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OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.
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Secuenciación del Exoma , Cardiopatías Congénitas , Diagnóstico Prenatal , Humanos , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/diagnóstico , Femenino , Embarazo , Secuenciación del Exoma/métodos , Diagnóstico Prenatal/métodosRESUMEN
INTRODUCTION: Pump thrombosis remains a feared complication following placement of durable left ventricular assist devices (LVAD) and can be particularly detrimental to individuals being bridged to heart transplantation. Complications associated with this malfunction not only increase morbidity related to right heart failure, hemolysis, and other organ failure, but may ultimately jeopardize a patient's heart transplant candidacy. Additionally, reoperation for durable ventricular device replacement not only poses additional surgical risks to patients but can potentially complicate or even prohibit transplantation in the future. CASE REPORT: This case report describes a novel configuration of temporary, groin-free, percutaneously-deployed biventricular mechanical circulatory devices to support a patient with biventricular failure due to partial LVAD thrombosis. DISCUSSION/CONCLUSION: The use of less invasive mechanical support measures, such as the approach described here, may help patients achieve adequate hemodynamic support while allowing them to remain ambulatory and facilitate successful bridging to heart transplantation.
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Cancer cells frequently present elevated intracellular iron levels, which are thought to facilitate an enhanced proliferative capacity. Targeting iron metabolism within cancer cells presents an avenue to enhance therapeutic responses, necessitating the use of non-invasive models to modulate iron manipulation to predict responses. Moreover, the ubiquitous nature of iron necessitates the development of unique, non-invasive markers of metabolic disruptions to develop more personalized approaches and enhance the clinical utility of these approaches. Ferritin, an iron storage enzyme that is often upregulated as a response to iron accumulation, plays a central role in iron metabolism and has been frequently associated with unfavorable clinical outcomes in cancer. Herein, we demonstrate the successful utility, validation, and functionality of a doxycycline-inducible ferritin heavy chain (FtH) overexpression model in H1299T non-small-cell lung cancer (NSCLC) cells. Treatment with doxycycline increased the protein expression of FtH with a corresponding decrease in labile iron in vitro and in vivo, as determined by calcein-AM staining and EPR, respectively. Moreover, a subsequent increase in TfR expression was observed. Furthermore, T2* MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T2* relaxation times can be used to monitor changes in FtH expression in tumors with bidirectional correlations depending on the model system. Overall, this study describes the development of an FtH overexpression NSCLC model and its correlation with T2* mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Ferritinas/genética , Ferritinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Doxiciclina/farmacología , Neoplasias Pulmonares/diagnóstico por imagen , Hierro/metabolismo , Apoferritinas/genética , Apoferritinas/metabolismo , Imagen por Resonancia Magnética/métodosRESUMEN
Population contact patterns fundamentally determine the spread of directly transmitted airborne pathogens such as SARS-CoV-2 and influenza. Reliable quantitative estimates of contact patterns are therefore critical to modeling and reducing the spread of directly transmitted infectious diseases and to assessing the effectiveness of interventions intended to limit risky contacts. While many countries have used surveys and contact diaries to collect national-level contact data, local-level estimates of age-specific contact patterns remain rare. Yet, these local-level data are critical since disease dynamics and public health policy typically vary by geography. To overcome this challenge, we introduce a flexible model that can estimate age-specific contact patterns at the subnational level by combining national-level interpersonal contact data with other locality-specific data sources using multilevel regression with poststratification (MRP). We estimate daily contact matrices for all 50 US states and Washington DC from April 2020 to May 2021 using national contact data from the US. Our results reveal important state-level heterogeneities in levels and trends of contacts across the US over the course of the COVID-19 pandemic, with implications for the spread of respiratory diseases.
