é uma lesão óssea isquêmica que tem por consequência uma doença articular degenerativa. A região mais comumente afetada é a cabeça do fêmur, mas pode menos comumente afetar úmero, fêmur distal, tíbia e tálus. A ON relacionada à DF tem como origem a aglomeração de hemácias falciformes, leucócitos e plaquetas que obstruem a microvasculatura. Metade dos pacientes com HbSS desenvolve ON até os 35 anos. Outros fatores de risco incluem gênero masculino, alto índice de massa corporal, leucopenia, genótipo HbSS com traço α-talassêmico e episódios vaso-oclusivos frequentes. Ademais, não há estudos que afirmem categoricamente associação entre o tratamento com a hidroxiureia e o desenvolvimento de ON. Para necrose avascular de úmero, o principal fator de risco é a ON prévia de cabeça de fêmur, como foi o caso da segunda paciente. No úmero, a progressão é geralmente rápida, com o colapso podendo ocorrer até 6 meses após início dos sintomas, principalmente naqueles pacientes com HbSS. Nesses casos, a cirurgia é necessária para correção da lesão, podendo inclusive demandar substituição completa da articulação afetada. O prognóstico depende do estágio da ON no momento do diagnóstico, do tamanho da lesão, de sua localização e de outros fatores clínicos, avaliados com radiografias ou ressonância magnética. No diagnóstico precoce, o tratamento é apenas expectante, envolvendo emagrecimento, atividade física, fisioterapia e outras mudanças no estilo de vida. Os dois casos aqui apresentados são de pacientes do gênero feminino, sem leucopenia, com acometimento de regiões menos comuns. Isto nos alerta para estarmos atentos para sinais e sintomas desse agravo em pacientes com DF. Conclusão: A ON pode trazer importante morbidade para indivíduos com DF, principalmente nos diagnósticos tardios. Por isso, mesmo pacientes que apresentam fraco perfil epidemiológico para o desenvolvimento desse agravo devem ser investigados para descartá-lo.

Objetivo: O objetivo desta pesquisa foi a necessidade de conhecer o grau de satisfação dos pacientes pediátricos em tratamento oncológico portadores de leucemias e linfomas atendidos no Hospital Infantil Dr. Jeser Amarante Faria em Joinville, Santa Catarina, traçando um perfil epidemiológico destes pacientes, identificando pontos negativos e positivos e também as variáveis que subsidiam reexões quanto ao serviço e ao atendimento multidisciplinar. Materiais e métodos: O presente estudo foi descritivo, transversal e quantitativo. Os sujeitos participantes da pesquisa foram os responsáveis pela coleta de dados no período de Fevereiro a Julho de 2019. O formulário de coleta de dados foi preenchido pelos executores da pesquisa e conteve as a seguintes informações: idade, cor, sexo, procedência, tumor diagnosticado. Para a análise especicamente da satisfação dos usuários, foi utilizado parte do questionário da Pesquisa Mundial de Saúde (apêndice) da OMS. Para análise estatística foi utilizado o Microsoft Excel®. Resultados: O perl epidemiológico dos pacientes (idade, sexo, cor e procedência) foram retirados de seus respectivos prontuários. Do total dos entrevistados (n = 24), 10 estavam na Internação Hospitalar (IH) e 14 no Ambulatório Oncológico (AO). Destes, a média para idade foi de 7,5 anos (variando de 2 a 16 anos) e do outro grupo de 7,4 (variando de 2 a 18 anos). A maioria dos pacientes era do sexo masculino, tanto na IH quanto no AO, e apenas 1 paciente não havia registo quanto ao sexo, sendo classicado como “outro”. Quanto a cor da pele 22 pacientes eram brancos, 1 pardo e 1 não havia registro. Já em relação à procedência apenas 37,5% residiam em Joinville/SC, enquanto 62,5% eram de outras cidades. De forma geral, os escores médios foram semelhantes para Internação Hospitalar (IH) e Ambulatório Oncológico (AO), resultantes dos grandes percentuais em “bom”e “excelente”, excetuando-se o tempo gasto com deslocamento. A maioria dos escores medianos se concentraram em 100-80, demonstrando a excelente satisfação dos usuários, exceto o escore mediano atribuído ao tempo gasto com deslocamento entre os pacientes da IH de 60, e à visita de amigos e família de 70.Apesar de o tempo de espera gerar os menores graus de satisfação em todo os paísem nossa pesquisa o grau de satisfação foi alto, com escore mediano de 80. Discussão: Situado na maior cidade do estado de Santa Catarina, o HJAF é referência para atendimentos médico-hospitalares de crianças e adolescentes para 25 municípios das regiões norte e nordeste do estado. A partir do conhecimento da opinião dos usuários a cerca da assistência oferecida, os autores consideram importante para os gestores esses dados contribuindo na assistência multiprofissional, estrutura e suporte do serviço de oncologia pediátrica do serviço com base no atendimento humanizado, além de traçar um perfil dessa população alvo. Conclusão: Os pais das crianças portadoras de leucemias e linfomas acompanhados no serviço de Oncohematologia entrevistados apresentaram um alto grau de satisfação no que se refere aos serviços prestados no Hospital Infantil Jeser Amarante Faria. Não foram satisfatórios os itens relacionados à demora do tempo de deslocamento até a chegada ao serviço para atendimento médico, considerado extenso e, no ítem relacionado à visita e acompanhamento familiar durante a hospitalização o que foi alegado pelos entrevistados como sendo reflexo das normas do serviço.

