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1.
J Matern Fetal Neonatal Med ; 37(1): 2333923, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38584143

RESUMO

OBJECTIVE: To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam. METHODS: Women with singleton pregnancies (n = 5000) were recruited between 19+0-23+6 weeks' gestation at Tu Du Hospital, Ho Chi Minh City. Maternal serum was collected from 19+0-22+6 weeks' gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks' gestation were tested, with model tuning using clinical factors. Measured outcomes included all PTBs (any birth ≤37 weeks' gestation) and spontaneous PTBs (birth ≤37 weeks' gestation with clinical signs of initiation of parturition). RESULTS: Complete data were available for 4984 (99.7%) individuals. The cohort PTB rate was 6.7% (n = 335). We observed an inverse association between the IGFBP4/SHBG ratio and gestational age at birth (p = 0.017; AUC 0.60 [95% CI, 0.53-0.68]). Including previous PTB (for multiparous women) or prior miscarriage (for primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks' gestation). Optimal performance (AUC 0.74) was seen within 19-20 weeks' gestation, for BMI >21 kg/m2 and age 20-35 years. CONCLUSION: We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.


Assuntos
Nascimento Prematuro , Gravidez , Recém-Nascido , Humanos , Feminino , Adulto Jovem , Adulto , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/diagnóstico , Estudos de Coortes , Peptídeos Semelhantes à Insulina , Prognóstico , Globulina de Ligação a Hormônio Sexual , Vietnã/epidemiologia , Idade Gestacional , Biomarcadores
2.
J Med Screen ; : 9691413241232899, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38509806

RESUMO

OBJECTIVE: Many population-based breast screening programmes temporarily suspended routine screening following the COVID-19 pandemic onset. This study aimed to describe screening mammography utilisation and the pattern of screen-detected breast cancer diagnoses following COVID-19-related screening disruptions in Ireland. METHODS: Using anonymous aggregate data from women invited for routine screening, three time periods were examined: (1) January-December 2019, (2) January-December 2020, and (3) January-December 2021. Descriptive statistics were conducted and comparisons between groups were performed using chi-square tests. RESULTS: In 2020, screening mammography capacity fell by 67.1% compared to 2019; recovering to 75% of mammograms performed in 2019, during 2021. Compared to 2019, for screen-detected invasive breast cancers, a reduction in Grade 1 (14.2% vs. 17.2%) and Grade 2 tumours (53.4% vs. 58.0%) and an increase in Grade 3 tumours (32.4% vs. 24.8%) was observed in 2020 (p = 0.03); whereas an increase in Grade 2 tumours (63.3% vs. 58.0%) and a reduction in Grade 3 tumours (19.6% vs. 24.8%) was found in 2021 (p = 0.02). No changes in oestrogen receptor-positive or nodal-positive diagnoses were observed; however the proportion of oestrogen/progesterone receptor-positive breast cancers significantly increased in 2020 (76.2%; p < 0.01) and 2021 (78.7%; p < 0.001) compared to 2019 (67.8%). CONCLUSION: These findings demonstrate signs of a grade change for screen-detected invasive breast cancers early in the pandemic, with recovery evident in 2021, and without an increase in nodal positivity. Future studies are needed to determine the COVID-19 impact on long-term breast cancer outcomes including mortality.

3.
J Med Econ ; 25(1): 1255-1266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36377363

RESUMO

OBJECTIVES: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment. METHODS: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p < .05). RESULTS: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% (p = .029) and 8.5% (p = .001), respectively; neonatal costs' point estimate by 16% (p = .098); and moderate-to-severe neonatal morbidity/mortality by 29% (p = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity. CONCLUSIONS: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.


Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of illness and death in newborns. In the United States, more than 10% of infants are born prematurely, and this rate is substantially higher in lower-income, inner-city and Black populations. Prematurity associates with greatly increased risk of short- and long-term medical complications and can generate significant costs throughout the lives of affected children. Annual U.S. health care costs to manage short- and long-term prematurity complications are estimated to exceed $25 billion.Clinical interventions, including case management (increased patient outreach, education and specialist care), pharmacological treatment and their combination can provide benefit to pregnancies at higher risk for preterm birth. Early and sensitive risk detection, however, remains a challenge.We have developed and validated a proteomic biomarker risk predictor for early identification of pregnancies at increased risk of preterm birth. The ACCORDANT study modeled treatments with real-world patient data from a racially and ethnically diverse U.S. population to compare the benefits of risk predictor testing plus clinical intervention for higher-risk pregnancies versus no testing and standard care. Measured outcomes included neonatal and maternal length of hospital stay, associated costs and neonatal morbidity and mortality. The model projected improved outcomes and reduced costs across all subjects, including ethnic and racial minority populations, when predicted higher-risk pregnancies were treated using case management with or without pharmacological treatment. The biomarker risk predictor shows high potential to be a clinically important component of risk stratification for pregnant women, leading to tangible gains in reducing the impact of preterm birth.


Assuntos
Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Nascimento Prematuro/prevenção & controle , Análise Custo-Benefício , Proteômica , Idade Gestacional , Biomarcadores
5.
Allergy ; 77(10): 3061-3069, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35960650

RESUMO

BACKGROUND: IgE-epitope profiling can accurately diagnose clinical peanut allergy. OBJECTIVE: We sought to determine whether sequential (linear) epitope-specific IgE (ses-IgE) profiling can provide probabilities of tolerating discrete doses of peanut protein in allergic subjects undergoing double-blind, placebo-controlled food challenges utilizing PRACTALL dosing. METHODS: Sixty four ses-IgE antibodies were quantified in blood samples using a bead-based epitope assay. A pair of ses-IgEs that predicts Cumulative Tolerated Dose (CTD) was determined using regression in 75 subjects from the discovery cohort. This epitope-based predictor was validated on 331 subjects from five independent cohorts (ages 4-25 years). Subjects were grouped based on their predicted values and probabilities of reactions at each CTD threshold were calculated. RESULTS: In discovery, an algorithm using two ses-IgE antibodies was correlated with CTDs (rho = 0.61, p < .05); this correlation was 0.51 (p < .05) in validation. Using the ses-IgE-based predictor, subjects were assigned into "high," "moderate," or "low" dose-reactivity groups. On average, subjects in the "high" group were four times more likely to tolerate a specific dose, compared with the "low" group. For example, predicted probabilities of tolerating 4, 14, 44, and 144 or 444 mg in the "low" group were 92%, 77%, 53%, 29%, and 10% compared with 98%, 95%, 94%, 88%, and 73% in the "high" group. CONCLUSIONS: Accurate predictions of food challenge thresholds are complex due to factors including limited responder sample sizes at each dose and variations in study-specific challenge protocols. Despite these limitations, an epitope-based predictor was able to accurately identify CTDs and may provide a useful surrogate for peanut challenges.


Assuntos
Arachis , Hipersensibilidade a Amendoim , Adolescente , Adulto , Alérgenos , Arachis/efeitos adversos , Criança , Pré-Escolar , Epitopos , Humanos , Imunoglobulina E , Hipersensibilidade a Amendoim/diagnóstico , Probabilidade , Adulto Jovem
6.
J Clin Med ; 11(10)2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35629011

RESUMO

The clinical management of pregnancy and spontaneous preterm birth (sPTB) relies on estimates of gestational age (GA). Our objective was to evaluate the effect of GA dating uncertainty on the observed performance of a validated proteomic biomarker risk predictor, and then to test the generalizability of that effect in a broader range of GA at blood draw. In a secondary analysis of a prospective clinical trial (PAPR; NCT01371019), we compared two GA dating categories: both ultrasound and dating by last menstrual period (LMP) (all subjects) and excluding dating by LMP (excluding LMP). The risk predictor's performance was observed at the validated risk predictor threshold both in weeks 191/7-206/7 and extended to weeks 180/7-206/7. Strict blinding and independent statistical analyses were employed. The validated biomarker risk predictor showed greater observed sensitivity of 88% at 75% specificity (increases of 17% and 1%) in more reliably dated (excluding-LMP) subjects, relative to all subjects. Excluding dating by LMP significantly improved the sensitivity in weeks 191/7-206/7. In the broader blood draw window, the previously validated risk predictor threshold significantly stratified higher and lower risk of sPTB, and the risk predictor again showed significantly greater observed sensitivity in excluding-LMP subjects. These findings have implications for testing the performance of models aimed at predicting PTB.

