RESUMEN
BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency. METHODS: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures. RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo. CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).
Asunto(s)
Piperazinas , Piruvato Quinasa , Quinolinas , Adulto , Anemia Hemolítica Congénita no Esferocítica/tratamiento farmacológico , Método Doble Ciego , Hemoglobinas/análisis , Hemoglobinas/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Piperazinas/farmacología , Piperazinas/uso terapéutico , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/tratamiento farmacológico , Quinolinas/farmacología , Quinolinas/uso terapéuticoRESUMEN
The stratified Cox model is commonly used for stratified clinical trials with time-to-event endpoints. The estimated log hazard ratio is approximately a weighted average of corresponding stratum-specific Cox model estimates using inverse-variance weights; the latter are optimal only under the (often implausible) assumption of a constant hazard ratio across strata. Focusing on trials with limited sample sizes (50-200 subjects per treatment), we propose an alternative approach in which stratum-specific estimates are obtained using a refined generalized logrank (RGLR) approach and then combined using either sample size or minimum risk weights for overall inference. Our proposal extends the work of Mehrotra et al, to incorporate the RGLR statistic, which outperforms the Cox model in the setting of proportional hazards and small samples. This work also entails development of a remarkably accurate plug-in formula for the variance of RGLR-based estimated log hazard ratios. We demonstrate using simulations that our proposed two-step RGLR analysis delivers notably better results through smaller estimation bias and mean squared error and larger power than the stratified Cox model analysis when there is a treatment-by-stratum interaction, with similar performance when there is no interaction. Additionally, our method controls the type I error rate while the stratified Cox model does not in small samples. We illustrate our method using data from a clinical trial comparing two treatments for colon cancer.
Asunto(s)
Simulación por Computador/estadística & datos numéricos , Determinación de Punto Final/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Neoplasias del Colon/epidemiología , Neoplasias del Colon/terapia , Determinación de Punto Final/métodos , Humanos , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Tamaño de la MuestraRESUMEN
Two-period two-treatment (2×2) crossover designs are commonly used in clinical trials. For continuous endpoints, it has been shown that baseline (pretreatment) measurements collected before the start of each treatment period can be useful in improving the power of the analysis. Methods to achieve a corresponding gain for censored time-to-event endpoints have not been adequately studied. We propose a method in which censored values are treated as missing data and multiply imputed using prespecified parametric event time models. The event times in each imputed data set are then log-transformed and analyzed using a linear model suitable for a 2×2 crossover design with continuous endpoints, with the difference in period-specific baselines included as a covariate. Results obtained from the imputed data sets are synthesized for point and confidence interval estimation of the treatment ratio of geometric mean event times using model averaging in conjunction with Rubin's combination rule. We use simulations to illustrate the favorable operating characteristics of our method relative to two other methods for crossover trials with censored time-to-event data, ie, a hierarchical rank test that ignores the baselines and a stratified Cox model that uses each study subject as a stratum and includes period-specific baselines as a covariate. Application to a real data example is provided.
Asunto(s)
Estudios Cruzados , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Análisis de Varianza , Bioestadística , Simulación por Computador , Interpretación Estadística de Datos , Determinación de Punto Final/estadística & datos numéricos , Humanos , Modelos Lineales , Modelos Estadísticos , Modelos de Riesgos Proporcionales , Factores de TiempoRESUMEN
BACKGROUND: The risk of mesothelioma has been shown to be associated with exposure to asbestos fibers. Most of the existing literature focuses on occupational exposure; however, non-occupational asbestos exposure has also been identified as an important risk factor. OBJECTIVE: To estimate the association between mesothelioma and non-occupational asbestos exposure, and evaluate control recruitment and exposure measurement methods. METHODS: A systematic literature review was conducted to identify case-control (CC) and cohort studies that examined the association between mesothelioma and non-occupational exposure to asbestos, including neighborhood, domestic, and household exposure. Meta-analysis was performed to estimate a summary relative risk estimate (SRRE) and 95% confidence interval using random-effects models. Subgroup analyses were also conducted by exposure type, gender, region, and fiber type. RESULTS: Twenty CC and 7 cohort studies were selected. Controls in CC studies were selected from the general population (55%), hospital records (18%), cancer registry (23%) and a combination of population and hospital records (5%). Multiple methods were used to measure neighborhood exposure (e.g., linear distance and direction of residence from an asbestos factory), domestic (e.g., whether living with an asbestos worker) and household exposure (e.g., whether involved in asbestos-containing home improvement projects). Primary meta-analyses suggested a SRRE of mesothelioma of 5.33 (95%CI: 2.53, 11.23) from neighborhood exposure, 4.31 (95%CI, 2.58, 7.20) from domestic exposure, and 2.41 (95%CI, 1.30, 4.48) from household exposure with large I2 statistics ranging from 83-99%. CONCLUSIONS: Non-occupational asbestos exposure is significantly associated with an elevated risk of mesothelioma. Funnel plots indicated a potential of publication bias. Some SRREs should be interpreted with cautions because of high between-studies heterogeneity.
