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INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.
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Importance: Although patients with myocarditis after COVID-19 mRNA vaccination appear to have a good prognosis near hospital discharge, their longer-term prognosis and management remain unknown. Objective: To study the cardiovascular complications of post-COVID-19 mRNA vaccination myocarditis and other types of myocarditis during an 18-month follow-up, as well as disease management based on a study of the frequency of medical procedures and drug prescriptions. Design, Setting, and Participants: In this cohort study based on the French National Health Data System, all individuals aged 12 to 49 years hospitalized for myocarditis in France between December 27, 2020, and June 30, 2022, were identified. Exposure: Individuals were categorized as having postvaccine myocarditis (within 7 days after COVID-19 mRNA vaccine), post-COVID-19 myocarditis (within 30 days of SARS-CoV-2 infection), or conventional myocarditis. Main Outcomes and Measures: The occurrence of clinical outcomes (hospital readmission for myopericarditis, other cardiovascular events, all-cause death, and a composite outcome of these events) over the 18 months following hospital admission were analyzed using weighted Cox models to standardize the comparisons with the conventional myocarditis group. Also, medical management after hospital discharge was longitudinally assessed using generalized estimated equation models. Results: In total, 4635 individuals were hospitalized for myocarditis: 558 with postvaccine myocarditis, 298 with post-COVID-19 myocarditis, and 3779 with conventional myocarditis. Patients with postvaccine myocarditis were younger than those with post-COVID-19 and conventional myocarditis (mean [SD] age of 25.9 [8.6], 31.0 [10.9], and 28.3 [9.4] years, respectively) and were more frequently men (84%, 67%, and 79%). Patients with postvaccine myocarditis had a lower standardized incidence of the composite clinical outcome than those with conventional myocarditis (32/558 vs 497/3779 events; weighted hazard ratio, 0.55 [95% CI, 0.36-0.86]), whereas individuals with post-COVID-19 myocarditis had similar results (36/298 events; weighted hazard ratio, 1.04 [95% CI, 0.70-1.52]). The standardized frequency of medical procedures and drugs prescribed in patients with postvaccine myocarditis or post-COVID-19 myocarditis followed a similar trend in the 18 months following hospital discharge to that of patients with conventional myocarditis. Conclusions and Relevance: Patients with post-COVID-19 mRNA vaccination myocarditis, contrary to those with post-COVID-19 myocarditis, show a lower frequency of cardiovascular complications than those with conventional myocarditis at 18 months. However, affected patients, mainly healthy young men, may require medical management up to several months after hospital discharge.
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INTRODUCTION: Early home visit programmes have been developed to help parents build an adequate relationship with their baby and to prevent child developmental delays and affective disorders. The "Appui Parental" programme is an intervention carried out by nursery nurses to provide intensive parental support to vulnerable families. Before extending this programme, it seemed necessary to evaluate its impact objectively. OBJECTIVES: The main aim is to determine the impact of the "Appui Parental" programme on the change in the child's symptoms. The secondary objectives are to evaluate its effects on mother-child interactions, self-assessed parental competence, perception of social support, primary caregiver's anxiety-depression symptoms, alliance with the nursery nurse, frequency of out-of-home placements, and nursery nurses' stress. METHOD: This non-randomized prospective multicentre study would include 44 families who receive the "Appui Parental" intervention for a one to 20-month-old child (intervention group) and 44 families with the same vulnerability criteria who receive care as usual by the maternal and child protection services (control group). The child, parents, mother-child interaction, nursery nurse-mother alliance, and nursery nurse's stress will be assessed at month one and month 18 after inclusion. Comparisons between groups will be performed. CONCLUSION: This study should provide the public authorities with objective data on this programme's impact and allow them to pursue its generalization. For professionals, the study should confirm the interest in close early parental support through home visits or should lead to rethinking some aspects of the programme.
