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1.
Transplant Cell Ther ; 28(5): 265.e1-265.e9, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35139398

RESUMO

The implementation of dual T-cell depletion comprising 4.5 mg/kg of antithymocyte globulin (ATG), post-transplantation cyclophosphamide, and cyclosporine A for reduced-intensity allogeneic hematopoietic cell transplantation (HCT) independent of donor source in 2015 significantly improved graft-versus-host disease (GVHD) control at our Institution. Further advances were made between 2017 to 2020 in supportive care of allogeneic HCT recipients and were the subject of this study, with 651 adults included. Transplant outcomes were compared between patients who underwent transplantation during Period 1 (2017-2018) and Period 2 (2019-2020). Main changes implemented during the study period were reduction of ATG dose from 4.5 to 2 mg/kg in matched unrelated donor transplants, abandoning of dual T-cell depletion in matched related donor transplants, combining dual T-cell depletion with myeloablative conditioning for selected patients, and reduction of the target therapeutic cyclosporine level from 200 to 400 ng/L to 150 to 250 ng/L. Other improvements included addition of ursodiol until day 100, implementation of a double responsible physician model, and personalized patient supportive care plan focused on activity and calorie intake. The reduction in intensity of GVHD prophylaxis provided comparable acute GVHD and moderate-severe chronic GVHD between both time periods. Altogether the described improvements in transplant methodology and supportive care showed that compared to Period 1, patients transplanted in Period 2 had superior 1-year overall survival, relapse-free survival, and non-relapse mortality and showed a trend toward better GVHD- and relapse-free survival, without an increase in relapse risk. This study reports the results of outcomes-directed improvements in transplantation design, GVHD prophylaxis, and supportive care, highlighting how transplantation outcomes can be improved through careful modifications in response to meticulously monitored outcomes.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Soro Antilinfocitário/uso terapêutico , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos
2.
Surg Infect (Larchmt) ; 23(3): 232-247, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35196154

RESUMO

Background: The principles of antimicrobial stewardship promote the appropriate prescribing of agents with respect to efficacy, safety, duration, and cost. Antibiotic resistance often results from inappropriate use (e.g., indication, selection, duration). We evaluated practice variability in duration of antimicrobials in surgical infection treatment (Rx) or prophylaxis (Px). Hypothesis: There is lack of consensus regarding the duration of antibiotic Px and Rx for many common indications. Methods: A survey was distributed to the Surgical Infection Society (SIS) regarding the use of antimicrobial agents for a variety of scenarios. Standard descriptive statistics were used to compare survey responses. Heterogeneity among question responses were compared using the Shannon Index, expressed as natural units (nats). Results: Sixty-three SIS members responded, most of whom (67%) have held a leadership position within the SIS or contributed as an annual meeting moderator or discussant; 76% have been in practice for more than five years. Regarding peri-operative Px, more than 80% agreed that a single dose is adequate for most indications, with the exceptions of gangrenous cholecystitis (40% single dose, 38% pre-operative +24 hours) and inguinal hernia repair requiring a bowel resection (70% single dose). There was more variability regarding the use of antibiotic Px for various bedside procedures with respondents split between none needed (range, 27%-66%) versus a single dose (range, 31%-67%). Opinions regarding the duration of antimicrobial Rx for hospitalized patients who have undergone a source control operation or procedure varied widely based on indication. Only two of 20 indications achieved more than 60% consensus despite available class 1 evidence: seven days for ventilator-associated pneumonia (77%), and four plus one days for perforated appendicitis (62%). Conclusions: Except for peri-operative antibiotic Px, there is little consensus regarding antibiotic duration among surgical infection experts, despite class 1 evidence and several available guidelines. This highlights the need for further high-level research and better dissemination of guidelines.