7.
J Clin Med ; 10(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34768605

RESUMO

Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of -1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB (p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan-Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth (p < 001, p = 0.0016) and rate of hospital discharge for both neonate (p < 0.001, p = 0.005) and mother (p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 (p = 0.0083,) and 7.4-fold higher (p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes.

8.
Allergy ; 76(12): 3789-3797, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33991353

RESUMO

BACKGROUND: Accurate diagnosis of peanut allergy is a significant clinical challenge. Here, a novel diagnostic blood test using the peanut bead-based epitope assay ("peanut BBEA") was developed utilizing the LEAP cohort and then validated using two independent cohorts. METHODS: The development of the peanut BBEA diagnostic test followed the National Academy of Medicine's established guidelines with discovery performed on 133 subjects from the non-interventional arm of the LEAP trial and an independent validation performed on 82 subjects from the CoFAR2 and 84 subjects from the POISED study. All samples were analyzed using the peanut BBEA methodology, which measures levels of IgE to two Ara h 2 sequential (linear) epitopes and compares their combination to a threshold pre-specified in the model development phase. When a patient has an inconclusive outcome by skin prick testing (or sIgE), IgE antibody levels to this combination of two epitopes can distinguish whether the patient is "Allergic" or "Not Allergic." Diagnoses of peanut allergy in all subjects were confirmed by double-blind placebo-controlled food challenge and subjects' ages were 7-55 years. RESULTS: In the validation using CoFAR2 and POISED cohorts, the peanut BBEA diagnostic test correctly diagnosed 93% of the subjects, with a sensitivity of 92%, specificity of 94%, a positive predictive value of 91%, and negative predictive value of 95%. CONCLUSIONS: In validation of the peanut BBEA diagnostic test, the overall accuracy was found to be superior to existing diagnostic tests for peanut allergy including skin prick testing, peanut sIgE, and peanut component sIgE testing.


Assuntos
Mapeamento de Epitopos , Hipersensibilidade a Amendoim , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Hipersensibilidade a Amendoim/diagnóstico , Reprodutibilidade dos Testes , Adulto Jovem
9.
Am Surg ; 84(6): 1079-1085, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981652

RESUMO

Centers for disease control (CDC) Guidelines for Field Triage are effective when proper implementation by EMS personnel is paired with surgeon willingness to care for trauma victims. We hypothesized that in a state with an immature trauma system, a discrepancy exists between medic and surgeon perception of surgical readiness, coinciding with inconsistent implementation of protocols. Surveys were conducted among medics and general surgeons. Destination protocols, trauma center locations, surgeon readiness, and interest in trauma were assessed. A standard clinical trauma scenario was also used. Surgeon willingness to operate is not affected by working outside of trauma centers or interest in trauma. Medics working far from trauma centers are less confident in local surgeon's willingness to operate and less likely to have destination protocols. Trauma center proximity affects medic perception of surgeon willingness to operate, but mere presence of general surgeons does not. In a trauma scenario, surgeon willingness to operate was related to medic perception but not action. In rural states, most surgeons do not work in trauma centers and most medics do not work near them. Although most responding surgeons indicate willingness to operate, medics are confident of such willingness only half the time. This disparity results in inconsistent use of the CDC guidelines. Although most medics report protocols for destination determination, nearly one-fourth of victims are taken to the geographically closest centers, sometimes with no surgeon at all. Efforts at medic training, enhancing surgeon readiness, and alignment of goals are necessary for the CDC Guidelines to be effective.