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COVID-19 , Enfermedades Transmisibles , Gripe Humana , Estados Unidos/epidemiología , Humanos , SARS-CoV-2 , Pandemias , COVID-19/epidemiología , Enfermedades Transmisibles/epidemiología , Gripe Humana/epidemiologíaRESUMEN
BACKGROUND: Whole blood (WB) is carried by special operations forces as part of a remote damage control resuscitation strategy. The effects of an underwater mission on the quality and coagulation profile of WB were simulated by exposure to hyperbaric pressures in a chamber. METHODS: WB units collected in CPDA-1 were exposed to three different combinations of hyperbaric pressure and duration of exposure: Group A 153.52 kPa (15.24 msw; 1.52 atm) for 4 h; n = 9, Group B 506.63 kPa (50.29 msw; 5.00 atm) for 1 h; n = 9, Group C 153.52 kPa (15.24 msw; 1.52 atm) for 1 h; n = 7. The following parameters were measured on each unit: prothrombin time/international normalized ratio, activated partial thromboplastin time, thromboelastography and concentration determinations of platelets, lactate, fibrinogen, and lactate dehydrogenase. Each sample underwent baseline, prepressurization, immediate postpressurization, and 6 h postpressurization laboratory testing. RESULTS: Six hours following hyperbaric exposure, the lactate concentration in group C was higher than prepressurization measurement and the platelet concentration in Group A was lower than prepressurization measurement. There were no changes in any of the other analyzed biochemical, coagulation and thromboelastogram parameters following exposure to hyperbaric stress. DISCUSSION: These data suggest that pressurization of WB up to 5 atm did not impact parameters tested. Changes observed in lactate and platelet count need further study, as well as complementary testing of red blood cell integrity. Further investigation of the hyperbaric extremes is necessary to determine if there is a damage inducing pressure to which WB should not be exposed.
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Personal Militar , Plaquetas , Conservación de la Sangre , Humanos , Lactatos , TromboelastografíaRESUMEN
Skeletal toxicity has been reported following exposure to polychlorinated biphenyl (PCB) mixtures. However, molecular mechanisms remain poorly understood. We exposed groups of male 4-5-week-old Sprague-Dawley rats to 3,3', 4, 4', 5-pentachlorobiphenyl (PCB 126), a dioxin-like coplanar PCB congener by a single i.p. injection of 5 µmol/kg in soy oil vehicle or vehicle alone. After 4 weeks, rats were euthanized. PCB exposure resulted in hypocalcemia (P < 0.05) and significant increases in serum PTH without changes in serum phosphorous. Hyperparathyroidism was accompanied by increased expression of mRNAs of vitamin D3 metabolizing cytochrome P450 enzymes CYP27B1 and CYP24 in the kidney (P < 0.05). PCB exposure also reduced body weight, serum IGF-1, and hepatic expression of mRNAs encoding the male-specific GH-pattern-regulated CYP2C11 and CYP3A2 relative to controls (P < 0.05). PCB exposure reduced long bone length, diameter, and surface area, but increased trabecular thickness and volume (P < 0.05). Serum osteocalcin (P < 0.05), a marker and a regulator of bone formation, was reduced, but PCB exposure had no effect on the bone resorption marker RatLaps. Exposure of human intestinal Caco-2 cells to 10-100 nM PCB 126 in the presence of vitamin D3 resulted in inhibition of mRNAs for the calcium transporters TRPV6 and PMCA1b (P < 0.05). In addition, PCB 126 suppressed osteoblastogenesis in primary bone marrow mesenchymal stem cell cultures which was blunted by the AhR antagonist CH-223191. These data provide novel evidence that skeletal toxicity after exposure to PCB 126 is a result of disruption of calcium homeostasis and the GH-IGF-1 axis, and involves direct AhR-mediated effects on bone formation.
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Calcio/metabolismo , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Animales , Biomarcadores/metabolismo , Células CACO-2 , Disruptores Endocrinos/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Glucuronidasa/genética , Glucuronidasa/metabolismo , Hormona del Crecimiento/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Klotho , Masculino , Ratas Sprague-Dawley , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Tibia/diagnóstico por imagen , Tibia/efectos de los fármacos , Tibia/crecimiento & desarrollo , beta Catenina/metabolismoRESUMEN
Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, we investigated the role of dietary fat type in tumor promotion by high-fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth.