Assuntos
Anti-Infecciosos , Cirurgiões , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Antibioticoprofilaxia , Consenso , Humanos , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/prevenção & controle
3.
NAR Genom Bioinform ; 4(1): lqab125, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35156021

RESUMO

Deep targeted sequencing technologies are still not widely used in clinical practice due to the complexity of the methods and their cost. The Molecular Inversion Probes (MIP) technology is cost effective and scalable in the number of targets, however, suffers from low overall performance especially in GC rich regions. In order to improve the MIP performance, we sequenced a large cohort of healthy individuals (n = 4417), with a panel of 616 MIPs, at high depth in duplicates. To improve the previous state-of-the-art statistical model for low variant allele frequency, we selected 4635 potentially positive variants and validated them using amplicon sequencing. Using machine learning prediction tools, we significantly improved precision of 10-56.25% (P < 0.0004) to detect variants with VAF > 0.005. We further developed biochemically modified MIP protocol and improved its turn-around-time to ∼4 h. Our new biochemistry significantly improved uniformity, GC-Rich regions coverage, and enabled 95% on target reads in a large MIP panel of 8349 genomic targets. Overall, we demonstrate an enhancement of the MIP targeted sequencing approach in both detection of low frequency variants and in other key parameters, paving its way to become an ultrafast cost-effective research and clinical diagnostic tool.

4.
Eur J Haematol ; 108(5): 430-436, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35100661

RESUMO

INTRODUCTION: Increasing survival of patients with multiple myeloma (MM) has resulted in an increased recognition of therapy-related hematological malignancies (t-MDS/AML, t-ALL, and t-CMML). There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HCT) in this patient population. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent HCT for t-MDS/AML, t-ALL, and t-CMML developing after receiving treatment for MM at our center. Patients were analyzed for myeloma characteristics and therapy, time to diagnosis of therapy-related hematological neoplasms, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS). RESULTS: Twenty patients underwent HCT for therapy-related hematological malignancies after MM (t-MDS/AML = 13, t-ALL = 6, t-CMML = 1). Median(range) age at time of transplant was 62.5 (49-73) years and 70% (n = 14) were male. The most common cytogenetic abnormality was complex/monosomal karyotype in 30% (n = 6) followed by monosomy/deletion of chromosome 5 or 7 in 15% (n = 3) of patients each. Donors were human leukocyte antigen matched (10/10 or 6/6) siblings in 30% (n = 6), unrelated in 60% (n = 12) and haploidentical in 10% (n = 2) patients. Estimated 2-year OS and RFS for the whole cohort were 53.1% and 47.2% respectively. There was a trend toward better survival in patients with t-ALL when compared to t-MDS/AML; however, the difference was not statistically significant. We did not find any pre-transplant or post-transplant factors that were predictive of survival outcomes after multivariate analysis. CONCLUSIONS: Allogeneic HCT provides substantial long-term disease-free survival in a proportion of patients with MM-associated therapy-related hematological malignancies. Multicenter studies with more patients and longer follow-up may provide additional information about factors affecting outcomes.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mieloma Múltiplo , Segunda Neoplasia Primária , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos
5.
Am Surg ; : 31348221074242, 2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35099317

RESUMO

BACKGROUND: Since 2013, we have offered a robust "Introduction to Surgery" elective (ITS) for preclinical medical students. The present study investigates whether participants of the ITS elective were more likely to match into surgical residencies than non-ITS participants. METHODS: This is a retrospective case-control study of medical students from two medical schools in Southern California who participated in the ITS elective and those who did not. Descriptive results and univariate analysis using STATA were utilized to analyze the de-identified data who matched between 2016 and 2021 were included. RESULTS: Overall, 87 (8.9%) of the 982 matched students participated in the ITS elective, with an increase in participation from 1.2% in 2016 to 13.9% in 2021 (P < .001). Among ITS participants, 49.4% matched into a surgical specialty compared to only 22.9% for non-ITS students (P < .001). There was no difference between ITS and non-ITS students with regards to procedural specialty match (14.9% vs 12.6%, P = .537). CONCLUSION: ITS participants were more than twice as likely to match into a surgical specialty than non-participants. Future qualitative research will help discern the relative impact of the ITS course versus a student's baseline predisposition to surgery.

