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AIMS/HYPOTHESIS: Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS: A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS: Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION: In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.
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Metformina , Placenta , Humanos , Femenino , Embarazo , Metformina/farmacología , Metformina/uso terapéutico , Metformina/metabolismo , Trofoblastos/metabolismo , Cesárea , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/metabolismoRESUMEN
OBJECTIVE: Endoleaks following thoracic endovascular aortic repair (TEVAR) can lead to the need for re-intervention and aortic rupture. Given the recent recall of a specific thoracic stent graft type due to concerns about type IIIb endoleak (T3bE), in which blood leaks through the stent graft fabric, the aim was to characterise patterns of T3bEs among available TEVAR devices. METHODS: Reports related to thoracic stent grafts in the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database between 2010 and 2020 were reviewed. Proportional reporting ratios (PRRs) and chi squared tests were used to assess for the presence of a signal of association between device type and T3bE. A PRR > 2 and chi squared value > 4 with three or more reports overall constituted a signal of association. The institutional database of patients undergoing TEVAR for thoracic aneurysms since 2002 was also queried for T3bE. RESULTS: There were 7 328 MAUDE reports available for analysis. When analysing T3bEs in the MAUDE database, the lowest PRR was 0.36 (95% confidence interval [CI] 0 - 1.03 in Gore CTAG, nine T3bE among 1 328 reports) and the highest was 2.07 (95% CI 1.72 - 2.42 in Medtronic Valiant, 64 T3bE among 2 520 reports). The T3bE chi squared value for Medtronic Valiant was 17.3. The relationship between Medtronic Valiant and T3bE was ascertainable by MAUDE data as early as 2013. Among 542 TEVARs for an aneurysm indication at Duke University Hospital since 2002, there were eight T3bEs - all in devices with sutured on graft material. CONCLUSION: The Medtronic Valiant device met criteria for association with type IIIb endoleaks in the FDA's MAUDE database and met those criteria as early as 2013. A possible relationship between woven graft fabric and T3bEs is supported by the observation that all types of T3bE that occurred among a large number of TEVARs at the institution followed placement of grafts with sutured on woven fabric.
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Aneurisma de la Aorta Torácica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Endofuga/etiología , Endofuga/cirugía , Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Reparación Endovascular de Aneurismas , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Stents , Aneurisma de la Aorta Torácica/cirugía , Diseño de Prótesis , Estudios RetrospectivosRESUMEN
BACKGROUND: Infective endocarditis (IE) involving the aortic valve and root is associated with high risk requiring thoughtful surgical decision-making. The impact of valve and conduit choices and patient factors on long-term outcomes in this patient population is poorly documented. METHODS: From January 1976 to December 2013, 485 patients underwent aortic root and valve replacement at a single institution. Cox's proportional hazard model identified predictors of long-term survival and cumulative incidence functions were compared to assess need for reoperation with death as a competing risk. RESULTS: Median age at time of operation was 56.6 years (interquartile range: 23.1) with the indication for operation being endocarditis in 14.6% (n = 71). Stentless root replacement was used in 70% IE versus 34% non-IE (p < .001). Endocarditis at time of root replacement did not have a significant impact on survival through 15 years (IE: 37.3% vs. non-IE: 42.5%; log-rank; p = .13). After multivariable adjustment, survival was similar between patients with and without endocarditis (hazard ratio: 1.1; 95% confidence interval: [0.77, 1.62]; p = .57). Freedom from reoperation at 15 years did not vary significantly by endocarditis status (IE: 95.9% vs. non-IE: 73.6%; p = .07). Among endocarditis patients, freedom from reoperation at 10 years was similar between homograft and stentless bioprosthetic conduits (95.3% vs. 88.5%; log-rank; K-sample; p = .46). CONCLUSIONS: In a sample with frequent use of stentless prostheses, aortic root replacement for infective endocarditis had acceptable risk and long-term survival similar to root replacement for other indications. In the setting of endocarditis, root replacement with homograft or stentless bioprosthetic root has excellent durability through 15 years.
