Abstract: In 2020, the COVID-19 pandemic followed a two-wave pattern in most countries. Hospital admission for COVID-19 in one wave or another could have affected mortality, especially among the older persons. The objective of this study was to evaluate whether the admission of older patients during the different waves, before SARS-CoV-2 vaccination was available, was associated with a different mortality. We compared the mortality rates of patients hospitalized during 2020 before (first wave) and after (second wave) July 7, 2020, included in the SEMI-COVID-19 Registry, a large, multicenter, retrospective cohort of patients admitted to 126 Spanish hospitals for COVID-19. A multivariate logistic regression analysis was performed to control for changes in either the patient or disease profile. As of December 26, 2022, 22,494 patients had been included (17,784 from the first wave and 4710 from the second one). Overall mortality was 20.4% in the first wave and 17.2% in the second wave (risk difference (RD) − 3.2%; 95% confidence interval (95% CI) − 4.4 to − 2.0). Only patients aged 70 and older (10,973 patients: 8571 in the first wave and 2386 in the second wave) had a significant reduction in mortality (RD − 7.6%; 95% CI − 9.7 to − 5.5) (unadjusted relative risk reduction: 21.6%). After adjusting for age, comorbidities, variables related to the severity of the disease, and treatment received, admission during the second wave remained a protective factor. In Spain, patients aged 70 years and older admitted during the second wave of the COVID-19 pandemic had a significantly lower risk of mortality, except in severely dependent persons in need of corticosteroid treatment. This effect is independent of patient characteristics, disease severity, or treatment received. This suggests a protective effect of a better standard of care, greater clinical expertise, or a lesser degree of healthcare system overload.

Abstract: Production Engineering research practice in Brazil is reviewed, emphasizing the activities developped by graduation and post-graduation courses, and research groups. This paper presents an assessment of Production Engineering teaching activities and research lines subjects, pointing out the various modifications and evolution ocurred on these fields. Global economics scenarios forecasts for the next decade are introduced and evaluated, in oder to predict Production Engineering position and evolution in this period. A set of suggestions and recommendations are presented on the subjects of personnel improvement, new courses formation and priorities for operation and investment.

Abstract: RESUMOINTRODUÇÃO: O câncer infantojuvenil vem se apresentando como a segunda causa de óbito na população entre 0 e 19 anos no Brasil, atrás apenas das causas externas. As tecnologias de informação e comunicação, especificamente, a telessaúde, revela-se uma mola propulsora na triagem de suspeitas de neoplasias malignas, além de promover a integração da equipe da atenção primária à saúde e a do centro de referência, diminuindo distâncias, e promovendo educação continuada igualitária.OBJETIVO: Associar os resultados do pré e pós-testes e descrever as teleconsultorias enviadas após a intervenção do projeto FIQUE ATENTO: PODE SER CÂNCER: A telessaúde como ferramenta para a suspeição precoce do câncer infantojuvenil, realizado com profissionais da atenção primária à saúde em Recife-Pernambuco.MÉTODO: Trata-se de um estudo quase-experimental sem grupo controle, descritivo, com abordagem quantitativa. Realizado nos anos de 2015 e 2016, a partir da análise de dados secundários da Plataforma de Telessaúde HealthNET da RedeNutes, do Núcleo de Telessaúde da Universidade Federal de Pernambuco. Utilizou-se o software EpiInfo 7.2 como suporte estatístico para o cálculo das frequências absolutas e relativas, assim como para as medidas de associação. Adotou-se o p-valor menor que 0,05 para o cálculo de significância estatística. O projeto foi aprovado sob o número do CAAE 50707515.7.0000.5208.RESULTADOS: Os profissionais, após a intervenção, mostraram maior desenvolvimento com relação aos conhecimentos obtidos sobre epidemiologia (p 〈 0,001), e sinais e sintomas das neoplasias infantojuvenis (p 〈 0,001). Foram geradas oito teleconsultorias com tempo médio de resposta de 53,32 horas, em que 50% (4) foram casos clínicos e tiveram seus encaminhamentos qualificados, e nenhum precisou ser regulado à unidade de referência.CONCLUSÃO: A telessaúde mostra-se como uma ferramenta com potencial de educação permanente, contribuindo para o diagnóstico precoce do câncer infantojuvenil, aumentando as chances de cura e sobrevida. Palavras-chave: Saúde da Criança; Saúde do Adolescente; Neoplasias; Telessaúde; Atenção primária à saúde.