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Carcinogénesis/patología , Dieta Alta en Grasa/efectos adversos , Proteínas de Unión al GTP/metabolismo , Microbioma Gastrointestinal/fisiología , Neoplasias Hepáticas/etiología , Proto-Oncogenes/fisiología , Animales , Ácidos y Sales Biliares/metabolismo , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiología , Carcinoma Hepatocelular/patología , Grasas de la Dieta/efectos adversos , Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos/metabolismo , Femenino , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Hígado/microbiología , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Chronic alcohol consumption increases bone resorption and decreases bone formation. A major component of ethanol (EtOH) pathology in bone is the generation of excess reactive oxygen species (ROS). The ROS-generating NADPH oxidase-4 (NOX4) is proposed to drive much of the EtOH-induced suppression of bone formation. Here, 13-week-old male wild-type (WT) and NOX4-/- mice were pair fed (PF) a high-fat (35%), Lieber-DeCarli liquid diet with or without EtOH at 30% of their total calories for 12 weeks. Micro-computed tomography analysis demonstrated significant decreases in trabecular bone volume/total volume (BV/TV) percentage and cortical thickness in WT, EtOH-fed mice compared with PF controls. EtOH-fed NOX4-/- mice also displayed decreased trabecular BV/TV and trabecular number compared with PF (P < 0.05). However, NOX4-/- mice were protected against EtOH-induced decreases in cortical thickness (P < 0.05) and decreases in collagen1 and osteocalcin mRNA expression in cortical bone (P < 0.05). In WT and NOX4-/- vertebral bone, EtOH suppressed expression of Wnt signaling components that promote osteoblast maturation. A role for NOX4 in EtOH inhibition of osteoblast differentiation was further demonstrated by protection against EtOH inhibition of osteoblastogenesis in ex vivo bone marrow cultures from NOX4-/-, but not p47phox-/- mice lacking active NADPH oxidase-2. However, bone marrow cultures from NOX4-/- mice formed fewer osteoblastic colonies compared with WT cultures (P < 0.05), suggesting a role for NOX4 in the maintenance of mesenchymal progenitor cell populations. These data suggest that NOX4 deletion is partially protective against EtOH effects on osteoblast differentiation, but may predispose bone to osteogenic impairments.
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Hueso Esponjoso/citología , Eliminación de Gen , NADPH Oxidasa 4/deficiencia , NADPH Oxidasa 4/genética , Osteoblastos/citología , Animales , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/efectos de los fármacos , Hueso Esponjoso/fisiología , Etanol/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Microtomografía por Rayos XRESUMEN
BACKGROUND: Glutathione S-transferase A4-4 (GSTA4) is a key enzyme for removal of toxic lipid peroxidation products such as 4-hydroxynonenal (4-HNE). In this study, we examined the potential role of GSTA4 on protein carbonylation and progression of alcoholic liver disease by examining the development of liver injury in male wild-type (WT) SV/J mice and SV/J mice lacking functional GSTA4 (GSTA4-/- mice). METHODS: Adult male WT and GSTA4-/- mice were fed chow (N = 10 to 12) or high-fat Lieber-DeCarli liquid diets containing up to 28% calories as ethanol (EtOH) (N = 18 to 20) for 116 days. At the end of the study, half of the EtOH-fed mice were acutely challenged with an EtOH binge (3 g/kg given intragastrically) 12 hours before sacrifice. Carbonylation of liver proteins was assessed by immunohistochemical staining for 4-HNE adduction and by comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) of purified carbonylated proteins. RESULTS: Chronic EtOH intake significantly increased hepatic 4-HNE adduction and protein carbonylation, including carbonylation of ribosomal proteins. EtOH intake also resulted in steatosis and increased serum alanine aminotransferase. Hepatic infiltration with B cells, T cells, and neutrophils and mRNA expression of pro-inflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)γ was modest in WT mice. However, an EtOH binge increased hepatic necrosis, hepatic cell proliferation, and expression of TNFα mRNA (p < 0.05). EtOH treatment of GSTA4-/- mice increased B-cell infiltration and increased mRNA expression of TNFα and IFNγ and of matrix remodeling markers MMP9, MMP13, and Col1A1 (p < 0.05). GSTA4-/- mice exhibited panlobular rather than periportal distribution of 4-HNE-adducted proteins and increased overall 4-HNE staining after EtOH binge. Comprehensive LC-MS of carbonylated proteins identified 1,022 proteins of which 189 were unique to the GSTA4-/- group. CONCLUSIONS: These data suggest long-term adaptation to EtOH in WT mice does not occur in GSTA4-/- mice. Products of lipid peroxidation appear to play a role in inflammatory responses due to EtOH. And EtOH effects on B-cell infiltration and autoimmune responses may be secondary to formation of carbonyl adducts.