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Bioprótesis , Endocarditis , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Válvula Aórtica/cirugía , Endocarditis/cirugía , Humanos , Reoperación , Estudios RetrospectivosRESUMEN
Given the pervasive nature of child abuse and neglect, multilevel public health approaches are necessary. Implementation science can help in understanding the most effective ways to build infrastructure and support delivery of such approaches. In this theoretical paper, we describe the implementation of the Positive Parenting Program (Triple P), an evidence-based population-level parenting program in South Carolina. While implementation science has informed how to move population-level efforts to scale, we discuss challenges that persist in practice, such as when there is a need for multiple stakeholders to understand, support, and apply implementation best practices in a systematic and consistent way. To address this challenge, we introduce the role of a Community Capacity Coach, who lives in the local community and works towards the implementation of Triple P. The Coach is responsible for bridging gaps between the local community and statewide support systems. We detail the ways in which the Coach's role aligns with key intermediary functions, and how the Coach is embedded within the larger Triple P statewide support system. We then discuss the assessment of the Coach's impact; and conclude with future directions and next steps for this role within Triple P South Carolina.
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Maltrato a los Niños/prevención & control , Ciencia de la Implementación , Tutoría/métodos , Responsabilidad Parental , Creación de Capacidad/organización & administración , Niño , Humanos , South CarolinaRESUMEN
The link between youth homelessness and mental health functioning was examined using state population-representative 2015 Youth Risk Behavior Survey (YRBS) data. The moderating role of victimization and perceived teacher support also was examined. Consistent with hypotheses, results indicated that homelessness was associated with greater mental health challenges, more victimization, and less teacher support. The association between homelessness and mental health was not moderated by perceived teacher support. However, victimization experiences served as a moderator such that more victimization exacerbated the effect of homelessness on mental health challenges. This study supports the utility of the YRBS for gaining understanding of the experiences and needs of youth experiencing homelessness and adds to the growing literature on predictors of individual differences in mental health functioning of these vulnerable youth.
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Víctimas de Crimen/psicología , Jóvenes sin Hogar/psicología , Salud Mental , Maestros , Apoyo Social , Prevención del Suicidio , Suicidio , Adolescente , Femenino , Humanos , Individualidad , Masculino , Asunción de Riesgos , Habilidades Sociales , Suicidio/psicología , Encuestas y Cuestionarios , Estados Unidos , Poblaciones Vulnerables/estadística & datos numéricosRESUMEN
The encephalomyocarditis virus (EMCV) 3C protease (3Cpro) is one of a small number of viral proteins whose concentration is known to be regulated by the cellular ubiquitin-proteasome system. Here we report that the ubiquitin-conjugating enzyme UbcH7/UBE2L3 and the ubiquitin-protein ligase E6AP/UBE3A are components of a previously unknown EMCV 3Cpro-polyubiquitylating pathway. Following the identification of UbcH7/UBE2L3 as a participant in 3Cpro ubiquitylation, we purified a UbcH7-dependent 3Cpro-ubiquitylating activity from mouse cells, which we identified as E6AP. In vitro reconstitution assays demonstrated that E6AP catalyzes the synthesis of 3Cpro-attached Lys48-linked ubiquitin chains, known to be recognized by the 26S proteasome. We found that the 3Cpro accumulates to higher levels in EMCV-infected E6AP knockdown cells than in control cells, indicating a role for E6AP in in vivo 3Cpro concentration regulation. We also discovered that ARIH1 functions with UbcH7 to catalyze EMCV 3Cpro monoubiquitylation, but this activity does not influence the in vivo 3Cpro concentration.