Abstract: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. Methods: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score–matched models. Results: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9–3.6], 4.0 [95% CI, 3.6–4.5] , and 5.5 [95% CI, 5.0–6.1] events per 100 patient-years in strata 〈 75, 75– 〈 90, ≥90 mg/dL, respectively; P trend 〈 0.0001) and after adjustment for low-density lipoprotein cholesterol ( P trend =0.035). Higher baseline apoB stratum was associated with greater relative ( P trend 〈 0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78–4.79], 3.09 [95% CI, 2.69–3.54] , and 2.41 [95% CI, 2.11–2.76] events per 100 patient-years in strata ≥50, 〉 35– 〈 50, and ≤35 mg/dL, respectively). Compared with propensity score–matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol but not vice versa. Conclusions: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01663402.

Abstract: Multiple myeloma in the central nervous system (CNS) is an extremely rare condition, described in over 100 cases in the literature. In this article, the authors report the case of a 55-year-old female patient, subjected to an autologous bonemarrow transplant, and, furthermore, to a brain tissue biopsy with immunohistochemistry confirmation, revealing infiltration by a great amount of plasma cells, compatible with the clinical history of multiple myeloma. The patient was then subjected to CNS adjuvant radiotherapy, with constant observation by clinical oncology and monthly pamidronate disodium prescription. Despite being an incurable pathology, radiation therapy showed important local control. 

Abstract: Herein we report the synthesis and characterization of a new copper(I) complex with triphenylphosphine (PPh 3 ) and N ‐(2‐thiophenecarbonyl)‐ N ’‐(3‐Cl, 4‐F‐phenyl)thiourea (HL), as ligands. The complex was characterized by vibrational (FTIR and FT‐Raman) and multinuclear ( 1 H, 13 C { 1 H}, 31 P{ 1 H}) NMR spectroscopies. The crystalline structure of the complex was determined by single‐crystal X‐ray diffraction, confirming that a neutral binuclear compound, identified as [Cu(PPh 3 )(L‐κ 2 ‐N,μ‐S)] 2 , was obtained. The anionic thiourea ligand coordinates to the metal through the sulfur and nitrogen atoms in an unusual bidentate κ 2 ‐N,μ‐S coordination mode. The complex is a dimer sited on a crystallographic center of symmetry. Each Cu 2 (μ‐S) 2 cation bridges trough the sulfur atoms of two symmetry related thiourea moieties and is also coordinated to the nitrogen atom of the thiourea ligand and the phosphorus atom from PPh 3 co‐ligand, forming a slightly distorted tetrahedral geometry. An intramolecular N−H⋅⋅⋅O=C hydrogen bond is observed in the anionic ligand, forming a six‐membered ring that stabilizes the N−H thioamide group. Hirshfeld surface analysis shows that the molecules are connected by weak intermolecular contacts C⋅⋅⋅C, H⋅⋅⋅C and H⋅⋅⋅H which add to the stability of the crystalline packing. The in vitro cytotoxicity study of the complex indicates that it is more active against human lung carcinoma cells (A549), when compared to the free ligand.

