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1.
PLoS One ; 17(9): e0274615, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107978

RESUMO

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5-10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS causing genes. We have reported that in both the G93A-hSOD1 and G59S-hDCTN1 mouse models, SJL mice demonstrated a more severe phenotype than C57BL6 mice. From reciprocal intercrosses between G93A-hSOD1 transgenic mice on SJL and C57BL6 strains, we identified a major quantitative trait locus (QTL) on mouse chromosome 17 that results in a significant shift in lifespan. In this study we generated reciprocal intercrosses between transgenic G59S-hDCTN1 mice on SJL and C57BL6 strains and identified survival QTLs on mouse chromosomes 17 and 18. The chromosome 17 survival QTL on G93A-hSOD1 and G59S-hDCTN1 mice partly overlap, suggesting that the genetic modifiers located in this region may be shared by these two ALS models despite the fact that motor neuron degeneration is caused by mutations in different proteins. The overlapping region contains eighty-seven genes with non-synonymous variations predicted to be deleterious and/or damaging. Two genes in this segment, NOTCH3 and Safb/SAFB1, have been associated with motor neuron disease. The identification of genetic modifiers of motor neuron disease, especially those modifiers that are shared by SOD1 and dynactin-1 transgenic mice, may result in the identification of novel targets for therapies that can alter the course of this devastating illness.


Assuntos
Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Esclerose Lateral Amiotrófica/metabolismo , Animais , Modelos Animais de Doenças , Complexo Dinactina/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença dos Neurônios Motores/genética , Locos de Características Quantitativas/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética
2.
Adv Health Sci Educ Theory Pract ; 27(1): 107-124, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34533684

RESUMO

Dyslexia is a Specific Learning Difficulty that impacts on reading and writing abilities. During the COVID-19 pandemic, medical schools have been forced to undertake distance learning and assessment. The wider literature suggested that e-learning might pose additional challenges for dyslexic students. Here we explore their overall experiences of learning/studying during this time in a phenomenological study. Five medical students were interviewed in depth and the audio-recordings were transcribed verbatim. Transcripts then underwent an interpretive phenomenological analysis. Our results highlighted a largely positive experience, with an improved culture of togetherness, freedom and sense of control. They also revealed issues with a lack of clinical exposure, potential negative impacts on ranking positions for those with dyslexia, and possible cheating in exams. There are some surprising results-in particular the positive responses to how remote learning was delivered. These seemed to put our participants more on a par with their non-dyslexic colleagues-except in some examinations. It is our hope that medical educators may resist a return to 'the way things have always been done' when the pandemic has resolved, and by doing so, continue to foster this new, positive culture and paradigm shift.


Assuntos
COVID-19 , Dislexia , Estudantes de Medicina , COVID-19/epidemiologia , Dislexia/diagnóstico , Dislexia/epidemiologia , Humanos , Aprendizagem , Pandemias
3.
4.
EMBO Mol Med ; 13(1): e12595, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33270986

RESUMO

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Disfunção Cognitiva , Demência Frontotemporal , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/genética , Disfunção Cognitiva/genética , Humanos , Aprendizado de Máquina
6.
BMC Med Educ ; 19(1): 277, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340792

RESUMO

BACKGROUND: The term 'dyslexia' refers to a condition that impacts upon reading and writing abilities whilst not altering intelligence. Individuals with dyslexia may have difficulties with the speed and accuracy and their reading and writing, amongst other issues. Dyslexia is not automatically considered a disability but is a protected characteristic under the UK Equality Act (2010), and therefore employers and educational institutions are required to provide 'reasonable adjustments' in order to allow individuals to reach their full potential. There is a lack of research on this issue, but what little there is suggests that doctors feel as though any support they received ended when they graduated from medical school. MAIN BODY: A core distinction between medical school and medical practice is the requirement to prescribe medicines as registered medical practitioners. Junior doctors have to master this complex and potentially hazardous skill "on the job", with a perceived lack of support. Here, we open up a debate about the potential impact of dyslexia on prescribing, and the need to find supports that may be effective in enabling doctors with dyslexia prescribe medicines safely and effectively - and thus reach their full potential as medical practitioners and promote patient safety. CONCLUSION: We argue that medical schools and hospitals could immediately provide dyslexia awareness training in both undergraduate and postgraduate settings. We discuss electronic prescribing systems, and conclude that research is required to identify effective supports for junior doctors with dyslexia.