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Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Virus de la Encefalomiocarditis/enzimología , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Virales/química , Proteínas Virales/metabolismo , Proteasas Virales 3C , Animales , Cisteína Endopeptidasas/genética , Virus de la Encefalomiocarditis/genética , Técnicas de Silenciamiento del Gen , Interacciones Huésped-Patógeno , Ratones , Células 3T3 NIH , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Proteínas Virales/genéticaRESUMEN
BACKGROUND: Large-scale animal feeding operations compromise regional air quality in the rural US through emission of pollutants, such as ammonia gas. Exposure to airborne pollution from animal feeding operations may cause pediatric asthma exacerbations in surrounding communities. OBJECTIVES: To describe spatial and temporal patterns in ambient ammonia concentrations in an agricultural region, and to investigate associations between short-term fluctuations in ammonia and subsequent changes in respiratory health in children with asthma. METHODS: For 13 months in the Yakima Valley of Washington State, 14 monitors sampled ammonia in outdoor air for 24-hour periods every 6 days. School-age children with asthma (n = 51) were followed for two health outcomes: biweekly reports of asthma symptoms and quick relief medication usage, and daily measurements of forced expiratory volume in 1 second. We assessed associations between each outcome and ammonia using generalized estimating equations. RESULTS: Twenty-four-hour ammonia concentrations varied from 0.2 to 238.1 µg/m during the study period and displayed a strong correlation with proximity to animal feeding operations. The percentage of forced expiratory volume in 1 second was 3.8% lower (95% confidence interval = 0.2, 7.3) per interquartile increase in 1-day lagged ammonia concentration and 3.0% lower (95% confidence interval = 0.5, 5.8) for 2-day lagged concentration. We observed no associations between self-reported asthma symptoms or medication usage and estimated ammonia exposure. CONCLUSIONS: Ammonia concentrations were elevated in this community and strongly predicted by proximity to animal feeding operations. Ammonia's association with acute lung function decrements in children with asthma in the surrounding community may be causal or, alternatively, ammonia may be a marker for other pollutants from animal feeding operations associated with respiratory effects.
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Contaminación del Aire Interior/estadística & datos numéricos , Amoníaco , Crianza de Animales Domésticos/estadística & datos numéricos , Asma/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Agricultura , Contaminación del Aire/estadística & datos numéricos , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Niño , Investigación Participativa Basada en la Comunidad , Femenino , Volumen Espiratorio Forzado , Humanos , Estudios Longitudinales , Masculino , Washingtón/epidemiología , Tiempo (Meteorología)RESUMEN
BACKGROUND: During an inspection by the Occupational Safety and Health Administration (OSHA) of a small coal slag processing plant with 12 current workers, four cases of pneumoconiosis were identified among former workers. METHODS: The OSHA investigation consisted of industrial hygiene sampling, a review of medical records, and case interviews. RESULTS: Some personal sampling measurements exceeded the OSHA Permissible Exposure Limit (PEL) for total dust exposures of 15 mg/m(3), and the measured respirable silica exposure of 0.043 mg/m(3), although below OSHA's current PEL for respirable dust containing silica, was above the American Conference of Governmental Industrial Hygienists' Threshold Limit Value (TLV). Chest x-rays for all four workers identified small opacities consistent with pneumoconiosis. CONCLUSION: This is the first known report of lung disease in workers processing coal slag and raises concerns for workers exposed to coal slag dust.
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Contaminantes Ocupacionales del Aire/efectos adversos , Industria del Carbón , Polvo/análisis , Exposición Profesional/efectos adversos , Neumoconiosis/diagnóstico , Adulto , Contaminantes Ocupacionales del Aire/análisis , Análisis por Conglomerados , Carbón Mineral/análisis , Carbón Mineral/toxicidad , Femenino , Humanos , Masculino , Metales/análisis , Metales/toxicidad , Persona de Mediana Edad , Exposición Profesional/análisis , Neumoconiosis/etiología , Dióxido de Silicio/análisis , Dióxido de Silicio/toxicidad , Estados Unidos , United States Occupational Safety and Health AdministrationRESUMEN
Inhalation of beryllium is associated with the development of sensitization; however, dermal exposure may also be important. The primary aim of this study was to elucidate relationships among exposure pathways in four different manufacturing and finishing facilities. Secondary aims were to identify jobs with increased levels of beryllium in air, on skin, and on surfaces; identify potential discrepancies in exposure pathways, and determine if these are related to jobs with previously identified risk. Beryllium was measured in air, on cotton gloves, and on work surfaces. Summary statistics were calculated and correlations among all three measurement types were examined at the facility and job level. Exposure ranking strategies were used to identify jobs with higher exposures. The highest air, glove, and surface measurements were observed in beryllium metal production and beryllium oxide ceramics manufacturing jobs that involved hot processes and handling powders. Two finishing and distribution facilities that handle solid alloy products had lower exposures than the primary production facilities, and there were differences observed among jobs. For all facilities combined, strong correlations were found between air-surface (rp ≥ 0.77), glove-surface (rp ≥ 0.76), and air-glove measurements (rp ≥ 0.69). In jobs where higher risk of beryllium sensitization or disease has been reported, exposure levels for all three measurement types were higher than in jobs with lower risk, though they were not the highest. Some jobs with low air concentrations had higher levels of beryllium on glove and surface wipe samples, suggesting a need to further evaluate the causes of the discrepant levels. Although such correlations provide insight on where beryllium is located throughout the workplace, they cannot identify the direction of the pathways between air, surface, or skin. Ranking strategies helped to identify jobs with the highest combined air, glove, and/or surface exposures. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file describing the forms of beryllium materials encountered during production and characteristics of the aerosols by process areas.].