Objetivos: O processo de doação de plaquetas por aférese (PLF) ou de plasma convalescente (PC) pode gerar reações adversas (RA) durante ou após o procedimento. Pela experiência negativa, as reações podem impedir que indivíduos se tornem doadores frequentes. Assim, é importante detectar as RA mais frequentes. Usualmente, se consegue esses dados através da observação antes da liberação pós-doação. Outra possibilidade seria a busca ativa, contatando os doadores pós-procedimento. O estudo objetivou comparar as RA entre doadores de PC (busca ativa) e PLF (observação) no Hemocentro de Goiás (HEMOGO). Materiais e métodos: Estudo observacional, prospectivo, sem intervenção realizado no HEMOGO. Foram avaliados 184 PFL de 23/04/2020 a 11/11/2020 e 61 PC entre 30/06/2020 a 11/09/2020. Dados demográficos foram coletados dos prontuários e analisados quanto à distribuição de sexo e idade. Resultados: Foram realizadas 184 PLF e 61 de PC. Para a PLF, 5 RA foram relatadas em indivíduos do sexo feminino, com 80% delas entre 18 a 30 anos. A reação mais comum nesse grupo foi lipotimia. Nenhum doador do sexo masculino reportou RA. Quanto à doação do PC, 14 homens relataram RA na busca ativa. A maioria tinha 31 a 40 anos e a maior parte das queixas foi dor/hematoma no local da punção e fraqueza. Ademais, 8 mulheres relataram reações, com 62,5% entre 18 e 30 anos. Grande parte delas reportou formigamento/hematoma no local da punção e sensação de rubor. A análise estatística mostrou que para PLF o sexo influencia nas RA e a idade não tem influência nesses eventos. Ainda, para PC, as RA não se correlacionaram com o sexo, mas tiveram correlação com a idade. Discussão: RA em aférese são esperadas devido ao tempo de procedimento mais longo, ao volume extracorpóreo ou alterações de fluidos. No estudo observamos um maior número de RA relatadas em doadores de PC em comparação aos de PLF. Outros estudos comparativos também observaram um aumento significativo no número de RA relatadas quando se realiza a busca ativa por RA. Houve diferenças quanto ao tipo de RA experimentada pelos doadores. Enquanto os doadores de PFL relataram sintomas sistêmicos, os de PC relataram sintomas locais. Isso pode estar relacionado ao próprio processo de doação, uma vez que reações vasovagais foram as RA imediatas mais comumente observadas após a doação. Estudos que avaliaram RA reportadas após busca ativa também observaram maior número de sintomas locais como hematoma e dor local. Na análise demográfica, sexo e idade influenciaram nas queixas reportadas por doadores de PFL e PC, respectivamente. Alguns estudos reportam que o sexo feminino e doadores mais jovens reportam mais RA, independente do tipo de doação. Porém devido a critérios de exclusão para doação, havia menos doadores de PC do sexo feminino, o que pode ter uma correlação negativa entre o sexo feminino e RA em PFL. Conclusão: As RA dos doadores de PC e PLF constituem um parâmetro significativo para a avaliação das repercussões desses procedimentos, tendo idade e sexo dos doadores como possíveis fatores preditores. Nesse estudo, a idade foi fator negativo para a RA pós doação de PC, enquanto o sexo foi fator negativo para as RA pós PLF. Destarte, a investigação desses eventos se torna necessária para o aperfeiçoamento da doação de PC e/ou de PLF, haja vista que, com a emergência da pandemia da COVID-19, essas técnicas tornaram-se importantes no cotidiano médico.