Assuntos
Atitude do Pessoal de Saúde , Auxiliares de Emergência/psicologia , Cirurgiões/psicologia , Transporte de Pacientes , Triagem , Ferimentos e Lesões/cirurgia , Competência Clínica , Protocolos Clínicos , Humanos , Kentucky , Transferência da Responsabilidade pelo Paciente , Volição
10.
Chest ; 154(3): 491-500, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29496499

RESUMO

BACKGROUND: Lung nodules are a diagnostic challenge, with an estimated yearly incidence of 1.6 million in the United States. This study evaluated the accuracy of an integrated proteomic classifier in identifying benign nodules in patients with a pretest probability of cancer (pCA) ≤ 50%. METHODS: A prospective, multicenter observational trial of 685 patients with 8- to 30-mm lung nodules was conducted. Multiple reaction monitoring mass spectrometry was used to measure the relative abundance of two plasma proteins, LG3BP and C163A. Results were integrated with a clinical risk prediction model to identify likely benign nodules. Sensitivity, specificity, and negative predictive value were calculated. Estimates of potential changes in invasive testing had the integrated classifier results been available and acted on were made. RESULTS: A subgroup of 178 patients with a clinician-assessed pCA ≤ 50% had a 16% prevalence of lung cancer. The integrated classifier demonstrated a sensitivity of 97% (CI, 82-100), a specificity of 44% (CI, 36-52), and a negative predictive value of 98% (CI, 92-100) in distinguishing benign from malignant nodules. The classifier performed better than PET, validated lung nodule risk models, and physician cancer probability estimates (P < .001). If the integrated classifier results were used to direct care, 40% fewer procedures would be performed on benign nodules, and 3% of malignant nodules would be misclassified. CONCLUSIONS: When used in patients with lung nodules with a pCA ≤ 50%, the integrated classifier accurately identifies benign lung nodules with good performance characteristics. If used in clinical practice, invasive procedures could be reduced by diverting benign nodules to surveillance. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov).


Assuntos
Biomarcadores/sangue , Neoplasias Pulmonares/sangue , Nódulos Pulmonares Múltiplos/sangue , Proteínas de Neoplasias/sangue , Proteômica/métodos , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade
11.
Curr Opin Biotechnol ; 51: 123-129, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29427919

RESUMO

Recently, the first two multiplexed tests using selective reaction monitoring (SRM-MS) mass spectrometry have entered clinical practice. Despite different areas of indication, risk stratification in lung cancer and preterm birth, they share multiple steps in their development strategies. Here we review these strategies and their implications for successful translation of biomarkers to clinical practice. We believe that the identification of blood protein panels for the identification of disease phenotypes is now a reproducible and standard (albeit complex) process.


Assuntos
Biomarcadores/análise , Proteínas Sanguíneas/análise , Neoplasias/diagnóstico , Proteômica/métodos , Humanos , Neoplasias/sangue , Medicina de Precisão
12.
PLoS One ; 12(5): e0177635, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28545097

RESUMO

It is estimated that over 1.5 million lung nodules are detected annually in the United States. Most of these are benign but frequently undergo invasive and costly procedures to rule out malignancy. A risk predictor that can accurately differentiate benign and malignant lung nodules could be used to more efficiently route benign lung nodules to non-invasive observation by CT surveillance and route malignant lung nodules to invasive procedures. The majority of risk predictors developed to date are based exclusively on clinical risk factors, imaging technology or molecular markers. Assessed here are the relative performances of previously reported clinical risk factors and proteomic molecular markers for assessing cancer risk in lung nodules. From this analysis an integrated model incorporating clinical risk factors and proteomic molecular markers is developed and its performance assessed on a subset of 222 lung nodules, between 8mm and 20mm in diameter, collected in a previously reported prospective study. In this analysis it is found that the molecular marker is most predictive. However, the integration of clinical and molecular markers is superior to both clinical and molecular markers separately. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT01752101).