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Contaminantes Ocupacionales del Aire/análisis , Berilio/análisis , Metalurgia , Exposición Profesional/análisis , Aerosoles , Polvo/análisis , Monitoreo del Ambiente/métodos , Guantes Protectores , Humanos , PielRESUMEN
A rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for determination of levels of the organophosphorus (OP) pesticides chlorpyrifos (CPF), azinphos methyl (AZM), and their oxygen analogs chlorpyrifos-oxon (CPF-O) and azinphos methyl-oxon (AZM-O) on common active air sampling matrices. XAD-2 resin and polyurethane foam (PUF) matrices were extracted with acetonitrile containing stable-isotope labeled internal standards (ISTD). Analysis was accomplished in Multiple Reaction Monitoring (MRM) mode, and analytes in unknown samples were identified by retention time (±0.1 min) and qualifier ratio (±30% absolute) as compared to the mean of calibrants. For all compounds, calibration linearity correlation coefficients were ≥0.996. Limits of detection (LOD) ranged from 0.15-1.1 ng/sample for CPF, CPF-O, AZM, and AZM-O on active sampling matrices. Spiked fortification recoveries were 78-113% from XAD-2 active air sampling tubes and 71-108% from PUF active air sampling tubes. Storage stability tests also yielded recoveries ranging from 74-94% after time periods ranging from 2-10 months. The results demonstrate that LC-MS/MS is a sensitive method for determining these compounds from two different matrices at the low concentrations that can result from spray drift and long range transport in non-target areas following agricultural applications. In an inter-laboratory comparison, the limit of quantification (LOQ) for LC-MS/MS was 100 times lower than a typical gas chromatography-mass spectrometry (GC-MS) method.
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Contaminantes Atmosféricos/análisis , Cromatografía Liquida/métodos , Monitoreo del Ambiente/métodos , Organotiofosfatos/análisis , Plaguicidas/análisis , Espectrometría de Masas en Tándem/métodos , Límite de Detección , Poliestirenos/química , Poliuretanos/química , Factores de TiempoRESUMEN
BACKGROUND: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders. METHODS: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism. RESULTS: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity (PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin (CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma (TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression. CONCLUSIONS: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption.