6.
Pediatr Emerg Care ; 38(1): e287-e291, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33105460

RESUMO

OBJECTIVES: Helicopter emergency medical services (HEMS) are used for 16% of pediatric trauma. National HEMS guidelines advised that triage criteria be standardized for pediatric patients. A national report found pediatric HEMS associated with decreased mortality compared with ground emergency medical services (GEMS) but did not control for transport time. We hypothesized that the rate of HEMS has decreased nationally and the mortality risk for HEMS to be similar when adjusting for transport time compared with GEMS. METHODS: The Pediatric Trauma Quality Improvement Program (2014-2016) was queried for patients younger than 16 years transported by HEMS or GEMS. A multivariable logistic regression was used. RESULTS: From 25,647 patients, 4527 (17.7%) underwent HEMS. The rate of HEMS from scene decreased from 21.2% in 2014 to 18.2% in 2016. The rate of HEMS for minor trauma (Injury Severity Score <15) decreased from 14.9% in 2014 to 13.5% in 2016 and major trauma (Injury Severity Score > 15) from 38.4% in 2014 to 35.9% in 2016. After controlling for predictors of mortality and transport time, HEMS was associated with decreased risk of mortality for only those with major injuries transferred from scene (odds ratio, 0.48; 95% confidence interval, 0.26-0.88; P = 0.01) compared with GEMS. CONCLUSIONS: The rate of HEMS in pediatric trauma has decreased. However, there is room for improvement as 14% of those with minor trauma are transported by HEMS. Given the similar risk of mortality compared with GEMS, further development of guidelines that avoid the unnecessary use of HEMS appears warranted. However, utilization of HEMS for transport of pediatric major trauma should continue.


Assuntos
Resgate Aéreo , Serviços Médicos de Emergência , Ferimentos e Lesões , Aeronaves , Criança , Humanos , Escala de Gravidade do Ferimento , Estudos Retrospectivos , Centros de Traumatologia , Ferimentos e Lesões/terapia
7.
Pediatr Emerg Care ; 38(1): e360-e364, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181791

RESUMO

OBJECTIVES: Only 21 states have mandatory helmet laws for pediatric bicyclists. This study sought to determine the incidence of helmeted riders among pediatric bicyclists involved in a collision and hypothesized the risk of a serious head and cervical spine injuries to be higher in nonhelmeted bicyclists (NHBs) compared with helmeted bicyclists (HBs). METHODS: The Pediatric Trauma Quality Improvement Program (2014-2016) was queried for pediatric (age <16 years) bicyclists involved in a collision. Helmeted bicyclists were compared with NHBs. A serious injury was defined by an abbreviated injury scale grade of greater than 2. RESULTS: From 3693 bicyclists, 3039 (82.3%) were NHBs. Compared with HBs, NHBs were more often Black (21.6% vs 3.8%, P < 0.001), Hispanic (17.5% vs 9.3%, P < 0.001), without insurance (4.6% vs 2.4%, P = 0.012), and had a higher rate of a serious head injury (24.6% vs 9.3%, P < 0.001). Both groups had similar rates of complications and mortality (P > 0.05). The associated risk of a serious head (odds ratio = 3.17, P < 0.001) and spine injury (odds ratio = 0.41, P = 0.012) were higher and lower respectively in NHBs. Associated risks for cervical spine fracture or cord injury were similar (P > 0.05). CONCLUSIONS: Pediatric bicyclists involved in a collision infrequently wear helmets, and NHBs was associated with higher risks of serious head injury. However, the associated risk of serious spine injury among NHBs was lower. The associated risks for cervical spine fracture or cervical cord injuries were similar. Nonhelmeted bicyclists were more likely to lack insurance and to be Black or Hispanic. Targeted outreach programs may help decrease the risk of injury, especially in at-risk demographics.