ABSTRACT The objective of this study was to evaluate the effects of dietary inclusion of protected sodium butyrate (PSB) on the intestinal development and feed nutrient metabolizability of commercial laying hens. The birds started to receive the treatment rations at 58 weeks of age. At 76 weeks of age the laying hens were distributed in a randomized block design to four treatments (0, 105, 210 and 300 g t-1/PSB), six replicates, and two birds/replicate. The nitrogen balance (NB), ether extract balance (EEB), dry matter metabolizability coefficient, nitrogen, ether extract, ash, apparent metabolizable energy (AME), and AME corrected by nitrogen (AMEn) were evaluated. For assessment of intestinal development, we evaluated the duodenum, jejunum, ileum, cecum, and colorectal lengths, the relative intestine weight and villus height, crypt depth, and villus:crypt ratio of the duodenum, jejunum, and ileum. A decreasing linear effect was observed in the duodenum length, while an increasing linear effect was observed in the height of the duodenum and jejunum villi. A quadratic effect was found in the jejunum crypt depth. A linear increasing effect was found on the villus:crypt ratio of the duodenum and jejunum, and a quadratic effect was observed in the ileum. Quadratic and increasing linear effects were observed in the NB and EEB, respectively. Additionally, increasing linear effects were observed in the AME and AMEn. The dietary addition of 300 g t-1 of PSB improved intestinal development and energy metabolizability of the diet.

Guava produced in Bengaluru in Karnataka is also transported to distant markets like Cochin in Kerala and Chennai in Tamil Nadu. An assessment of post harvest loss (PHL) was done in these markets. The main marketing channel followed was: Producer  PHC  Distant Market WS Retailer  Consumer Marketing practices followed in marketing of pink flesh guava and losses occurring at the wholesale (transit) and retailers’ level (storage) in the distant market - Kerala were studied from wholesalers and retailers. The PHL at the wholesalers’ level was observed to be 3.6 per cent mainly due to pressed and crushed fruits during transit. The retail level loss was 4.59 per cent which was mainly due to storage for more than two days resulting in decaying, rotting, yellowing etc. Average price received by the wholesaler was Rs.29.92/kg with a margin of Rs.6.21/kg (20.75%). The retailers received a price of Rs.46.54/kg with a margin of Rs.16.35/kg (35.13%). Marketing practices followed in marketing of pink flesh guava and losses occurring at the wholesale (transit) and retailers’ level (storage) in the distant market - Chennai (Tamil Nadu) were studied with wholesalers in Coimbeedu market and retailers in different parts of Chennai. The PHL at the wholesalers’ level was observed to be 4.62 per cent mainly due to pressed and crushed fruits during transit. The retail level loss was 6.09 per cent which was due to pressing of fruits during handling. The wholesaler received a margin of 22.91 percent in trading of guava fruits. The retailers received a margin of 45.72 per cent. The Karnataka farmers can take advantage of the higher prices prevalent in the distant markets and increase their income. Pathological investigation indicated that losses occurred at different stages of handling due to Styler end rot, Anthracnose, Canker, thrips attack etc., which needs to be addressed. The storage losses of pink flesh guava were estimated as 5.89 % after 4 days of storage at room temperature (24-32°C) that constituted mainly the physiological loss in weight (PLW). Spoilage started after 5 days of storage (10.5 %) and reached to 28.31 % by 6 days of storage. After 4 days of storage, guava fruits lose weight to the extent of 6 per cent and the spoilage starts after 5 days. Hence, care should be taken to dispose of the fruits within five days of harvest.