Assuntos
Prescrições de Medicamentos , Dislexia , Segurança do Paciente , Educação Médica , Corpo Clínico Hospitalar
7.
Hum Mol Genet ; 28(7): 1136-1152, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520996

RESUMO

Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.


Assuntos
Paraplegia Espástica Hereditária/genética , Espastina/genética , Animais , Transporte Axonal/fisiologia , Axônios/metabolismo , Modelos Animais de Doenças , Mutação com Ganho de Função/genética , Haploinsuficiência , Haplótipos , Camundongos , Camundongos Transgênicos , Microtúbulos/metabolismo , Proteínas Mutantes/genética , Mutação , Neurônios/metabolismo , Paraplegia Espástica Hereditária/fisiopatologia , Espastina/fisiologia
8.
Neurobiol Aging ; 73: 190-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368160

RESUMO

The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe-mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.


Assuntos
Esclerose Lateral Amiotrófica/genética , Degeneração Lobar Frontotemporal/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético/genética , Idoso , Alelos , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Proteínas de Ligação a DNA/genética , Feminino , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/etiologia , Degeneração Lobar Frontotemporal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Prognóstico , Risco
9.
Crit Care Med ; 45(12): 1989-1996, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28837430

RESUMO

OBJECTIVE: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. DESIGN: Prospective observational cohort study (NCT01810328). SETTING: Two level-one trauma centers in the United States. PATIENTS: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long-term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95). CONCLUSIONS: Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.


Assuntos
Doença Crônica/epidemiologia , Estado Terminal/epidemiologia , Unidades de Terapia Intensiva/estatística & dados numéricos , Centros de Traumatologia/estatística & dados numéricos , Ferimentos não Penetrantes/epidemiologia , Adulto , Fatores Etários , Idoso , Transfusão de Sangue/estatística & dados numéricos , Doença Crônica/mortalidade , Estado Terminal/mortalidade , Infecção Hospitalar/epidemiologia , Feminino , Humanos , Hipotensão/epidemiologia , Escala de Gravidade do Ferimento , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/epidemiologia , Alta do Paciente , Prognóstico , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Choque Hemorrágico/epidemiologia , Ferimentos não Penetrantes/mortalidade
10.
Clin Infect Dis ; 64(7): 877-885, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28034881

RESUMO

BACKGROUND: Shock frequently complicates necrotizing fasciitis (NF) caused by group A Streptococcus (GAS) or Staphylococcus aureus. Intravenous immunoglobulin (IVIG) is sometimes administered for presumptive toxic shock syndrome (TSS), but its frequency of use and efficacy are unclear. METHODS: Adult patients with NF and vasopressor-dependent shock undergoing surgical debridement from 2010 to 2014 were identified at 130 US hospitals. IVIG cases were propensity-matched and risk-adjusted. The primary outcome was in-hospital mortality and the secondary outcome was median length of stay (LOS). RESULTS: Of 4127 cases of debrided NF with shock at 121 centers, only 164 patients (4%) at 61 centers received IVIG. IVIG subjects were younger with lower comorbidity indices, but higher illness severity. Clindamycin and vasopressor intensity were higher among IVIG cases, as was coding for TSS and GAS. In-hospital mortality did not differ between matched IVIG and non-IVIG groups (crude mortality, 27.3% vs 23.6%; adjusted odds ratio, 1.00 [95% confidence interval, .55-1.83]; P = .99). Early IVIG (≤2 days) did not alter this effect (P = .99). Among patients coded for TSS, GAS, and/or S. aureus, IVIG use was still unusual (59/868 [6.8%]) and lacked benefit (P = .63). Median LOS was similar between IVIG and non-IVIG groups (26 [13-49] vs 26 [11-43]; P = .84). Positive predictive values for identifying true NF and debridement among IVIG cases using our algorithms were 97% and 89%, respectively, based on records review at 4 hospitals. CONCLUSIONS: Adjunctive IVIG was administered infrequently in NF with shock and had no apparent impact on mortality or hospital LOS beyond that achieved with debridement and antibiotics.