Assuntos
Pneumopatias/diagnóstico , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiplos/patologia , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Pneumopatias/metabolismo , Pneumopatias/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/metabolismo , Estudos Prospectivos , Proteômica , Curva ROC , Fatores de Risco , Tomografia Computadorizada por Raios X
13.
Biopolymers ; 108(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27539157

RESUMO

We report on peptide-based ligands matured through the protein catalyzed capture (PCC) agent method to tailor molecular binders for in vitro sensing/diagnostics and in vivo pharmacokinetics parameters. A vascular endothelial growth factor (VEGF) binding peptide and a peptide against the protective antigen (PA) protein of Bacillus anthracis discovered through phage and bacterial display panning technologies, respectively, were modified with click handles and subjected to iterative in situ click chemistry screens using synthetic peptide libraries. Each azide-alkyne cycloaddition iteration, promoted by the respective target proteins, yielded improvements in metrics for the application of interest. The anti-VEGF PCC was explored as a stable in vivo imaging probe. It exhibited excellent stability against proteases and a mean elimination in vivo half-life (T1/2 ) of 36 min. Intraperitoneal injection of the reagent results in slow clearance from the peritoneal cavity and kidney retention at extended times, while intravenous injection translates to rapid renal clearance. The ligand competed with the commercial antibody for binding to VEGF in vivo. The anti-PA ligand was developed for detection assays that perform in demanding physical environments. The matured anti-PA PCC exhibited no solution aggregation, no fragmentation when heated to 100°C, and > 81% binding activity for PA after heating at 90°C for 1 h. We discuss the potential of the PCC agent screening process for the discovery and enrichment of next generation antibody alternatives.


Assuntos
Química Click/métodos , Biblioteca de Peptídeos , Peptídeos/química , Fator A de Crescimento do Endotélio Vascular/química , Sequência de Aminoácidos , Animais , Anticorpos/administração & dosagem , Anticorpos/química , Anticorpos/metabolismo , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Toxinas Bacterianas/química , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Varredura Diferencial de Calorimetria , Catálise , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Feminino , Células HT29 , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Ligantes , Masculino , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacocinética , Ligação Proteica , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Am J Obstet Gynecol ; 214(5): 633.e1-633.e24, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26874297

RESUMO

BACKGROUND: Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE: To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN: A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS: The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION: A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.


Assuntos
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Nascimento Prematuro/sangue , Globulina de Ligação a Hormônio Sexual/análise , Biomarcadores/sangue , Feminino , Humanos , Espectrometria de Massas , Gravidez , Segundo Trimestre da Gravidez/sangue , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade
15.
Lung ; 193(6): 1023-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26376647

RESUMO

Evaluation of indeterminate pulmonary nodules is a complex challenge. Most are benign but frequently undergo invasive and costly procedures to rule out malignancy. A plasma protein classifier was developed that identifies likely benign nodules that can be triaged to CT surveillance to avoid unnecessary invasive procedures. The clinical utility of this classifier was assessed in a prospective-retrospective analysis of a study enrolling 475 patients with nodules 8-30 mm in diameter who had an invasive procedure to confirm diagnosis at 12 sites. Using this classifier, 32.0 % (CI 19.5-46.7) of surgeries and 31.8 % (CI 20.9-44.4) of invasive procedures (biopsy and/or surgery) on benign nodules could have been avoided. Patients with malignancy triaged to CT surveillance by the classifier would have been 24.0 % (CI 19.2-29.4). This rate is similar to that described in clinical practices (24.5 % CI 16.2-34.4). This study demonstrates the clinical utility of a non-invasive blood test for pulmonary nodules.


Assuntos
Biomarcadores Tumorais/sangue , Proteínas Sanguíneas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Nódulo Pulmonar Solitário/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncoscopia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Biópsia Guiada por Imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e Especificidade , Nódulo Pulmonar Solitário/diagnóstico , Nódulo Pulmonar Solitário/patologia , Tomografia Computadorizada por Raios X , Carga Tumoral
16.
J Vis Exp ; (102): e52979, 2015 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-26325674

RESUMO

To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492.