Introduction. Inflammatory myofibroblastic tumor (IMT) is a rare form of children neoplasm, characterized by intermediate biological behavior. In case of this, pathological diagnostics and valid tumor prognosis are difficult to perform; practitioners are not familiar enough with this pathology. Aim - to get an idea of the tumor morphological features, approaches to differential diagnosis of IMT, spreading in pediatric oncopathology, based on a review of modern literature. Material and methods. The retrospective analysis of soft tissue tumors in children operated for the period from 2007 to 2017 in Samara City Children's Clinical Hospital №1 n.a. Ivanova N.N. was performed. Among 1344 tumors, 5 cases verified as were detected IMT Results. Own clinical observations with children’s sex and age, tumor localization and speed of development, results of surgical treatment, tumor description in gross and in histological specimens, results of additional methods used in differential diagnostics from sarcomas are presented. Conclusions. Taking into account the tendency of tumor recurrence, the conclusion of the importance of morphological study of margins of tumor resection is made.

Aim - to study the structure of levator ani muscle in men and women of the first and second adult periods and elder group according to CT scan. Materials and methods. Data from CT scans of 40 patients aged 20 to 70 years were used. In the "Autoplan" system, in the semi-automatic mode, threedimensional models of levator ani muscle were created. Results. Three-dimensional models of levator ani muscle were created and described: for young women and men of all ages, a keel-shaped and funnel-shaped levator ani muscle forms; and for women of advanced age - horseshoe form.

The study developed a model to predict the response to therapy of children with chronic hepatitis C (CHC) based on a system of multivariate analysis. The mathematical model allows timely correction of treatment, significantly increasing the number of early virologic responses and reducing the probability of recurrence of the disease. Aim -optimization of treatment prior to the onset of therapy with subsequent forecasting of the effectiveness of therapy based on multivariate regression analysis. Materials and methods. The study included 116 patients at the age of 3-18 years with CHC in the replicative phase. Children with CHC were divided into 2 groups of 58 patients. Observations in children with CHC were made using clinical, biochemical, immunological and instrumental methods of research, which helped to obtain the most complete information about children with chronic viral hepatitis C. In the course of the conducted multiple regression analysis, we selected the most significant indicators for the establishment of the resulting mathematical model. Results. The method of forecasting response to therapy in chronic hepatitis C in children, developed on the basis of multivariate regression analysis and mathematical modelling of the most important immunological and biochemical parameters, is clinically efficient and justified.

In this study, we evaluated the diagnostic and prognostic value of the neutrophil gelatinase-associated lipocalin-2 (NGAL) level in urine as an early marker of renal dysfunction in preterm infants with very low and extremely low body weight. Aim - evaluation of diagnostic and prognostic significance of the urinary NGAL level as an early biomarker of acute kidney injury (AKI) in preterm infants. Materials and methods. The study included 104 premature babies, 78 of which formed the main group (AKI), and 26 babies - the comparison group (non-AKI). The main criterion for acute kidney injury in neonates according to neonatal classification AKIN (2011) is creatinine level > 1.5 mg/dL at the age of not earlier than 48 hours after birth. Results. The study identified a statistically significant correlation in the level of NGAL in the urine of children from the main and comparison groups. Conclusion. Biomarkers of kidney damage can give more accurate information than creatinine for the early diagnosis of AKI in children. In a comprehensive assessment of a child, it is necessary to take note of the indicators of renal function (creatinine, GFR) and biomarkers of injury (NGAL). This approach will allow performing the diagnostics and therapy of early AKI in children based on structural and functional criteria.

Summary: Background: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. Methods: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. Findings: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2–2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3–0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2–18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46–13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99–17·34]) or anaesthesia complications (11·47 (1·20–109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7–5·0). Interpretation: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. Funding: Medical Research Council of South Africa.