Asunto(s)
Amianto/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Mesotelioma/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Factores de RiesgoRESUMEN
AIMS: Disability, an individual's reduced capacity to perform physical tasks encountered in daily routine, is associated with urinary incontinence in the elderly. Our objective was to determine if urinary incontinence is associated with disability in community-dwelling women 40 years and older. METHODS: Cross-sectional study among US women ≥40 years (n = 4,458) from National Health and Nutrition Examination Surveys 2005-2010. We estimated the age-stratified weighted prevalence and factors independently associated with disability (Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), mobility, and functional limitations) in women with and without urinary incontinence while controlling for confounders of the association between disability and urinary incontinence. RESULTS: The weighted prevalence of all disabilities was higher in women with urinary incontinence than women without urinary incontinence across most decades of life with the greatest difference in the prevalence of mobility disabilities: 40-49 years (12.1% vs. 7.0%), 50-59 years (17.0% vs. 9.2%), 60-69 years (28.3% vs. 19.8%), and 70+ years (43.8% vs. 33.0%, all P < 0.05). On multivariable analysis, after controlling for the confounding effect of age, co-morbidities, and income-poverty ratio, urinary incontinence was weakly associated with disabilities. The adjusted odds ratio (95% confidence interval) of disabilities for urinary incontinence was ADL 1.96 (1.07, 3.58), IADL 1.18 (0.78, 1.78), mobility 1.26 (1.01, 1.56), and functional limitations 1.36 (1.07, 1.73). CONCLUSIONS: Urinary incontinence is weakly associated with disabilities and cannot be implicated as a cause of disability in community dwelling women.
Asunto(s)
Incontinencia Urinaria/epidemiología , Actividades Cotidianas , Adulto , Factores de Edad , Anciano , Estudios Transversales , Evaluación de la Discapacidad , Femenino , Encuestas Epidemiológicas , Humanos , Renta , Persona de Mediana Edad , Limitación de la Movilidad , Encuestas Nutricionales , Pobreza , Prevalencia , Factores Socioeconómicos , Estados Unidos/epidemiología , Incontinencia Urinaria/etiología , Adulto JovenRESUMEN
ABSTRACT: Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Eritropoyesis , Sobrecarga de Hierro , Piruvato Quinasa , Errores Innatos del Metabolismo del Piruvato , Humanos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/tratamiento farmacológico , Eritropoyesis/efectos de los fármacos , Adulto , Piruvato Quinasa/deficiencia , Masculino , Femenino , Persona de Mediana Edad , Adulto Joven , Alanina/uso terapéutico , Alanina/análogos & derivados , Piperazinas , QuinolinasRESUMEN
BACKGROUND: Maintenance therapy for major depressive disorder (MDD) is typically recommended at the dose on which the patient was stabilized. However, for some patients, dose alteration may be required. We investigated multiple vortioxetine doses versus placebo for relapse prevention in patients achieving remission with vortioxetine 10 mg daily. METHODS: In this US-based, randomized withdrawal study, outpatients (N = 1106, aged 18-75 years) with recurrent MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥26), a current major depressive episode (MDE) (8 weeks-18 months' duration), and ≥2 previous MDEs were treated with open-label vortioxetine 10 mg once daily orally for 16 weeks. Responders at week 8 (≥50% MADRS score reduction) achieving remission (MADRS score ≤12) at weeks 14 and 16 (N = 580) were randomized to vortioxetine 5, 10, or 20 mg or placebo in a 32-week double-blind period. The primary outcome was time to first relapse over the first 28 weeks; secondary outcomes (relapse, change in total MADRS, Clinician Global Impression-Severity [CGI-S]) were evaluated at 32 weeks. RESULTS: Time to relapse was longer and cumulative relapse rates were lower for vortioxetine 5 mg (19.3%), 10 mg (17.9%), and 20 mg (17.4%) versus placebo (32.5%) over 28 weeks (p<0.05 for all). CGI-S scores remained stable and adverse events were generally mild-to-moderate. LIMITATIONS: Extrapolation of results to patients achieving remission with vortioxetine doses other than 10 mg should be made with caution. CONCLUSION: For patients with MDD achieving symptomatic remission at 10 mg/day, all doses of vortioxetine were effective for relapse prevention, with acceptable tolerability.