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BACKGROUND: The BNT162b2 (Pfizer-BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. OBJECTIVE: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. DESIGN: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. SETTING: France, 27 December 2020 to 20 July 2021. PATIENTS: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). MEASUREMENTS: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer-BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). RESULTS: No association was found between the Pfizer-BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford-AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). LIMITATIONS: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. CONCLUSION: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. PRIMARY FUNDING SOURCE: None.
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Vacinas contra COVID-19 , COVID-19 , Infarto do Miocárdio , Embolia Pulmonar , Acidente Vascular Cerebral , Ad26COVS1 , Adulto , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/etiologia , Embolia Pulmonar/complicações , Embolia Pulmonar/etiologia , RNA Mensageiro , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Vacinação/efeitos adversosRESUMO
Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner's ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person's own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships.
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Relações Interpessoais , Aprendizado de Máquina , Características da Família , Feminino , Humanos , Estudos Longitudinais , Masculino , AutorrelatoRESUMO
In brief: The insulin-like 3 (INSL3) hormone produced by Leydig cells is essential for proper male sex differentiation, but the regulation of Insl3 expression remains poorly understood. This study describes a new physical and functional cooperation between the nuclear receptors SF1 and COUP-TFII in Insl3 expression. Abstract: INSL3, a hormone abundantly produced by Leydig cells, is essential for testis descent during fetal life and bone metabolism in adults. The mechanisms regulating Insl3 expression in Leydig cells have been studied in several species but remain poorly understood. To date, only a handful of transcription factors are known to activate the Insl3 promoter and include the nuclear receptors AR, NUR77, COUP-TFII, and SF1, as well as the Krüppel-like factor KLF6. Some of these transcription factors are known to transcriptionally cooperate on the Insl3 promoter, but the mechanisms at play remain unknown. Here, we report that COUP-TFII and SF1 functionally cooperate on the Insl3 promoter from various species but not on the Inha, Akr1c14, Cyp17a1, Hsd3b1, Star, Gsta3, and Amhr2 promoters that are known to be regulated by COUP-TFII and/or SF1. The Insl3 promoter contains species-conserved binding sites for COUP-TFII (-91 bp) and SF1 (-134 bp). Mutation of either the COUP-TFII or the SF1 sequence had no impact on the COUP-TFII/SF1 cooperation, but the mutation of both binding sites abolished the cooperation. In agreement with this, we found that COUP-TFII and SF1 physically interact in Leydig cells. Finally, we report that the transcriptional cooperation is not limited to COUP-TFII and SF1 as it also occurred between all NR2F and NR5A family members. Our data provide new mechanistic insights into the cooperation between the orphan nuclear receptors COUP-TFII and SF1 in the regulation of Insl3 gene expression in Leydig cells.
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Fator II de Transcrição COUP , Insulina , Células Intersticiais do Testículo , Proteínas , Fator Esteroidogênico 1 , Adulto , Sítios de Ligação , Fator II de Transcrição COUP/genética , Fator II de Transcrição COUP/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Regiões Promotoras Genéticas , Proteínas/genética , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Testículo/metabolismoRESUMO
We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.
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Vacinas contra COVID-19 , COVID-19 , Viés , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Projetos de Pesquisa , VacinaçãoRESUMO
BACKGROUND: Long-term psychological impacts of the COVID-19 pandemic on healthcare workers remain unknown. We aimed to determine the one-year progression of burnout and mental health since pandemic onset, and verify if protective factors against psychological distress at the beginning of the COVID-19 pandemic (Cyr et al. in Front Psychiatry; 2021) remained associated when assessed several months later. METHODS: We used validated questionnaires (Maslach Burnout Inventory, Hospital Anxiety and Depression and posttraumatic stress disorder [PTSD] Checklist for DSM-5 scales) to assess burnout and psychological distress in 410 healthcare workers from Quebec, Canada, at three and 12 months after pandemic onset. We then performed multivariable regression analyses to identify protective factors of burnout and mental health at 12 months. As the equivalent regression analyses at three months post-pandemic onset had already been conducted in the previous paper, we could compare the protective factors at both time points. RESULTS: Prevalence of burnout and anxiety were similar at three and 12 months (52% vs. 51%, p = 0.66; 23% vs. 23%, p = 0.91), while PTSD (23% vs. 11%, p < 0.0001) and depression (11% vs. 6%, p = 0.001) decreased significantly over time. Higher resilience was associated with a lower probability of all outcomes at both time points. Perceived organizational support remained significantly associated with a reduced risk of burnout at 12 months. Social support emerged as a protective factor against burnout at 12 months and persisted over time for studied PTSD, anxiety, and depression. CONCLUSIONS: Healthcare workers' occupational and mental health stabilized or improved between three and 12 months after the pandemic onset. The predominant protective factors against burnout remained resilience and perceived organizational support. For PTSD, anxiety and depression, resilience and social support were important factors over time.