The current experiments searching for neutrinoless double-β (0νββ) decay also collect large statistics of Standard Model allowed two-neutrino double-β (2νββ) decay events. These can be used to search for Beyond Standard Model (BSM) physics via 2νββ decay spectral distortions. 100Mo has a natural advantage due to its relatively short half-life, allowing higher 2νββ decay statistics at equal exposures compared to the other isotopes. We demonstrate the potential of the dual read-out bolometric technique exploiting a 100Mo exposure of 1.47 kg × years, acquired in the CUPID-Mo experiment at the Modane underground laboratory (France). We set limits on 0νββ decays with the emission of one or more Majorons, on 2νββ decay with Lorentz violation, and 2νββ decay with a sterile neutrino emission. In this analysis, we investigate the systematic uncertainty induced by modeling the 2νββ decay spectral shape parameterized through an improved model, an effect never considered before. This work motivates searches for BSM processes in the upcoming CUPID experiment, which will collect the largest amount of 2νββ decay events among the next-generation experiments.

Visualization of the temporomandibular joint (TMJ) is constantly evolving with the improvement of technology. Magnetic resonance imaging is commonly used to evaluate the TMJ due to the high contrast resolution and the ability to obtain dynamic images to demonstrate the functional capability of the joint. Aim - to determine the functional changes after TMJ splint therapy conducted at various stages of intra-articular disorders. Data and methods. We conducted a survey, clinical examination and MRI of TMJ of 37 patients with temporomandibular disorders (TMD). Two groups of patients were formed according to the received MR picture of TMJ. Results. The study highlighted that regression of pain in TMJ and masticatory muscles, and normalization of functional parameters after splint rehabilitation occur more often in the first group of patients, who have disorders of the articular disc of the TMJ. Conclusion. In both groups of patients we noted positive dynamics of functional parameters of TMJ, reduction of pain in TMJ and masticatory muscles. Though 36,8% of the second group of patients, who have bone remodeling of TMJ condyles, didn’t show dynamics of functional parameters. Consequently, the use of splint in one third of patients with temporomandibular joint condyles destruction is effective for TMJ and muscular pain reduction.

Abstract This study evaluated the performance, carcass yield and quality, and physiological stress indicators of broilers of three genetic strains reared at three housing densities for 29 days. A total of 828 day-old male chicks, with average initial weight of 40.0± 2.0g were used. Three genetic strains (Cobb 500, Ross 808, and Ross 508, with 276 birds each) and three housing densities (17, 19, and 21 broilers/m²) were tested. A completely randomized experimental design in a 3 x 3 factorial arrangement, with four replicates of 23 birds each, was applied. The following responses were evaluated: performance parameters (average weekly body weight, average daily gain, feed intake, feed conversion ratio), physiological stress indicators (blood glucose levels, blood cell counts), and carcass yield and quality (dermatosis, bruising, dermatitis, and femoral degeneration scores). Average weekly body weight (BW) and daily weight gain (DWG) were not influenced by rearing density (p≥0.05), but Cobb 500 broilers were the heaviest during the analyzed period. In the second week, Ross 508 birds showed better feed conversion ratio (FCR) when housed at the density of 17 broilers/m² (p≤0.001), whereas the best FCR of Ross 808 and Cobb 500 broilers was obtained at 21 broilers/m² (p≤0.001). Carcass yield was not influenced by the treatments (p≥0.05). Physiological stress indicators were not affected by the treatments, and remained within normal ranges (p≥0.05). Dermatosis scores (scratches) increased (p≤0.05) when housing density increased from 17 to 19 broilers /m².

This study aimed at identifying the factors that affect the economic efficiency of broiler breeder production using the analysis of stochastic profit frontier function. Data were collected in 48 broiler breeder farms contracted by a commercial company located in southwestern Paraná, Brazil. The collected data refer to the last batch of fertile eggs that was delivered to the company, between January, 2008, and July, 2009. The following parameters were evaluated: production of hatching eggs per hen (number of eggs/hen), hatchability (hatch %), feed intake per hatching egg (g feed/ egg), production scale (number of birds/batch), farmer's experience in production activities, and labor type. Factors, such as area of occupied land, electricity costs, and invested capital were also evaluated. Results showed that the cost of electricity, as well as area of occupied land, production scale, and feed intake per hatching egg significantly affect the economic efficiency of the broiler breeder farms in Southwestern Paraná, Brazil.