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Placenta , Preeclampsia , Humanos , Embarazo , Femenino , Placenta/metabolismo , Cesárea , Retardo del Crecimiento Fetal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Hipoxia/metabolismo , Oxígeno/metabolismo , Fenotipo , GenómicaRESUMEN
A number of recent toxicity studies have highlighted the increased potency of oxygen analogs (oxons) of several organophosphorus (OP) pesticides. These findings were a major concern after environmental oxons were identified in environmental samples from air and surfaces following agricultural spray applications in California and Washington State. This paper reports on the validity of oxygen analog measurements in air samples for the OP pesticide, chlorpyrifos. Controlled environmental and laboratory experiments were used to examine artificial formation of chlorpyrifos-oxon using OSHA Versatile Sampling (OVS) tubes as recommended by NIOSH method 5600. Additionally, we compared expected chlorpyrifos-oxon attributable to artificial transformation to observed chlorpyrifos-oxon in field samples from a 2008 Washington State Department of Health air monitoring study using non-parametric statistical methods. The amount of artificially transformed oxon was then modeled to determine the amount of oxon present in the environment. Toxicity equivalency factors (TEFs) for chlorpyrifos-oxon were used to calculate chlorpyrifos-equivalent air concentrations. The results demonstrate that the NIOSH-recommended sampling matrix (OVS tubes with XAD-2 resin) was found to artificially transform up to 30% of chlorpyrifos to chlorpyrifos-oxon, with higher percentages at lower concentrations (< 30 ng/m3) typical of ambient or residential levels. Overall, the 2008 study data had significantly greater oxon than expected by artificial transformation, but the exact amount of environmental oxon in air remains difficult to quantify with the current sampling method. Failure to conduct laboratory analysis for chlorpyrifos-oxon may result in underestimation of total pesticide concentration when using XAD-2 resin matrices for occupational or residential sampling. Alternative methods that can accurately measure both OP pesticides and their oxygen analogs should be used for air sampling, and a toxicity equivalent factor approach should be used to determine potential health risks from exposures.
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BACKGROUND: Stent graft-induced new entry has been described in thoracic endovascular aortic repair for aortic dissection. The incidence of stent graft-induced aortic wall injury (SAWI) related to iatrogenic injury in nondissections is incompletely described. We describe incidence, risk factors, and outcomes of SAWI. METHODS: All post-thoracic endovascular aortic repair computed tomography angiograms (January 2005 to December 2018) were reviewed for radiographic evidence of SAWI. Endograft-induced aortic dissections were likewise considered SAWI. Patient characteristics, time to SAWI, and need for reintervention were noted. Cox proportional hazards modeling was used to identify risk factors for SAWI. RESULTS: Within the study cohort (n = 430), 38 patients (9%) had SAWI during a median follow-up of 2.3 years (interquartile range, 4.8); 42% (n = 16) were proximal, 53% (n = 20) distal, and 5% (n = 2) both proximal and distal. Nine (23%) were distal intimal flap injuries in dissection cases, thus subclassifying them as stent graft-induced new entry. Twenty-nine percent of SAWI (n = 11) required reintervention. Of these, 45% (n = 5) were open, and 55% (n = 6) were endovascular. Thoracic endovascular aortic repair for acute dissection had a higher incidence of SAWI development (hazard ratio 4.6; 95% confidence interval, 2.4 to 9; P < .001) as compared with other indications. Use of devices with proximal bare springs or barbs was also associated with increased SAWI incidence (hazard ratio 5.3; 95% confidence interval, 2.6 to 11.0; P < .001). CONCLUSIONS: The rate of SAWI after thoracic endovascular aortic repair is low (9%), but nearly one third will require reintervention. Thoracic endovascular aortic repair in the setting of acute dissection and use of devices with proximal bare springs or barbs were associated with an increased incidence of SAWI.