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Esgotamento Profissional , COVID-19 , Angústia Psicológica , Humanos , COVID-19/epidemiologia , Pandemias , SARS-CoV-2 , Depressão/epidemiologia , Pessoal de Saúde/psicologia , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/psicologia , Ansiedade/epidemiologiaRESUMO
BACKGROUND: Extra energy intake is commonly recommended for pregnant women to support fetal growth. However, relevant data regarding variations in energy intake and expenditure, body mass index and gestational weight gain (GWG) are frequently not considered. This study aimed to investigate how energy intake during pregnancy and gestational weight gain (GWG) are associated with birth weight. METHODS: Early pregnant women were recruited into a Japanese nationwide prospective birth cohort study between 2011 and 2014. We analysed data of 89,817 mother-child pairs of live-born non-anomalous singletons after excluding births before 28 weeks or after 42 weeks. Energy intake during pregnancy was estimated from self-administered food frequency questionnaires (FFQ) and was stratified into low, medium, and high. Participants completed the FFQ in mid-pregnancy (mean 27.9 weeks) by recalling food consumption at the beginning of pregnancy. Effects of energy intake on birth weight and mediation by GWG were estimated using the Karlson-Holm-Breen method; the method separates the impact of confounding in the comparison of conditional and unconditional parameter estimates in nonlinear probability models. Relative risks and risk differences for abnormal birth size were calculated. RESULTS: Mean daily energy intake, GWG, and birth weight were 1682.1 (533.6) kcal, 10.3 (4.0) kg, and 3032.3 (401.4) g, respectively. 6767 and 9010 women had small-for-gestational-age and large-for-gestational-age infants, respectively. Relative to low energy intake, moderate and high intakes increased adjusted birth weights by 13 g and 24 g, respectively: 58 and 69% of these effects, respectively, were mediated by GWG. Compared with the moderate energy intake group, the low energy intake group had seven more women per 1000 women with a small-for-gestational-age birth, whereas the high energy intake group had eight more women per 1000 women with a large-for-gestational-age birth. CONCLUSION: GWG mediates the effect of energy intake on birth weight. All pregnant women should be given adequate nutritional guidance for optimal GWG and fetal growth.
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Ganho de Peso na Gestação , Peso ao Nascer , Índice de Massa Corporal , Estudos de Coortes , Ingestão de Energia , Feminino , Humanos , Japão/epidemiologia , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Aumento de PesoRESUMO
Prospective memory (PM) problems in aging and, to a greater extent, in mild cognitive impairment (MCI), compromise functional independence. This study examined the effectiveness of a cognitive training program based on visual imagery to improve PM among older adults with and without MCI. Participants were older adults, 24 with MCI and 24 cognitively healthy (HOA). Half of them (12 MCI and 12 HOA) were randomly assigned to the PM training program, the other half to the no-training control group. All participants also completed a pre- and post-test evaluation, including neuropsychological tests, questionnaires, and the Ecological Test of Prospective Memory (TEMP). There was no significant effect of the intervention on the TEMP total, event-based or time-based scores for either the MCI or HOA groups. However, the trained MCI group committed fewer false alarms (i.e., more efficient identification of prospective cues) in the event-based condition of the TEMP at post-test. On the other hand, all trained participants performed better than control participants on retrospective memory tests, which suggests that visual imagery-based training is more effective to improve retrospective memory than PM. Possible explanations for these results are explored.