Assuntos
Fasciite Necrosante/complicações , Fasciite Necrosante/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Choque/complicações , Choque/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Fasciite Necrosante/diagnóstico , Fasciite Necrosante/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pontuação de Propensão , Estudos Retrospectivos , Índice de Gravidade de Doença , Choque/diagnóstico , Choque/mortalidade , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , Staphylococcus aureus , Streptococcus pyogenes , Resultado do Tratamento , Estados Unidos , Adulto Jovem
11.
Proc Natl Acad Sci U S A ; 110(9): 3507-12, 2013 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-23401516

RESUMO

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.


Assuntos
Genômica , Inflamação/genética , Doença Aguda , Adolescente , Adulto , Animais , Queimaduras/genética , Queimaduras/patologia , Modelos Animais de Doenças , Endotoxemia/genética , Endotoxemia/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/genética , Fatores de Tempo , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia , Adulto Jovem
12.
Ann Surg ; 255(5): 993-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22470077

RESUMO

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in trauma care at 7 academic level I trauma centers in which patients were treated on the basis of a series of standard operating procedures (SOPs). BACKGROUND: Injury remains the leading cause of death for those younger than 45 years. This study describes the baseline patient characteristics and well-defined outcomes of persons hospitalized in the United States for severe blunt trauma. METHODS: We followed 1637 trauma patients from 2003 to 2009 up to 28 hospital days using SOPs developed at the onset of the study. An extensive database on patient and injury characteristics, clinical treatment, and outcomes was created. These data were compared with existing trauma benchmarks. RESULTS: The study patients were critically injured and were in shock. SOP compliance improved 10% to 40% during the study period. Multiple organ failure and mortality rates were 34.8% and 16.7%, respectively. Time to recovery, defined as the time until the patient was free of organ failure for at least 2 consecutive days, was developed as a new outcome measure. There was a reduction in mortality rate in the cohort during the study that cannot be explained by changes in the patient population. CONCLUSIONS: This study provides the current benchmark and the overall positive effect of implementing SOPs for severely injured patients. Over the course of the study, there were improvements in morbidity and mortality rates and increasing compliance with SOPs. Mortality was surprisingly low, given the degree of injury, and improved over the duration of the study, which correlated with improved SOP compliance.


Assuntos
Benchmarking , Avaliação de Resultados em Cuidados de Saúde , Procedimentos Cirúrgicos Operatórios/normas , Ferimentos não Penetrantes/cirurgia , APACHE , Adulto , Estado Terminal , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/epidemiologia , Ferimentos não Penetrantes/mortalidade , Adulto Jovem
13.
J Exp Med ; 208(13): 2581-90, 2011 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-22110166

RESUMO

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.


Assuntos
Queimaduras/metabolismo , Regulação da Expressão Gênica , Genoma Humano , Leucócitos/metabolismo , Transcrição Gênica , Imunidade Adaptativa , Adulto , Queimaduras/imunologia , Queimaduras/patologia , Estado Terminal , Endotoxinas/administração & dosagem , Feminino , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Leucócitos/imunologia , Masculino , Índices de Gravidade do Trauma
14.
Shock ; 34(4): 346-51, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20844410