Assuntos
Traumatismos Craniocerebrais , Traumatismos da Coluna Vertebral , Acidentes de Trânsito , Adolescente , Ciclismo , Vértebras Cervicais/lesões , Criança , Traumatismos Craniocerebrais/epidemiologia , Traumatismos Craniocerebrais/etiologia , Traumatismos Craniocerebrais/prevenção & controle , Dispositivos de Proteção da Cabeça , Humanos , Traumatismos da Coluna Vertebral/epidemiologia , Traumatismos da Coluna Vertebral/etiologia
8.
Transplant Cell Ther ; 28(1): 50.e1-50.e8, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34656808

RESUMO

This study investigated the single-center incidence and risk factors for bloodstream infections (BSIs) in 651 adults who underwent allogeneic hematopoietic cell transplantation (alloHCT) between 2015 and 2019 and explored the impact of these BSIs on post-transplantation outcomes. Antibiotic prophylaxis with ciprofloxacin was given during the aplastic phase. Overall, the median patient age was 57 years, 79.7% of patients received an alternative donor graft, and 68.7% received post-transplantation cyclophosphamide (PTCy) as part of their graft-versus-host disease (GVHD) prophylaxis. Of the 651 patients, 358 (55.0%) had at least 1 episode of BSI, and the overall mortality rate secondary to this complication was 7.5% (12.6% among those diagnosed with at least 1 episode of BSI). BSI was more often diagnosed during the first 30 days (58.7%), and gram-positive bacteria were the most prevalent microorganisms isolated during the entire post-transplantation follow-up (62%). A high Disease Risk Index (hazard ratio [HR], 1.47; P < .029) and receipt of PTCy-based GVHD prophylaxis (HR, 3.33; P < .001) were identified as risk factors for BSI. Additionally, univariate analysis showed that patients diagnosed with a BSI during post-transplantation follow-up had worse overall survival (HR, 2.48; P < .001) and higher nonrelapse mortality (HR, 2.68; P < .001) than those without BSI. In conclusion, alloHCT recipients with a BSI had a higher risk of mortality compared with those who did not develop BSI. The inclusion of PTCy as part of GVHD prophylaxis was identified as an independent risk factor for BSI during early post-transplantation follow-up. Single-center analyses focused on reporting the incidence and risk factors for BSI highlight the need for active implementation of preemptive strategies to decrease BSI incidence in the alloHCT setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Sepse , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Estados Unidos
9.
Nat Mater ; 21(1): 95-102, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34663951

RESUMO

Liquids and solids are two fundamental states of matter. However, our understanding of their three-dimensional atomic structure is mostly based on physical models. Here we use atomic electron tomography to experimentally determine the three-dimensional atomic positions of monatomic amorphous solids, namely a Ta thin film and two Pd nanoparticles. We observe that pentagonal bipyramids are the most abundant atomic motifs in these amorphous materials. Instead of forming icosahedra, the majority of pentagonal bipyramids arrange into pentagonal bipyramid networks with medium-range order. Molecular dynamics simulations further reveal that pentagonal bipyramid networks are prevalent in monatomic metallic liquids, which rapidly grow in size and form more icosahedra during the quench from the liquid to the glass state. These results expand our understanding of the atomic structures of amorphous solids and will encourage future studies on amorphous-crystalline phase and glass transitions in non-crystalline materials with three-dimensional atomic resolution.

10.
Eur Respir J ; 59(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34625477

RESUMO

BACKGROUND: Our purpose was to summarise the prognostic associations between various clinical risk factors and development of acute respiratory distress syndrome (ARDS) following traumatic injury. METHODS: We conducted this review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies) guidelines. We searched six databases from inception through December 2020. We included English language studies describing the clinical risk factors associated with development of post-traumatic ARDS, as defined by either the American-European Consensus Conference or Berlin definition. We pooled adjusted odds ratios for prognostic factors using the random effects method. We assessed risk of bias using the QUIPS (Quality in Prognosis Studies) tool and certainty of findings using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. RESULTS: We included 39 studies involving 5 350 927 patients. We identified the amount of crystalloid resuscitation as a potentially modifiable prognostic factor associated with development of post-traumatic ARDS (adjusted OR 1.19, 95% CI 1.15-1.24 for each additional litre of crystalloid administered within the first 6 h after injury; high certainty). Non-modifiable prognostic factors with a moderate or high certainty of association with post-traumatic ARDS included increasing age, non-Hispanic White race, blunt mechanism of injury, presence of head injury, pulmonary contusion or rib fracture and increasing chest injury severity. CONCLUSIONS: We identified one important modifiable factor, the amount of crystalloid resuscitation within the first 24 h of injury, and several non-modifiable factors associated with development of post-traumatic ARDS. This information should support the judicious use of crystalloid resuscitation in trauma patients and may inform development of risk stratification tools.