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Aneurisma de la Aorta Torácica , Enfermedades de la Aorta , Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Lesiones del Sistema Vascular , Disección Aórtica/epidemiología , Disección Aórtica/etiología , Disección Aórtica/cirugía , Aneurisma de la Aorta Torácica/cirugía , Enfermedades de la Aorta/cirugía , Implantación de Prótesis Vascular/métodos , Procedimientos Endovasculares/métodos , Humanos , Incidencia , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Stents/efectos adversos , Resultado del Tratamiento , Lesiones del Sistema Vascular/cirugíaRESUMEN
PURPOSE: Next-generation sequencing (NGS) gene panels are frequently completed for patients with advanced non-small-cell lung cancer (NSCLC). Patients with highly actionable gene variants have improved outcomes and reduced toxicities with the use of corresponding targeted agents. We sought to identify barriers to targeted agent use within the Veterans Health Affairs' National Precision Oncology Program (NPOP). METHODS: A retrospective evaluation of patients with NSCLC who underwent NGS multigene panels through NPOP between July 2015 and February 2019 was conducted. Patients who were assigned level 1 or 2A evidence for oncogenic gene variants by an artificial intelligence offering (IBM Watson for Genomics [WfG]) and NPOP staff were selected. Antineoplastic drug prescriptions and provider notes were reviewed. Reasons for withholding targeted treatments were categorized. RESULTS: Of 1,749 patients with NSCLC who successfully underwent NGS gene panel testing, 112 (6.4%) patients were assigned level 1 and/or 2A evidence for available targeted treatments by WfG and NPOP staff. All highly actionable gene variants were within ALK, BRAF, EGFR, ERBB2, MET, RET, and ROS1. Of these, 36 (32.1%) patients were not prescribed targeted agents. The three most common reasons were (1) patient did not carry a diagnosis of metastatic disease (33.3%), (2) treating provider did not comment on the NGS results (25.0%), and (3) provider felt that patient could not tolerate therapy (19.4%). No patients were denied access to level 1 or 2A targeted drugs because of rejection of a nonformulary drug request. CONCLUSION: A substantial minority of patients with NSCLC bearing highly actionable gene variants are not prescribed targeted agents. Further provider- and pathologist-directed educational efforts and implementation of health informatics systems to provide real-time decision support for test ordering and interpretation are needed.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Veteranos , Inteligencia Artificial , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Medicina de Precisión , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Constrictive pericarditis is a rare, but increasingly recognized long-term postoperative complication of lung transplantation. Heightened clinical suspicion, improved diagnostic imaging, and effective surgical treatment of the disease have led to progressive awareness of the pathology. We present our institutional experience with constrictive pericarditis after lung transplant in an effort to investigate the cause and natural history of the disease. METHODS: From October 2005 to October 2018, 1234 patients underwent orthotopic lung transplantation at Duke University Hospital. An institutional database was queried to identify incident patients and determine baseline clinical data. At a median of 11.2 months (interquartile range = 4.6-28.6 mo), 10 patients (0.8%) developed constrictive pericarditis. Simple descriptive statistics were used to describe cohort characteristics and identify variables associated with constrictive pericarditis after lung transplantation. RESULTS: The indication for transplantation at index operation was idiopathic pulmonary fibrosis in 8 of 10 patients (1.2% of the 760 restrictive lung disease patients transplanted in the same time period). All 10 patients presented with worsening dyspnea and pleural effusions. Right heart catheterization confirmed constrictive physiology in all cases. Eight patients underwent pericardiectomy with improvement in cardiovascular hemodynamics and resolution of symptoms with no 30-day mortality. CONCLUSIONS: Diagnosis of constrictive pericarditis should be considered in patients with new-onset heart failure symptoms or recurrent pleural effusions within 2 years of lung transplantation. Idiopathic pulmonary fibrosis may be associated with increased risk for constrictive pericarditis. Pericardiectomy is a safe and effective treatment for posttransplant constrictive pericarditis.
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Trasplante de Pulmón/efectos adversos , Pericardiectomía/métodos , Pericarditis Constrictiva/etiología , Complicaciones Posoperatorias , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pericarditis Constrictiva/diagnóstico , Pericarditis Constrictiva/cirugía , Pronóstico , Estudios Retrospectivos , Factores de TiempoRESUMEN
Considering the association between children's quality of relationships with teachers and their academic adjustment, information pertaining to how abused children are functioning in their relationships with teachers could be useful in promoting their academic success- yet there has been limited research in this area. The purpose of this study was to use cluster analyses to explore within-group differences in relational schemas and quality of student-teacher relationships for 70 abused children. Two clusters of abused children emerged, and as hypothesized, there were significant differences in student-teacher relationships for the two clusters. The cluster with more positive relational schemas had less conflict and less dependency reported by their teachers compared to the cluster with negative relational schemas. However, there were no differences between the clusters in terms of closeness with teachers. Implications for practice in schools is discussed.