RESUMO

Excessive proinflammatory activation after trauma plays a role in late morbidity and mortality, including the development of multiple organ dysfunction syndrome (MODS). To date, identification of patients at risk has been challenging. Results from animal and human studies suggest that circulating interleukin 6 (IL-6) may serve as a biomarker for excessive inflammation. The purpose of this analysis was to determine the association of IL-6 with outcome in a multicenter developmental cohort and in a single-center validation cohort. Severely injured patients with shock caused by hemorrhage were evaluated within a multicenter developmental cohort (n = 79). All had blood drawn within 12 h of injury. Plasma IL-6 was determined by multiplex proteomic analysis. Clinical and outcome data were prospectively obtained. Within this developmental cohort, a plasma IL-6 level was determined for the subsequent development of MODS by developing a receiver operating curve and defining the optimal IL-6 level using the Youden Index. This IL-6 level was then evaluated within a separate validation cohort (n = 56). A receiver operating curve was generated for IL-6 and MODS development, with an IL-6 level of 350 pg/mL having the highest sensitivity and specificity within the developmental cohort. IL-6 was associated with MODS after adjusting for Acute Physiology and Chronic Health Evaluation, Injury Severity Score, male sex, and blood transfusions with an odds ratio of 3.9 (95% confidence interval, 1.33 - 11.19). An IL-6 level greater than 350 pg/mL within the validation cohort was associated with an increase in MODS score, MODS development, ventilator days, intensive care unit length of stay, and hospital length of stay. However, this IL-6 level was not associated with either the development of nosocomial infection or mortality. Elevation in plasma IL-6 seems to correlate with a poor prognosis. This measurement may be useful as a biomarker for prognosis and serve to identify patients at higher risk of adverse outcome that would benefit from novel therapeutic interventions.


Assuntos
Interleucina-6/sangue , Insuficiência de Múltiplos Órgãos/sangue , Adulto , Feminino , Hemorragia/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Choque/sangue , Choque/etiologia , Adulto Jovem
15.
Ann Surg ; 250(4): 531-9, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19730236

RESUMO

OBJECTIVE: We hypothesized that circulating leukocyte RNA profiles or "riboleukograms" detect ventilator-associated pneumonia after blunt trauma. SUMMARY BACKGROUND DATA: A pilot microarray study of 11 ventilator-associated pneumonia (VAP) patients suggested that 85 leukocyte genes can be used to diagnose VAP. Validation of this gene set to detect VAP was tested using data from an independent patient cohort. METHODS: A total of 158 intubated blunt trauma patients were enrolled at 5 centers, where 57 (36%) developed VAP. Patient age was 34.2 ± 11.1 years; 65% were male. Circulating leukocyte GeneChip U133 2.0 expression values were measured at time 0.5, 1, 4, 7, 14, 21, and 28 days after injury. DChip normalized leukocyte transcriptional profiles were analyzed using repeated measures logistic regression. A compound covariate model based on leukocyte gene transcriptional profiles in a training subset of patients was tested to determine predictive accuracy for VAP 4 days prior to clinical diagnosis in the test subset. RESULTS: Using gene expression values measured on each study day at an FDR <0.05, 27 (32%) of the 85 genes were associated with the diagnosis of VAP 1 to 4 days before diagnosis. However, the compound covariate model based on these 85-genes did not predict VAP in the test cohort better than chance (P = 0.27). In contrast, a compound covariate model based upon de novo transcriptional analysis of the 158 patients predicted VAP better than chance 4 days before diagnosis with a sensitivity of 57% and a specificity of 69%. CONCLUSION: Our results validate those described in a pilot study, confirming that riboleukograms are associated with the development of VAP days prior to clinical diagnosis. Similarly, a riboleukogram predictive model tested on a larger cohort of 158 patients was better than chance at predicting VAP days prior to clinical diagnosis.


Assuntos
Técnicas de Diagnóstico do Sistema Respiratório , Perfilação da Expressão Gênica/métodos , Leucócitos , Pneumonia Associada à Ventilação Mecânica/diagnóstico , RNA/genética , Ferimentos não Penetrantes/complicações , Adulto , Feminino , Humanos , Intubação Intratraqueal , Masculino , Valor Preditivo dos Testes , Sensibilidade e Especificidade
16.
Mol Med ; 15(7-8): 220-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19593405