Assuntos
Síndrome do Desconforto Respiratório , Soluções Cristaloides , Humanos , Razão de Chances , Prognóstico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Fatores de Risco
11.
J Trauma Acute Care Surg ; 92(3): 561-566, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34554135

RESUMO

BACKGROUND: Existing mortality prediction models have attempted to quantify injury burden following trauma-related admissions with the most notable being the Injury Severity Score (ISS). Although easy to calculate, it requires additional administrative coding. International Classification of Diseases (ICD)-based models such as the Trauma Mortality Prediction Model (TMPM-ICD10) circumvent these limitations, but they use linear modeling, which may not adequately capture the intricate relationships of injuries on mortality. Using ICD-10 coding and machine learning (ML) algorithms, the present study used the National Trauma Data Bank to develop mortality prediction models whose performance was compared with logistic regression, ISS, and TMPM-ICD10. METHODS: The 2015 to 2017 National Trauma Data Bank was used to identify adults following trauma-related admissions. Of 8,021 ICD-10 codes, injuries were categorized into 1,495 unique variables. The primary outcome was in-hospital mortality. eXtreme Gradient Boosting (XGBoost), a ML technique that uses iterations of decision trees, was used to develop mortality models. Model discrimination was compared with logistic regression, ISS, and TMPM-ICD10 using receiver operating characteristic curve and probabilistic accuracy with calibration curves. RESULTS: Of 1,611,063 patients, 54,870 (3.41%) experienced in-hospital mortality. Compared with those who survived, those who died more frequently suffered from penetrating trauma and had a greater number of injuries. The XGBoost model exhibited superior receiver operating characteristic curve (0.863 [95% confidence interval (CI), 0.862-0.864]) compared with logistic regression (0.845 [95% CI, 0.844-0.846]), ISS (0.828 [95% CI, 0.827-0.829]), and TMPM-ICD10 (0.861 [95% CI, 0.860-0.862]) (all p < 0.001). Importantly, the ML model also had significantly improved calibration compared with other methodologies (XGBoost, coefficient of determination (R2) = 0.993; logistic regression, R2 = 0.981; ISS, R2 = 0.649; TMPM-ICD10, R2 = 0.830). CONCLUSION: Machine learning models using XGBoost demonstrated superior performance and calibration compared with logistic regression, ISS, and TMPM-ICD10. Such approaches in quantifying injury severity may improve its utility in mortality prognostication, quality improvement, and trauma research. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; level III.


Assuntos
Classificação Internacional de Doenças , Aprendizado de Máquina , Ferimentos e Lesões/classificação , Ferimentos e Lesões/mortalidade , Conjuntos de Dados como Assunto , Árvores de Decisões , Humanos , Análise de Sobrevida
12.
Clin Lymphoma Myeloma Leuk ; 22(5): e327-e334, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34866020

RESUMO

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for hematological disease however can be complicated by relapse or graft failure (GF), for which second-HCT and donor lymphocyte infusions (DLI) are performed. This study aimed to compare outcomes following the two interventions. METHODS: We retrospectively investigated 89 patients with relapse or GF after first-HCT, 50 (56%) underwent second HCT and 39 (44%) received (DLI), from June 2011 to September 2020. RESULTS: Median age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2 year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%) (P = .03). For DLI patients, 2 year OS was 49% for GF and 45% for relapse patients (P = .49). For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI (P = .07). Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95% CI 0.26%-0.94%, P = .03), KPS at time of intervention (HR 2.10, 95% CI 1.14%-3.85%, P = .02) and time from first-HCT to intervention (HR 0.51, 95% CI 0.28%-0.93%, P = .03) as significant variables. CONCLUSION: Second-HCT may improve outcomes when performed for relapse post-transplant if patients achieve remission again, while DLI may be reserved for patients with active disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Linfócitos , Recidiva Local de Neoplasia , Estudos Retrospectivos
13.
Blood Adv ; 6(1): 100-107, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34768283

RESUMO

Decrease in DNA dioxygenase activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general downregulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, whereas 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was upregulated in MDS and inversely correlated with TET2 expression in wild-type cases. Although TET2 was reduced across all age groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2 deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.