Phosphodiesterase type 5 (PDE5) inhibitors modulate afferent nerve activity, increase nitric oxide activity resulting in the corpus cavernosal smooth muscle relaxation in the penis, prostate, urethra and bladder neck. According the European Urological Association guidelines, PDE5 inhibitors reduce the severity of moderate to severe symptoms of impaired urination in men with and without erectile dysfunction (ED). An overview of recent literature on the use of PDE5 inhibitors showed that they can be used clinically in the treatment of erectile dysfunction as well as in the therapy of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia and in patients with LUTS after radical prostatectomy. The aim of our study was to evaluate the role of tadalafil in restoring continence in patients after bilateral nerve-sparing robotic radical prostatectomy (bilateral NSRRPE).

Neutrinoless double beta decay (0νββ) is a yet unobserved nuclear process that would demonstrate Lepton number violation, a clear evidence of beyond standard model physics. The process two neutrino double beta decay (2νββ) is allowed by the standard model and has been measured in numerous experiments. In this Letter, we report a measurement of 2νββ decay half-life of ^{100}Mo to the ground state of ^{100}Ru of [7.07±0.02(stat)±0.11(syst)]×10^{18}  yr by the CUPID-Mo experiment. With a relative precision of ±1.6% this is the most precise measurement to date of a 2νββ decay rate in ^{100}Mo. In addition, we constrain higher-order corrections to the spectral shape, which provides complementary nuclear structure information. We report a novel measurement of the shape factor ξ_{3,1}=0.45±0.03(stat)±0.05(syst) based on a constraint on the ratio of higher-order terms from theory, which can be reliably calculated. This is compared to theoretical predictions for different nuclear models. We also extract the first value for the effective axial vector coupling constant obtained from a spectral shape study of 2νββ decay.

The quality of clinical education is dependenton learning experiences. The clinical teacher plays a key role insuccessful clinical education.The aims of the study were to determine which roles and attributesof physiotherapy clinical teachers contribute to a supportiveclinical learning environment according to physiotherapy studentsand their clinical teachers.The study protocol was approved by the Committee for HumanResearch at Stellenbosch University. A qualitative research designwas used. An interview schedule was developed based on existing literature. Data was analyzed using contentanalysis. Data was coded, categorized and conceptualized into key themes and patterns.All third year (n=40) and fourth year (n=40) undergraduate physiotherapy students and their clinical teachers(n=37) were eligible to participate. Semi-structured individual interviews were conducted with a purposivesample consisting of six third-year students, six fourth-year students and six clinical teachers (n=18). Written informedconsent was obtained from all participants prior to the interviews.The teacher as role model and facilitator of learning was emphasised. The attributes of the clinical teacher thatcreated a supportive learning environment were approachability, recognising student abilities and good communicationskills. The value of active involvement and individualism in learning was highlighted.The study confirmed that the clinical teacher is pivotal in the success of a physiotherapy clinical education program.The findings agree with the large body of international literature about supportive clinical learning environments.

Macrobrachium amazonicum is the most frequently consumed freshwater crustacean by river communities of the Amazon. Despite its relative abundance and vast knowledge on the species from data on cultivated specimens, little is known regarding its biology in the natural environment, especially its use of creeks that are strongly influenced by the tide. Specimens of Macrobrachium amazonicum were collected in September 2006 (dry season) and March 2007 (rainy season) from two perennial creeks of the Guajará Bay in the state of Pará (northern Brazil), using traps similar to the matapis used by local fishermen to identify the spatial distribution of the species. Shrimps of all sizes use the tidal creeks in both seasons, including for breeding purposes. The greatest abundance of the species occurred in headwater areas and in the dry season. It is suggested that abundant allochthonous organic matter and the preference for protected areas may explain the abundance and breeding activity of this species in the headwaters of the creeks.Macrobrachium amazonicum é o crustáceo dulcícola mais frequentemente consumido pelas populações ribeirinhas da Amazônia. Entretanto, apesar de sua relativa abundância e vasto conhecimento da espécie a partir de dados de cultivo, pouco se conhece sobre sua biologia no ambiente natural, especialmente quanto à forma de utilização de canais fortemente influenciados pelas marés. Amostras desse camarão foram coletadas em setembro/06 (período seco) e março/07 (período chuvoso), em dois canais perenes da Baía do Guajará, Pará, utilizando armadilhas (matapis) como as utilizadas pelos pescadores locais para identificar a distribuição espacial dos organismos. Os canais de maré são utilizados por camarões de todos os tamanhos nas duas estações do ano, inclusive para a reprodução. A maior abundância de indivíduos da espécie foi encontrada no período seco, nas áreas a montante dos canais . Postula-se que a abundante matéria orgânica alóctone e a busca de locais protegidos podem ser os fatores que explicam a concentração da abundância e da atividade reprodutiva nas áreas a montante dos canais.