Assuntos
Alternativas aos Testes com Animais/métodos , Córnea/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Irritantes/toxicidade , Testes de Toxicidade/métodos , Epitélio/efeitos dos fármacos , Substâncias Perigosas/classificação , Humanos , Irritantes/classificação , Engenharia Tecidual/métodos
17.
J Trauma Acute Care Surg ; 79(1): 98-103; discussion 104, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26091321

RESUMO

BACKGROUND: In 2012, we implemented a ready open trauma intensive care unit (TICU) bed process. Our hypothesis was that this process would decrease emergency department (ED) length of stay (LOS) in a cost-effective manner without worsening clinical outcomes. METHODS: We developed a charge nurse without a patient assignment to facilitate this open bed. We also provided team training for early ICU resuscitation. All Level 1 activations admitted directly to the TICU before and after the implementation were examined. Patients taken directly to the operating room from the ED, deaths within 24 hours of admission, and patients with nonsurvivable head injuries were excluded. Cost-effectiveness of the position was examined. RESULTS: Age (mean [SD], 45.78 [18.71] years), sex (74.7% male), and Injury Severity Score (ISS) (mean [SD], 17.27 [9.26]) were not significantly different. Median ED LOS for the postimplementation group decreased from 230 minutes to 66 minutes (p < 0.001). Median ICU LOS (from 3.29 to 2.98 days, p = 0.13) and total median hospital LOS (from 10.71 to 7.98 days, p = 0.06) decreased but were not statistically significant. Controlling for age, ISS, sex, and mechanism of injury the postimplementation group had a 29% reduction in ICU LOS (2.12 days), a 28% reduction in hospital LOS (4.34), and a 54% reduction in ED LOS (154 minutes). The LOS decreased despite a small increase in ISS (from 15.89 to 18.37). Observed/expected mortality did not differ between the groups, preimplementation/postimplementation of 0.87 and 0.92. Nursing productivity increased one nurse after implementation at a cost of $624 per day. The ICU LOS decrease of 1.6 days at a rate of $1,144 average ICU daily cost of room and board totaled $1,830 per patient. The decreased ICU LOS dollars minus the increase nurse pay resulted in an overall savings of $1,206 per patient. CONCLUSION: Rapid access to the TICU made possible by the charge nurse without a direct assignment and team training has a potential cost savings without adversely affecting patient outcomes. LEVEL OF EVIDENCE: Cost analysis, level III.


Assuntos
Unidades de Terapia Intensiva/organização & administração , Admissão do Paciente/economia , Ferimentos e Lesões/economia , Adulto , Idoso , Redução de Custos , Análise Custo-Benefício , Serviço Hospitalar de Emergência/organização & administração , Feminino , Humanos , Unidades de Terapia Intensiva/economia , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade
18.
Chest ; 148(6): 1405-1414, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26087071

RESUMO

BACKGROUND: Pulmonary nodules (PNs) are a common reason for referral to pulmonologists. The majority of data for the evaluation and management of PNs is derived from studies performed in academic medical centers. Little is known about the prevalence and diagnosis of PNs, the use of diagnostic testing, or the management of PNs by community pulmonologists. METHODS: This multicenter observational record review evaluated 377 patients aged 40 to 89 years referred to 18 geographically diverse community pulmonary practices for intermediate PNs (8-20 mm). Study measures included the prevalence of malignancy, procedure/test use, and nodule pretest probability of malignancy as calculated by two previously validated models. The relationship between calculated pretest probability and management decisions was evaluated. RESULTS: The prevalence of malignancy was 25% (n = 94). Nearly one-half of the patients (46%, n = 175) had surveillance alone. Biopsy was performed on 125 patients (33.2%). A total of 77 patients (20.4%) underwent surgery, of whom 35% (n = 27) had benign disease. PET scan was used in 141 patients (37%). The false-positive rate for PET scan was 39% (95% CI, 27.1%-52.1%). Pretest probability of malignancy calculations showed that 9.5% (n = 36) were at a low risk, 79.6% (n = 300) were at a moderate risk, and 10.8% (n = 41) were at a high risk of malignancy. The rate of surgical resection was similar among the three groups (17%, 21%, 17%, respectively; P = .69). CONCLUSIONS: A substantial fraction of intermediate-sized nodules referred to pulmonologists ultimately prove to be lung cancer. Despite advances in imaging and nonsurgical biopsy techniques, invasive sampling of low-risk nodules and surgical resection of benign nodules remain common, suggesting a lack of adherence to guidelines for the management of PNs.