Assuntos
Dioxigenases , Síndromes Mielodisplásicas , DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/genética , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo
14.
Haematologica ; 107(2): 358-370, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34615339

RESUMO

Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Biomarcadores , Crise Blástica/tratamento farmacológico , Epigênese Genética , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
15.
Ann Surg ; 275(1): 19-28, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34387202

RESUMO

PURPOSE: Trauma patients are at high risk of VTE. We summarize the efficacy and safety of LMWH versus UFH for the prevention of VTE in trauma patients. METHODS: We searched 6 databases from inception through March 12, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH versus UFH for thromboprophylaxis in adult trauma patients. We pooled effect estimates across RCTs and observational studies separately, using random-effects model and inverse variance weighting. We assessed risk of bias using the Cochrane tool for RCTs and the Risk of Bias in Non-Randomized Studies (ROBINS)-I tool for observational studies and assessed certainty of findings using Grading of Recommendations, Assessment, Development and Evaluations methodology. RESULTS: We included 4 RCTs (879 patients) and 8 observational studies (306,747 patients). Based on pooled RCT data, compared to UFH, LMWH reduces deep vein thrombosis (RR 0.67, 95% CI 0.50 to 0.88, moderate certainty) and VTE (RR 0.68, 95% CI 0.51 to 0.90, moderate certainty). As compared to UFH, LMWH may reduce pulmonary embolism [adjusted odds ratio from pooled observational studies 0.56 (95% CI 0.50 to 0.62)] and mortality (adjusted odds ratio from pooled observational studies 0.54, 95% CI 0.45 to 0.65), though based on low certainty evidence. There was an uncertain effect on adverse events (RR from pooled RCTs 0.80, 95% CI 0.48 to 1.33, very low certainty) and heparin induced thrombocytopenia [RR from pooled RCTs 0.26 (95% CI 0.03 to 2.38, very low certainty)]. CONCLUSIONS: Among adult trauma patients, LMWH is superior to UFH for deep vein thrombosis and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina/efeitos adversos , Heparina/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Ferimentos e Lesões/complicações , Humanos , Embolia Pulmonar/mortalidade , Embolia Pulmonar/prevenção & controle , Tromboembolia Venosa/mortalidade , Trombose Venosa/mortalidade , Trombose Venosa/prevenção & controle
16.
Br J Haematol ; 196(1): 136-145, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34496035

RESUMO

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.


Assuntos
Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Adulto , Idoso , Biomarcadores Tumorais , Criança , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Indução de Remissão , Falha de Tratamento , Adulto Jovem
17.
Am J Surg ; 223(4): 626-632, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34116794

RESUMO

BACKGROUND: This study aims to compare PTSD prevalence between seven medical specialties and to identify potential risk factors for PTSD. METHODS: A cross-sectional national survey of attending physicians (n = 2216) was conducted and screened for PTSD using the Primary Care PTSD Screen. Stepwise multivariable regression analysis with backward elimination identified potential risk factors. RESULTS: Overall prevalence of PTSD was 14% and ranged from 7% to 18% for psychiatrists and OBGYNs, respectively (p = 0.004). Six potential risk factors for PTSD included: emotional exhaustion, job dissatisfaction, lack of autonomy, working >60 h per week, poor camaraderie, and female gender (p < 0.05). CONCLUSIONS: The prevalence of PTSD in attending physicians is more than double that of the general population. Higher risk specialties include OBGYN and general surgery. Specialty-specific interventions targeted at reducing physician burnout and improving the physician work-environment are needed to improve physician wellness and reduce PTSD.