Asunto(s)
Trastorno Depresivo Mayor , Vortioxetina , Adolescente , Adulto , Anciano , Enfermedad Crónica , Trastorno Depresivo Mayor/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Persona de Mediana Edad , Recurrencia , Resultado del Tratamiento , Vortioxetina/administración & dosificación , Vortioxetina/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Mitapivat, an oral activator of pyruvate kinase (PK) in red blood cells (RBCs), has shown significant improvements in haemoglobin and haemolysis among patients with pyruvate kinase deficiency who were not receiving regular transfusions. We aimed to evaluate the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency receiving regular transfusions. METHODS: ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20 centres across Europe, North America, and Asia. Eligible participants were adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate kinase deficiency receiving regular transfusions (at least six episodes in the previous year). Participants received oral mitapivat during a 16-week dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose period. The primary endpoint was a reduction in transfusion burden (≥33% reduction in number of RBC units transfused during the fixed-dose period, compared with the participant's individual historical transfusion burden, standardised to 24 weeks). Efficacy and safety were assessed in all participants who received at least one dose of mitapivat. This trial is registered with ClinicalTrials.gov, NCT03559699, and is complete. FINDINGS: Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%] female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%] not reported) were enrolled and received at least one dose of mitapivat. Median duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in transfusion burden by at least 33% was found in ten (37%) participants (95% CI 19-58; p=0·0002). The most common treatment-emergent adverse events were increase in alanine aminotransferase (ten [37%] participants), headache (ten [37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five [19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events were related to study treatment: joint swelling (one participant [4%]) and an increase in aspartate aminotransferase (one participant [4%]). Three participants had serious treatment-emergent adverse events, none related to the study treatment: increased blood triglycerides, ovarian cyst, and renal colic (each in one participant [4%]). No treatment-related deaths were observed. INTERPRETATION: Mitapivat represents a novel therapy that can reduce transfusion burden in some adults with pyruvate kinase deficiency receiving regular transfusions, and is the first disease-modifying agent approved in this disease. FUNDING: Agios Pharmaceuticals.
Asunto(s)
Hemoglobinas , Piruvato Quinasa , Adolescente , Adulto , Alanina Transaminasa , Anemia Hemolítica Congénita no Esferocítica , Aspartato Aminotransferasas , Femenino , Humanos , Masculino , Preparaciones Farmacéuticas , Piperazinas , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato , Quinolinas , Resultado del Tratamiento , TriglicéridosRESUMEN
OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE). METHODS: The study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by evaluation of changes in seizure frequency from baseline. RESULTS: Eighteen patients (median age, 28.5 years) were enrolled and randomized, and 14 (78 %) completed the study. In Part A, TEAEs occurred in 71.4 % of soticlestat-treated patients and 100 % of placebo-treated patients. In Part B, the overall incidence of TEAEs was 68.8 %. In Part A, TEAEs that occurred in more than one patient in the soticlestat group were dysarthria (n = 3, 21.4 %), lethargy (n = 2, 14.3 %), upper respiratory tract infection (n = 2, 14.3 %), fatigue (n = 2, 14.3 %), and headache (n = 2, 14.3 %). Four patients discontinued treatment because of TEAEs, of whom two reported drug-related seizure clusters as serious TEAEs. There were no deaths. Pharmacokinetic analysis showed dose-dependent increases in systemic exposure and peak plasma soticlestat concentrations. At the end of Part B, the overall mean percent change from baseline in plasma 24HC was -80.97 %. Changes from baseline in median seizure frequency were +16.71 % and +22.16 % in the soticlestat and placebo groups, respectively, in Part A, and -36.38 % in all participants in Part B. CONCLUSION: Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome.