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Disfunção Cognitiva , Memória Episódica , Idoso , Humanos , Transtornos da Memória , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
Streptomyces coelicolor and Streptomyces lividans constitute model strains to study the regulation of antibiotics biosynthesis in Streptomyces species since these closely related strains possess the same pathways directing the biosynthesis of various antibiotics but only S. coelicolor produces them. To get a better understanding of the origin of the contrasted abilities of these strains to produce bioactive specialized metabolites, these strains were grown in conditions of phosphate limitation or proficiency and a comparative analysis of their transcriptional/regulatory proteins was carried out. The abundance of the vast majority of the 355 proteins detected greatly differed between these two strains and responded differently to phosphate availability. This study confirmed, consistently with previous studies, that S. coelicolor suffers from nitrogen stress. This stress likely triggers the degradation of the nitrogen-rich peptidoglycan cell wall in order to recycle nitrogen present in its constituents, resulting in cell wall stress. When an altered cell wall is unable to fulfill its osmo-protective function, the bacteria also suffer from osmotic stress. This study thus revealed that these three stresses are intimately linked in S. coelicolor. The aggravation of these stresses leading to an increase of antibiotic biosynthesis, the connection between these stresses, and antibiotic production are discussed.
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Proteômica , Streptococcus , Streptomyces coelicolor , Antibacterianos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Nitrogênio/metabolismo , Fosfatos/metabolismo , Proteômica/métodos , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismo , Fatores de Transcrição/metabolismo , Streptococcus/genética , Streptococcus/metabolismoRESUMO
Transplant vasculopathy is characterized by endothelial apoptosis, which modulates the local microenvironment. Milk fat globule epidermal growth factor 8 (MFG-E8), which is released by apoptotic endothelial cells, limits tissue damage and inflammation by promoting anti-inflammatory macrophages. We aimed to study its role in transplant vasculopathy using the murine aortic allotransplantation model. BALB/c mice were transplanted with fully mismatched aortic transplants from MFG-E8 knockout (KO) or wild type (WT) C57BL/6J mice. Thereafter, mice received MFG-E8 (or vehicle) injections for 9 weeks prior to histopathological analysis of allografts for intimal proliferation (hematoxylin and eosin staining) and leukocyte infiltration assessment (immunofluorescence). Phenotypes of blood leukocytes and humoral responses were also evaluated (flow cytometry and ELISA). Mice receiving MFG-E8 KO aortas without MFG-E8 injections had the most severe intimal proliferation (p < 0.001). Administration of MFG-E8 decreased intimal proliferation, especially in mice receiving MFG-E8 KO aortas. Administration of MFG-E8 also increased the proportion of anti-inflammatory macrophages among graft-infiltrating macrophages (p = 0.003) and decreased systemic CD4+ and CD8+ T-cell activation (p < 0.001). An increase in regulatory T cells occurred in both groups of mice receiving WT aortas (p < 0.01). Thus, the analarmin MFG-E8 appears to be an important protein for reducing intimal proliferation in this murine model of transplant vasculopathy. MFG-E8 effects are associated with intra-allograft macrophage reprogramming and systemic T-cell activation dampening.
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Antígenos de Superfície , Proteínas do Leite , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Aorta/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fator VIII , Glicolipídeos , Glicoproteínas , Gotículas Lipídicas , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Leite/genética , Proteínas do Leite/metabolismoRESUMO
Clinical symptoms attributed to gastro-esophageal reflux disease (GERD) in healthy term infants are non-specific and overlap with age-appropriate behaviours. This practice point reviews the evidence for medically recommended management of this common condition. Current recommendations to manage GERD include feeding modifications such as thickening feeds or avoiding cow's milk protein. There is limited evidence for pharmacological management, including acid suppressive therapy or prokinetic agents, with the risks of such treatments often outweighing possible benefits due to significant safety and side effect concerns. Acid-suppressive therapy should not be routinely used for infants with GERD and is most likely to be useful in the context of symptoms that suggest erosive esophagitis. Evidence for managing symptoms attributed to GERD in otherwise healthy term infants less than 1 year of age is presented, and the over-prescription of medications in this population is discouraged. Anticipatory guidance regarding the natural resolution of reflux symptoms is recommended.