RESUMO

Traumatic injuries frequently lead to infection, organ failure, and death. Health care providers rely on several injury scoring systems to quantify the extent of injury and to help predict clinical outcome. Physiological, anatomical, and clinical laboratory analytic scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE], Injury Severity Score [ISS]) are utilized, with limited success, to predict outcome following injury. The recent development of techniques for measuring the expression level of all of a person's genes simultaneously may make it possible to develop an injury scoring system based on the degree of gene activation. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. To test such a scoring system, we measured gene expression of peripheral blood leukocytes from patients within 12 h of traumatic injury. cRNA derived from whole blood leukocytes obtained within 12 h of injury provided gene expression data for the entire genome that were used to create a composite gene expression score for each patient. Total blood leukocytes were chosen because they are active during inflammation, which is reflective of poor outcome. The gene expression score combines the activation levels of all the genes into a single number which compares the patient's gene expression to the average gene expression in uninjured volunteers. Expression profiles from healthy volunteers were averaged to create a reference gene expression profile which was used to compute a difference from reference (DFR) score for each patient. This score described the overall genomic response of patients within the first 12 h following severe blunt trauma. Regression models were used to compare the association of the DFR, APACHE, and ISS scores with outcome. We hypothesized that patients with a total gene response more different from uninjured volunteers would tend to have poorer outcome than those more similar. Our data show that for measures of poor outcome, such as infections, organ failures, and length of hospital stay, this is correct. DFR scores were associated significantly with adverse outcome, including multiple organ failure, duration of ventilation, length of hospital stay, and infection rate. The association remained significant after adjustment for injury severity as measured by APACHE or ISS. A single score representing changes in gene expression in peripheral blood leukocytes within hours of severe blunt injury is associated with adverse clinical outcomes that develop later in the hospital course. Assessment of genome-wide gene expression provides useful clinical information that is different from that provided by currently utilized anatomic or physiologic scores.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Perfilação da Expressão Gênica/métodos , Traumatismos Cranianos Fechados/diagnóstico , Traumatismos Cranianos Fechados/genética , Índices de Gravidade do Trauma , Adolescente , Adulto , Feminino , Genômica/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico
17.
J Am Coll Surg ; 207(5): 690-7, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18954781

RESUMO

BACKGROUND: Damage-control laparotomy has become increasingly common after operative resuscitation of severe hemorrhagic shock after injury. Despite increased use, uncertainty exists about the safety and timing of enteral nutrition. The purpose of this study was to determine the safety and effect of immediate enteral nutrition. STUDY DESIGN: Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury and were limited to patients with an open abdomen and no hollow viscus injury. The immediate enteral nutrition cohort was defined as initiation of enteral feeds within 36 hours after acute resuscitation completion. Multivariate stepwise logistic regression was used to evaluate factors associated with immediate enteral nutrition. RESULTS: One hundred subjects met inclusion criteria; 32 immediate enteral nutrition and 68 nonimmediate enteral nutrition. Nearly all patients underwent fascial closure (93.8% immediate enteral nutrition versus 94.1% nonimmediate enteral nutrition), with an average closure day of 6.47 +/- 0.83 with immediate enteral nutrition and 8.55 +/- 0.85 with nonimmediate enteral nutrition (p = 0.129). No significant difference in multiorgan dyfunction syndrome, length of ventilator days, ICU days, hospital days, or mortality was seen between groups. The rate of pneumonia was significantly different: 14 (43.8%) in immediate enteral nutrition and 49 (72.1%) in nonimmediate enteral nutrition (p = 0.008). Immediate enteral nutrition remained independently associated with a reduction in pneumonia within our stepwise regression (odds ratio = 0.32; 95% CI, 0.13 to 0.79). CONCLUSIONS: Immediate enteral nutrition after damage control appears safe, with no effect on abdominal closure rate. In addition, the reduction in pneumonia associated with immediate enteral nutrition suggests a tangible benefit. Immediate enteral nutrition should be considered in patients with open abdomens after severe trauma.


Assuntos
Traumatismos Abdominais/terapia , Nutrição Enteral/métodos , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Choque Hemorrágico/terapia , Traumatismos Abdominais/complicações , Adulto , Estudos de Coortes , Feminino , Humanos , Laparotomia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Choque Hemorrágico/etiologia , Fatores de Tempo , Resultado do Tratamento
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