Assuntos
Gerenciamento Clínico , Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Nódulo Pulmonar Solitário , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico , Nódulos Pulmonares Múltiplos/epidemiologia , Nódulos Pulmonares Múltiplos/etiologia , Nódulos Pulmonares Múltiplos/terapia , Tomografia por Emissão de Pósitrons/métodos , Prevalência , Probabilidade , Medição de Risco , Nódulo Pulmonar Solitário/diagnóstico , Nódulo Pulmonar Solitário/epidemiologia , Nódulo Pulmonar Solitário/etiologia , Nódulo Pulmonar Solitário/terapia , Tomografia Computadorizada por Raios X/métodos , Estados Unidos/epidemiologia , Procedimentos Desnecessários/estatística & dados numéricos
19.
Altern Lab Anim ; 43(2): 101-27, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25995013

RESUMO

The 7th Amendment to the EU Cosmetics Directive and the EU REACH Regulation have reinforced the need for in vitro ocular test methods. Validated in vitro ocular toxicity tests that can predict the human response to chemicals, cosmetics and other consumer products are required for the safety assessment of materials that intentionally, or inadvertently, come into contact with the eye. The EpiOcular Eye Irritation Test (EIT), which uses the normal human cell-based EpiOcular™ tissue model, was developed to address this need. The EpiOcular-EIT is able to discriminate, with high sensitivity and accuracy, between ocular irritant/corrosive materials and those that require no labelling. Although the original EpiOcular-EIT protocol was successfully pre-validated in an international, multicentre study sponsored by COLIPA (the predecessor to Cosmetics Europe), data from two larger studies (the EURL ECVAM-COLIPA validation study and an independent in-house validation at BASF SE) resulted in a sensitivity for the protocol for solids that was below the acceptance criteria set by the Validation Management Group (VMG) for eye irritation, and indicated the need for improvement of the assay's sensitivity for solids. By increasing the exposure time for solid materials from 90 minutes to 6 hours, the optimised EpiOcular-EIT protocol achieved 100% sensitivity, 68.4% specificity and 84.6% accuracy, thereby meeting all the acceptance criteria set by the VMG. In addition, to satisfy the needs of Japan and the Pacific region, the EpiOcular-EIT method was evaluated for its performance after extended shipment and storage of the tissues (4-5 days), and it was confirmed that the assay performs with similar levels of sensitivity, specificity and reproducibility in these circumstances.


Assuntos
Olho/efeitos dos fármacos , Irritantes/toxicidade , Testes de Toxicidade/métodos , Alternativas aos Testes com Animais , Humanos
20.
Clin Proteomics ; 12(1): 3, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25838814

RESUMO

BACKGROUND: Current quantification methods for mass spectrometry (MS)-based proteomics either do not provide sufficient control of variability or are difficult to implement for routine clinical testing. RESULTS: We present here an integrated quantification (InteQuan) method that better controls pre-analytical and analytical variability than the popular quantification method using stable isotope-labeled standard peptides (SISQuan). We quantified 16 lung cancer biomarker candidates in human plasma samples in three assessment studies, using immunoaffinity depletion coupled with multiple reaction monitoring (MRM) MS. InteQuan outperformed SISQuan in precision in all three studies and tolerated a two-fold difference in sample loading. The three studies lasted over six months and encountered major changes in experimental settings. Nevertheless, plasma proteins in low ng/ml to low µg/ml concentrations were measured with a median technical coefficient of variation (CV) of 11.9% using InteQuan. The corresponding median CV using SISQuan was 15.3% after linear fitting. Furthermore, InteQuan surpassed SISQuan in measuring biological difference among clinical samples and in distinguishing benign versus cancer plasma samples. CONCLUSIONS: We demonstrated that InteQuan is a simple yet robust quantification method for MS-based quantitative proteomics, especially for applications in biomarker research and in routine clinical testing.

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