Assuntos
Esgotamento Profissional , Médicos , Transtornos de Estresse Pós-Traumáticos , Esgotamento Profissional/psicologia , Estudos Transversais , Feminino , Humanos , Satisfação no Emprego , Corpo Clínico Hospitalar , Médicos/psicologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Inquéritos e Questionários
18.
Leuk Lymphoma ; 63(1): 162-169, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34379028

RESUMO

Treatment-free remission is achievable in approximately half of patients with chronic myeloid leukemia who attain a sustained, deep molecular response with tyrosine-kinase inhibitor (TKI) therapy. We aimed to identify potential predictors of future achievement of stable MR4.5, defined as a sustained 4.5-log reduction in BCR-ABL1 transcripts for a minimum of 2 years, in 593 patients treated with imatinib as first-line TKI therapy. In multivariable analyses of patient and disease variables including baseline blood counts, disease phase, additional cytogenetic abnormalities, prior therapy, depth and rapidity of molecular response, the only predictor for future achievement of stable MR4.5 was molecular response at 6 months. In this study, patients failing to attain a molecular response of BCR-ABL1≤ 0.16%IS after 6 months of imatinib therapy were unlikely to subsequently achieve stable MR4.5 with imatinib. Our data suggest that achievement of BCR-ABL1≤ 0.16%IS at 6 months is predictive of future stable MR4.5.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
19.
Genetics ; 220(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34726729

RESUMO

In response to stressful growth conditions of high population density, food scarcity, and elevated temperature, young larvae of nematode Caenorhabditis elegans can enter a developmentally arrested stage called dauer that is characterized by dramatic anatomic and metabolic remodeling. Genetic analysis of dauer formation of C. elegans has served as an experimental paradigm for the identification and characterization of conserved neuroendocrine signaling pathways. Here, we report the identification and characterization of a conserved c-Jun N-terminal Kinase-like mitogen-activated protein kinase (MAPK) pathway that is required for dauer formation in response to environmental stressors. We observed that loss-of-function mutations in the MLK-1-MEK-1-KGB-1 MAPK pathway suppress dauer entry. A loss-of-function mutation in the VHP-1 MAPK phosphatase, a negative regulator of KGB-1 signaling, results in constitutive dauer formation, which is dependent on the presence of dauer pheromone but independent of diminished food levels or elevated temperatures. Our data suggest that the KGB-1 pathway acts in the sensory neurons, in parallel to established insulin and TGF-ß signaling pathways, to transduce the dauer-inducing environmental cues of diminished food levels and elevated temperature.


Assuntos
Caenorhabditis elegans , Animais
20.
Eur J Haematol ; 108(4): 288-297, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34905239

RESUMO

In donor selection for allogeneic stem cell transplant, several factors are considered for potential impact on transplant outcome. Previous publications suggested single HLA-mismatched unrelated donors (MMUD) may be equivalent to 10/10 matched unrelated donors (MUDs). We retrospectively examined factors affecting outcome in a single-center study using ATG followed by post-transplant cyclophosphamide, termed ATG-PTCy, GvHD prophylaxis. Fifty-two patients who received grafts from MMUD and 188 patients transplanted from MUD between January 2015 and December 2019, at Princess Margaret Cancer Centre, Canada, were enrolled. All patients received reduced-intensity conditioning. Overall survival for 9/10 recipients at 2 years was significantly worse, 37.2% versus 68.5% for 10/10 MUDs, p < .001, as were NRM at 1 year 39.5% versus 11.7%, p < .001, and GRFS at 2 years 29.8% versus 58.8%, p < .001, respectively, potentially due to higher incidence of infections including CMV. By multivariable analysis, factors correlating with survival negatively were DRI, and MMUD, whereas for NRM MMUD and increasing age were unfavorable. For GRFS significant unfavorable factors included donor age ≤32 years, female donor to male recipient, DRI high-very high and MMUD. These data suggest that MMUD, primarily HLA-A and HLA-B MMUD, confer significantly inferior outcome despite use of ATG-PTCy. Further development of novel conditioning regimens and GvHD prophylaxis is needed to mitigate these risks.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA-A , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Doadores não Relacionados
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