این پژوهش به بررسی عوامل و شاخص‏های مؤثر در کلاس‏های درس فعال در دورۀ متوسطه آ. پ شهر تهران اختصاص دارد. نوع تحقیق در این پژوهش با توجه به اهداف و ماهیت موضوع، پیمایشی مقطعی است. ابزار سنجش پژوهش حاضر را یک پرسشنامه 40 سؤالی تشکیل می‏دهد این پرسشنامه از جانب پژوهشگر تدوین شده است که روایی ابزار از طریق آزمون تحلیل عاملی و اعتبار آن به وسیلۀ آلفای کرونباخ با مقدار 94/0 محاسبه شده است. جامعۀ آماری پژوهش حاضر همۀ مدیران و معلمان دورۀ متوسطه آ. پ شهر تهران با تحصیلات کارشناسی ارشد و کلیۀ متخصصان تعلیم و تربیت با تحصیلات دکترا انتخاب شده‏اند. برای تجزیه و تحلیل داده‏ها علاوه بر توصیف داده‏ها از آزمون آماری موسوم به تحلیل عاملی استفاده شده است. نتایج به دست آمده نشان‏دهندۀ آن است که عوامل و مؤثر در کلاس‏های درس فعال عبارت‏اند از: 1) باور کردن خود، 2) مسئولیت‏پذیری دانش‏آموز، 3) رعایت کردن مقررات کلاسی، 4) همکلاس‏های دانش‏آموزان و 5) صحبت با والدین است. این نتایج با یافته‏های پژوهش همخوانی دارد.

Naja naja snake venom presents abundant thermostable peptides. Many of them possess useful pharmacological activity that may be employed for drug development. For the proteomic characterization of such toxins, in the present study, Naja naja venom solution was heated up to 100°C for 10, 30, 60, 120, 180 and 300 minutes and protein fractions of non-heated and heated venom were analyzed by two-dimensional nano-liquid chromatography coupled online with tandem mass spectrometry. After heating for 300 minutes, a total of 32 peptides were still detected in the supernatant. The identified peptides belong to the following groups: cardiotoxins, neurotoxins and cytotoxins. It was found that thermostable peptides are able to preserve their analgesic activity after a long heating time in formalin test. Mice injected with 15 μg/g of 60-minute heated venom or with 25 μg/g of 300-minute heated venom revealed even a better analgesic activity than those treated with lidocaine.

Toxoplasma gondii infection may lead to important pathological questions, especially in rural areas, where several sources of infection exist. Therefore, it is important to determine risk factors in order to establish adequate prophylactic measures. The present study aimed to assess the prevalence and risk factors involved in human toxoplasmosis infection in a rural community, in Eldorado, Mato Grosso do Sul State, Brazil. This community was composed of 185 farms - with 671 inhabitants - from which 20 were randomly chosen. In these farms, blood samples were collected from rural workers, who also answered a risk factor questionnaire. Serum samples were analyzed by means of direct agglutination test for the detection of anti-Toxoplasma gondii antibodies. From 73 samples collected, 79.45% were positive. None of the studied variables was significantly associated with the prevalence of the infection. However, among the individuals who reported eyesight impairments, 94.4% had anti-T. gondii antibodies, compared with 74.0% who did not report eyesight changes (p = 0.0594). Moreover, most individuals in the study (68.20%) were older than 18 years and presented 84.44% positivity, compared with 66.67% of positive individuals younger than 18 years old. We were able to conclude that a high prevalence of antibodies did not imply significant associations with the risk factors studied.