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Organophosphorus pesticides are some of the most widely used insecticides in the US, and spray drift may result in human exposures. We investigate sampling methodologies using the polyurethane foam passive air sampling device to measure cumulative monthly airborne concentrations of OP pesticides chlorpyrifos, azinphos-methyl, and oxygen analogs. Passive sampling rates (m(3)d(-1)) were determined using calculations using chemical properties, loss of depuration compounds, and calibration with side-by-side active air sampling in a dynamic laboratory exposure chamber and in the field. The effects of temperature, relative humidity, and wind velocity on outdoor sampling rates were examined at 23 sites in Yakima Valley, Washington. Indoor sampling rates were significantly lower than outdoors. Outdoor rates significantly increased with average wind velocity, with high rates (>4m(3)d(-1)) observed above 8ms(-1). In exposure chamber studies, very little oxygen analog was observed on the PUF-PAS, yet substantial amounts chlorpyrifos-oxon and azinphos methyl oxon were measured in outdoor samples. PUF-PAS is a practical and useful alternative to AAS because it results in little artificial transformation to the oxygen analog during sampling, it provides cumulative exposure estimates, and the measured sampling rates were comparable to rates for other SVOCs. It is ideal for community based participatory research due to low subject burden and simple deployment in remote areas.
Asunto(s)
Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente/instrumentación , Plaguicidas/análisis , Agricultura , Azinfosmetilo/análisis , Cloropirifos/análogos & derivados , Cloropirifos/análisis , Cromatografía Líquida de Alta Presión , Poliuretanos/química , Espectrometría de Masas en Tándem , TemperaturaRESUMEN
Side-by-side active air sampling for the organophosphorus (OP) pesticide, chlorpyrifos (CPF) and its oxygen analog, chlorpyrifos-oxon (CPF-O) was conducted with two recommended air sampling matrices: OSHA Versatile Sampling (OVS) tubes with XAD-2 resin, polyurethane foam (PUF) tubes, and passive PUF deposition disks. The study compared the proportion of artificially transformed CPF-O in the laboratory and in the field during a tree fruit application in Washington State. Lab results demonstrated that the NIOSH-recommended OVS tubes artificially transformed up to 32% of CPF to CPF-O during the sampling process, whereas PUF tubes had little to no artificial transformation (⩽0.1%). In the field, the proportion of CPF-O in the sample was significantly higher on OVS tubes than on PUF tubes (p<0.001), confirming that OVS tubes were converting a significant portion of CPF to CPF-O. In addition, PUF tubes reported measurable levels CPF-O in the field even when no artificial transformation was expected. We conclude that the PUF matrix is the superior sampling medium for OP oxygen analogs when compared to XAD-two resin. Community-located PUF tube samples 24h post-application had considerably higher levels CPF-O (16-21ngm(-3)) than near field samples during application (2-14ngm(-3)), suggesting that the oxygen analog is volatile and formed during atmospheric transport. It is recommended that worker and community risk assessments begin to take into consideration the presence of the more toxic oxygen analogs when measuring for OP pesticide mixtures.
Asunto(s)
Contaminantes Atmosféricos/análisis , Cloropirifos/análisis , Plaguicidas/análisis , Poliestirenos/química , Poliuretanos/química , Adsorción , Agricultura , Contaminantes Atmosféricos/química , Cloropirifos/química , Monitoreo del Ambiente , Oxígeno/química , Plaguicidas/química , Fotólisis , Rayos UltravioletaRESUMEN
This research describes the design, deployment, performance, and acceptability of a novel outdoor active air sampler to provide simultaneous measurements of multiple contaminants at timed intervals for the Aggravating Factors of Asthma in Rural Environment (AFARE) study-a longitudinal cohort of 50 children in Yakima Valley, Washington. The sampler was constructed of multiple sampling media connected to individual critical orifices and a rotary vane vacuum pump. It was connected to a timed control valve system to collect 24 hours samples every six days over 18 months. We describe a spatially representative approach with both quantitative and qualitative location criteria to deploy a network of 14 devices at participant residences in a rural region (20 × 60 km). Overall the sampler performed well, as the concurrent mean sample flow rates were within or above the ranges of recommended sampling rates for each exposure metric of interest. Acceptability was high among the study population of Hispanic farmworker participant households. The sampler design may prove useful for future urban and rural community-based studies with aims at collecting multiple contaminant data during specific time periods.