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Pain assessment and management are essential components of paediatric care. Developmentally appropriate pain assessment is an important first step in optimizing pain management. Self-reported pain should be prioritized. Alternatively, developmentally appropriate behavioural tools should be used. Acute pain management and prevention guidelines and strategies that combine physical, psychological, and pharmacological approaches should be accessible in all health care settings. Chronic pain is best managed using combined treatment modalities and counselling, with the primary goal of attaining functional improvement. The planning and implementation of pain management strategies for children should always be personalized and family-centred.
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L'évaluation et le traitement de la douleur sont des aspects essentiels des soins pédiatriques. L'évaluation de la douleur adaptée au développement représente une première étape importante pour en optimiser la prise en charge. L'autoévaluation de la douleur est à prioriser. Si c'est impossible, des outils appropriés d'évaluation du comportement, adaptés au développement, doivent être utilisés. Des directives et stratégies de prise en charge et de prévention de la douleur aiguë, qui combinent des approches physiques, psychologiques et pharmacologiques, doivent être accessibles dans tous les milieux de soins. Le meilleur traitement de la douleur chronique fait appel à une combinaison de modalités thérapeutiques et de counseling, dans l'objectif premier d'obtenir une amélioration fonctionnelle. La planification et la mise en Åuvre de stratégies de prise en charge de la douleur chez les enfants doivent toujours être personnalisées et axées sur la famille.
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Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
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Cromossomos Humanos Par 12 , Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Aberrações Cromossômicas , Análise Citogenética , Feminino , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/terapia , PrognósticoRESUMO
Our study aimed to analyze the risk of hematologic malignancies (HM) associated with the use of G-CSF with chemotherapy for BC. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident breast cancer between 2007 and 2015, who received chemotherapy for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL) and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Among a total of 122 373 BC survivors, 38.9% received chemotherapy only and 61.1% received chemotherapy + G-CSF. Overall, 781 cases of hematologic malignancies occurred. We observed a nonsignificant increase in the risk of AML (aHR, 1.3; 95% CI, 1.0-1.7), of MDS (aHR, 1.3; 95% CI, 0.9-1.8) and of ALL/LL (aHR, 2.0; 95% CI, 1.0-4.4) among patients treated by chemotherapy + G-CSF compared to chemotherapy only. In analyses by dose, we observed a slight increase in the risk of AML (1-3 doses: aHR, 1.2; 95% CI, 0.8-1.7/4+ doses: aHR, 1.3; 95% CI, 1.0-1.8) and of MDS (1-3 doses: aHR, 1.1; 95% CI, 0.7-1.7/4+ doses: aHR, 1.4; 95% CI, 1.0-1.9), a significant increase in risk of ALL (1-3 doses: aHR, 1.5; 95% CI, 0.5-3.9 / 4+ doses: aHR, 2.3; 95% CI, 1.0-5.1) with increasing cycles of G-CSF. Our population-based study showed that the ALL/LL was the only HM at increased risk with the use of growth factors with a possible dose-effect relationship. Our data regarding the risk of all the other HM are reassuring.