Abstract: Introduction: FOXO3A is a transcription factor shown to be involved in all-trans retinoic acid (ATRA)-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia (APL). Its biological activity may be significantly enhanced upon metformin, raising the possibility that ATRA and Metformin may act synergistically; which could be useful to overcome ATRA resistance. Despite progress in APL treatment, approximately 10-15% of patients will relapse after treatment with ATRA and anthracyclines and frequently present with ATRA resistance. Relapsed patients respond well to arsenic trioxide (ATO) treatment, but the cost of ATO is a significant barrier in many countries. Aims: Here, we investigated the effects of in vitro treatment with ATRA plus metformin in APL cell lines and primary blasts, and quantified FOXO3A expression and correlated its levels with treatment outcome in a cohort of patients enrolled in the International Consortium on Acute Leukemia (ICAPL2006) study. Finally, we evaluated the effect of induced overexpression of FOXO3A gene in regards to cell viability and proliferation. Methods: Primary leukemic blasts from hCG-PMLRARα transgenic mice (TM; n=4) and APL patients (age, 25-47y; n=4) were treated with metformin alone (5mM/ 10mM) or in combination with ATRA (1µM) and evaluated for cell viability. In addition, 106 patients (age, 18-82y) with newly diagnosed APL enrolled in the ICAPL2006 study were included. As controls, eight samples of bone marrow mononuclear cells (BMMC) from healthy volunteers (age, 18-60y) were analyzed. To validate our data, FOXO3A transcript levels from an independent cohort was used (31 patients from Amazonia!, Probe n. 204131_s_at, and five normal BMMC samples included in the same databank). NB4/NB4R2 (ATRA-resistant) cell lines were transduced with FOXO3A or empty vector (control). After synchronization using double thymidine block, transduced cells were submitted to proliferation and cell cycle assays. For dose-response curves, cells were treated with graded concentrations of ATRA, ATO and metformin. For the apoptosis analysis, cells were treated with ATRA (1µM), metformin (5mM) and combination for 24, 48 and 72 hours. The granulocytic differentiation in response to ATRA treatment was evaluated based on the CD11b surface levels. Results: In primary cells (from TM/APL patients) a 2-fold reduction in viable cells was observed after metformin and metformin plus ATRA treatment (P 〈 .05), compared to only 0.5-fold reduction rate using ATRA alone. In the clinical setting, APL patients expressed a lower absolute level of FOXO3A than normal BMMC (P 〈 .001). These results were corroborated in an external validation cohort (P=.004). The retrospective analysis of patients enrolled in the ICAPL2006 study revealed that the baseline characteristics were similar between patients with low and high FOXO3A levels. Low FOXO3A expression was associated with lower DFS (84%; 95% CI: 63-94%)(HR: 1.25, 95% CI: 0.64-10.4) and OS (76%; 95% CI: 63-84%) (HR: 1.43, 95% CI: 0.12-1.48). The overexpression of FOXO3A in APL cell lines was associated with reduced basal cell viability (P=.02), clonogenicity (P=.001), and proliferation (P=.001) in both APL cell lines. Subsequent cell cycle analysis showed no significant difference between FOXO3A-cells and controls in normal conditions and when treated with ATRA. Using a nonlinear regression analysis, IC50 for ATO was significantly lower for NB4-FOXO3A cells (0.27μM) than control (2.27µM), with no corresponding response for NB4R2 cell line (2µM for empty vector vs 1.46μM for NB4R2 FOXO3A). NB4 (IC50: 14mM) and NB4R2 (IC50: 4.2mM) FOXO3A cells presented higher sensibility to metformin treatment versus control group (IC50: 23mM for NB4; IC50: 22mM for NB4R2). For ATRA treatment alone, only NB4-FOXO3A presented increased sensitivity to ATRA (P=.001). In accordance, ATRA treatment (alone or in combination with metformin) increased the drug-induced apoptosis in a time-dependent manner (P 〈 .05) in NB4-FOXO3A cells, but had no effect on NB4R2-FOXO3A, which presented increased apoptosis rate only with metformin treatment. The differentiation rate was higher in FOXO3A-expressing cells (P 〈 .05). Conclusion: Based on clinical and functional data, the FOXO3A pathway could be an interesting target to overcome ATRA resistance in APL in offsetting where ATO is unavailable in low- and middle-income countries. Disclosures Tallman: BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding; Orsenix: Other: Advisory board. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Lowenberg:Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.