Asunto(s)
Anticonvulsivantes , Síndrome de Lennox-Gastaut , Adulto , Anticonvulsivantes/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Piperidinas/efectos adversos , Estudios Prospectivos , Piridinas/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Traditional randomized withdrawal studies have assessed the efficacy of antidepressants for reducing relapse and recurrence of major depressive episodes (MDEs) but have not compared dose reduction, increase, or maintenance within the same study. METHODS: Here we present the development, implementation, and preliminary data from the open-label period of an ongoing phase 4, non-traditional, randomized withdrawal study. Designed to evaluate the efficacy of vortioxetine across its approved dose range for relapse prevention, the study enrolled adult patients with recurrent major depressive disorder (MDD), Montgomery-Åsberg Depression Rating Scale (MADRS) ≥ 26, and history of ≥2 MDEs. After a 16-week, open-label, fixed-dose (vortioxetine 10 mg once daily) period, patients meeting response criteria (≥50% reduction in MADRS total score, Weeks 8-16) and remission criteria (MADRS total score ≤12, Weeks 14 and 16) were randomized to vortioxetine 5, 10, or 20 mg, or placebo in a 32-week double-blind treatment period. RESULTS: Of 1106 patients enrolled, 510 completed the open-label period (mean age: 45.7 years; mean MADRS = 5.0; predominantly female, white, and never smokers) and were eligible for randomization in the ongoing double-blind period. LIMITATIONS: Study is ongoing; only data from the open-label period are available for evaluation. CONCLUSIONS: Preliminary analysis suggests that patient baseline characteristics were not a factor in response to and stabilization with vortioxetine during the open-label period. The lack of flexibility in dosing, however, may have reduced the number of patients qualifying for randomization. This study design may provide useful information for optimizing the long-term efficacy and tolerability of vortioxetine treatment for MDD.
Asunto(s)
Trastorno Depresivo Mayor , Adulto , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/prevención & control , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Piperazinas/uso terapéutico , Datos Preliminares , Prevención Secundaria , Sulfuros/uso terapéutico , Resultado del Tratamiento , VortioxetinaRESUMEN
BACKGROUND: Patients with major depressive disorder (MDD) show impairments in cognitive functioning, including deficits on performance-based measures of functional capacity. A proportion of patients with MDD may achieve higher scores at baseline, and may not show a detectable response to treatment. How to identify these cases is the goal of this investigation. METHODS: Retrospective analyses of data from the CONNECT study with vortioxetine were performed to determine whether the Work Limitations Questionnaire (WLQ) can be used to exclude very high-performing patients on the functional capacity outcome measure, University of California San Diego Performance-Based Skills Assessment (UPSA), in studies evaluating cognitive function impairment in MDD, to identify those with greater potential for treatment response. The post-hoc analyses included data on cognitive function assessed with a Digit Symbol Substitution Test (DSST) from vortioxetine-treated patients. RESULTS: WLQ score >13 identified patients with greater impairments in UPSA-Brief (UPSA-B). Patients with WLQ scores >13, but not with scores ≤13, showed statistically significant improvements with vortioxetine treatment in UPSA-B and DSST compared with placebo. LIMITATIONS: Study limitations include small sample size and use of post-hoc analyses. The generalizability of this analysis is limited to working patients with MDD. CONCLUSIONS: The WLQ can be used to identify patients with MDD with high potential for treatment response in studies evaluating cognitive function impairment while excluding patients likely to achieve ceiling scores on UPSA. This approach helps identify higher performers on potential outcomes measures without biasing the study by requiring a specific UPSA cutoff score for eligible participants.