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Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias Hematológicas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , França/epidemiologia , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Neoplasias Hematológicas/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/induzido quimicamenteAssuntos
Vacinas contra COVID-19 , Doenças Cardiovasculares , Imunização Secundária , Vacinas Combinadas , Humanos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/etiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/uso terapêutico , Imunização Secundária/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/etiologia , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/etiologia , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/etiologia , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/uso terapêuticoRESUMO
Vitamin K antagonists (VKAs) have been used in 1% of the world's population for prophylaxis or treatment of thromboembolic events for 64 years. Impairment of osteoblast function and osteoporosis has been described in patients receiving VKAs. Given the involvement of cells of the bone marrow microenvironment (BMM), such as mesenchymal stem cells (MSCs) and macrophages, as well as other factors such as the extracellular matrix for the maintenance of normal hematopoietic stem cells (HSCs), we investigated a possible effect of VKAs on hematopoiesis via the BMM. Using various transplantation and in vitro assays, we show here that VKAs alter parameters of bone physiology and reduce functional HSCs 8-fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and, to a lesser extent, MSCs of the BMM and integrin ß3-AKT signaling in HSCs as at least partly causative of this effect, with VKAs not being directly toxic to HSCs. In patients, VKA use associates with modestly reduced leukocyte and monocyte counts, albeit within the normal reference range. VKAs decrease human HSC engraftment in immunosuppressed mice. Following published examples that alteration of the BMM can lead to hematological malignancies in mice, we describe, without providing a causal link, that the odds of VKA use are higher in patients with vs without a diagnosis of myelodysplastic syndrome (MDS). These results demonstrate that VKA treatment impairs HSC function via impairment of the BMM and the periostin/integrin ß3 axis, possibly associating with increased MDS risk.
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Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Microambiente Celular/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Vitamina K/antagonistas & inibidores , Animais , Anticoagulantes/farmacologia , Biomarcadores , Moléculas de Adesão Celular/metabolismo , Relação Dose-Resposta a Droga , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/metabolismo , Vitamina K/farmacologia , Varfarina/farmacologiaRESUMO
BACKGROUND: Malaria is one of the most prevalent and deadliest illnesses in sub-Saharan Africa. Despite recent gains made towards its control, many African countries still have endemic malaria transmission. This study aimed to assess malaria burden at household level in Kongo central province, Democratic Republic of Congo (DRC), and the impact of community participatory Water, Sanitation and Hygiene (WASH) Action programme. METHODS: Mixed method research was conducted in two semi-rural towns, Mbanza-Ngungu (a WASH action site) and Kasangulu (a WASH control site) in DRC between 1 January 2017 through March 2018, involving 625 households (3,712 household members). Baseline and post-intervention malaria surveys were conducted with the use of World Bank/WHO Malaria Indicator Questionnaire. An action research consisting of a six-month study was carried out which comprised two interventions: a community participatory WASH action programme aiming at eliminating mosquito breeding areas in the residential environment and a community anti-malaria education campaign. The latter was implemented at both study sites. In addition, baseline and post-intervention malaria rapid diagnostic test (RDT) was performed among the respondents. Furthermore, a six-month hospital-based epidemiological study was conducted at selected referral hospitals at each site from 1 January through June 2017 to determine malaria trend. RESULTS: Long-lasting insecticide-treated net (LLIN) was the most commonly used preventive measure (55%); 24% of households did not use any measures. Baseline malaria survey showed that 96% of respondents (heads of households) reported at least one episode occurring in the previous six months; of them only 66.5% received malaria care at a health setting. In the Action Research, mean incident household malaria cases decreased significantly at WASH action site (2.3 ± 2.2 cases vs. 1.2 ± 0.7 cases, respectively; p < 0.05), whereas it remained unchanged at the Control site. Similar findings were observed with RDT results. Data collected from referral hospitals showed high malaria incidence rate, 67.4%. Low household income (ORa = 2.37; 95%CI: 1.05-3.12; p < 0.05), proximity to high risk area for malaria (ORa = 5.13; 95%CI: 2-29-8.07; p < 0.001), poor WASH (ORa = 4.10; 95%CI: 2.11-7.08; p < 0.001) were predictors of household malaria. CONCLUSION: This research showed high prevalence of positive malaria RDT among the responders and high household malaria incidence, which were reduced by a 6-month WASH intervention. DRC government should scale up malaria control strategy by integrating efficient indoor and outdoor preventive measures and improve malaria care accessibility.