Asunto(s)
Cognición , Disfunción Cognitiva/psicología , Trastorno Depresivo Mayor/psicología , Empleo/psicología , Autoinforme , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , Vortioxetina/uso terapéuticoRESUMEN
AIM: We compared three statistical methods in selecting a panel of serum lipid biomarkers for mesothelioma and asbestos exposure. MATERIALS & METHODS: Serum samples from mesothelioma, asbestos-exposed subjects and controls (40 per group) were analyzed. Three variable selection methods were considered: top-ranked predictors from univariate model, stepwise and least absolute shrinkage and selection operator. Crossed-validated area under the receiver operating characteristic curve was used to compare the prediction performance. RESULTS: Lipids with high crossed-validated area under the curve were identified. Lipid with mass-to-charge ratio of 372.31 was selected by all three methods comparing mesothelioma versus control. Lipids with mass-to-charge ratio of 1464.80 and 329.21 were selected by two models for asbestos exposure versus control. CONCLUSION: Different methods selected a similar set of serum lipids. Combining candidate biomarkers can improve prediction.
Asunto(s)
Amianto/efectos adversos , Biomarcadores de Tumor/sangre , Análisis Químico de la Sangre/métodos , Exposición a Riesgos Ambientales/efectos adversos , Lípidos/sangre , Mesotelioma/sangre , Estadística como Asunto/métodos , Estudios de Casos y Controles , HumanosRESUMEN
We examine the feasibility of phytoremediation as an alternative strategy to limit the exposure of asbestos in site with asbestos-containing materials. We collected soils from four locations from two sites-one with naturally occurring asbestos, and another, a superfund site, where asbestos-containing materials were disposed over decades-and performed ecotoxicology tests. We also performed two experiments with crop cultivar and two grasses from serpentine ecotype and cultivar to determined best choice for phytoremediation. Asbestos concentrations in different size fractions of soils varied by orders of magnitude. However, different asbestos concentrations had little effect on germination and root growth. Presence of co-contaminants such as heavy metals and lack of nutrients affected plant growth to different extents, indicating that several of these limiting factors should be considered instead of the primary contaminant of concern. Crop cultivar survived on asbestos-contaminated soil. Grasses from serpentine ecotype did not show higher biomass than the cultivar. Overall, these results showed that soil conditions play a critical role in screening different crop species for phytoremediation and that asbestos concentration has limited to no effect on plant growth. Our study provided a framework for phytoremediation of asbestos-contaminated sites to limit long-term asbestos exposure.
Asunto(s)
Amianto/análisis , Monitoreo del Ambiente/métodos , Metales Pesados/análisis , Poaceae/química , Contaminantes del Suelo/análisis , Suelo/química , Biodegradación Ambiental , Biomasa , Desarrollo de la Planta , Poaceae/crecimiento & desarrollo , Estados UnidosRESUMEN
PURPOSE: This study aimed to examine the separate effects of maternal and paternal history on the onset of asthma in children and evaluate the relationship between age of asthma onset in parents and risk of asthma in their children. METHODS: We used data from the third National Health and Nutrition Examination Survey. We developed new continuous standardized scores for survey data to quantify parental history that incorporated both the occurrence of asthma and the age at onset, and associated these scores with asthma risk in the children. The association analysis was adjusted for sex and obesity status. RESULTS: Children with maternal history have elevated asthma risk (hazard ratio of 3.71, 95% CI: 1.19-11.60) than those without, and those whose mothers had earlier age of onset have increased risk of asthma compared to those whose mothers had later age of onset. On the contrary, paternal history had a relatively smaller effect that may be only detectable in larger samples (hazard ratio of 2.17, 95% CI: 0.69-6.79). CONCLUSION: Maternal asthma history was strongly associated with the onset of asthma in the second generation, and children whose mother had an earlier age of onset had an increased risk of 3.71. For an approximately 10-year decrease in mother's age at onset of asthma, the risk of asthma for the offspring increased by 1.37-fold. Using our new risk scores led to smaller standard errors and thus more precise estimates than using a binary indicator.