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Etanol/toxicidad , Glutatión Transferasa/deficiencia , Glutatión Transferasa/genética , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/metabolismo , Carbonilación Proteica/fisiología , Animales , Etanol/administración & dosificación , Glutatión Transferasa/química , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías Alcohólicas/patología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Carbonilación Proteica/efectos de los fármacos , Estructura Secundaria de ProteínaRESUMEN
BACKGROUND: Chronic alcohol consumption leads to increased fracture risk and an elevated risk of osteoporosis by decreasing bone accrual through increasing osteoclast activity and decreasing osteoblast activity. We have shown that this mechanism involves the generation of reactive oxygen species (ROS) produced by NADPH oxidases. It was hypothesized that different dietary antioxidants, N-acetyl cysteine (NAC; 1.2 mg/kg/d), and α-tocopherol (Vit.E; 60 mg/kg/d) would be able to attenuate the NADPH oxidase-mediated ROS effects on bone due to chronic alcohol intake. METHODS: To study the effects of these antioxidants, female mice received a Lieber-DeCarli liquid diet containing ethanol (EtOH) with or without additional antioxidant for 8 weeks. RESULTS: Tibias displayed decreased cortical bone mineral density in both the EtOH and EtOH + antioxidant groups compared to pair-fed (PF) and PF + antioxidant groups (p < 0.05). However, there was significant protection from trabecular bone loss in mice fed either antioxidant (p < 0.05). Microcomputed tomography analysis demonstrated a significant decrease in bone volume (bone volume/tissue volume) and trabecular number (p < 0.05), along with a significant increase in trabecular separation in the EtOH compared to PF (p < 0.05). In contrast, the EtOH + NAC and EtOH + Vit.E did not statistically differ from their respective PF controls. Ex vivo histologic sections of tibias were stained for nitrotyrosine, an indicator of intracellular damage by ROS, and tibias from mice fed EtOH exhibited significantly more staining than PF controls. EtOH treatment significantly increased the number of marrow adipocytes per mm as well as mRNA expression of aP2, an adipocyte marker in bone. Only NAC was able to reduce the number of marrow adipocytes to PF levels. EtOH-fed mice exhibited reduced bone length (p < 0.05) and had a reduced number of proliferating chondrocytes within the growth plate. NAC and Vit.E prevented this (p < 0.05). CONCLUSIONS: These data show that alcohol's pathological effects on bone extend beyond decreasing bone mass and suggest a partial protective effect of the dietary antioxidants NAC and Vit.E at these doses with regard to alcohol effects on bone turnover and bone morphology.
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Antioxidantes/administración & dosificación , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/inducido químicamente , Enfermedades Óseas Metabólicas/prevención & control , Etanol/toxicidad , Animales , Densidad Ósea/fisiología , Enfermedades Óseas Metabólicas/metabolismo , Femenino , Ratones , Distribución Aleatoria , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
PURPOSE: The adverse health effects from climate change demand action from the nursing profession. This article examines the calls to action, the status of climate change in nursing education, and challenges and recommendations for nursing education related to climate change and human health. ORGANIZING CONSTRUCT: Discussion paper. FINDINGS: The integration of climate change into nursing education is essential so that knowledge, skills, and insights critical for clinical practice in our climate-changing world are incorporated in curricula, practice, research, and policy. Our Ecological Planetary Health Model offers a framework for nursing to integrate relevant climate change education into nursing curricula and professional nursing education. Nursing education can offer a leadership role to address the mitigation, adaptation, and resilience strategies for climate change. CONCLUSIONS: An ecological framework is valuable for nursing education regarding climate change through its consideration of political, cultural, economic, and environmental interrelationships on human health and the health of the planet. Knowledge of climate change is important for integration into basic and advanced nursing education, as well as professional education for nurses to address adverse health impacts, climate change responses policy, and advocacy roles. CLINICAL RELEVANCE: For current and future nurses to provide care within a climate-changing environment, nursing education has a mandate to integrate knowledge about climate change issues across all levels of nursing education. Competence in nursing practice follows from knowledge and skill acquisition gained from integration of climate change content into nursing education.
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Cambio Climático , Educación en Enfermería/organización & administración , Salud Ambiental/educación , Curriculum , Humanos , Investigación en Educación de Enfermería , Investigación en Evaluación de EnfermeríaRESUMEN
Chronic ethyl alcohol (EtOH) consumption results in reactive oxygen species (ROS) generation in bone and osteopenia due to increased bone resorption and reduced bone formation. In this study, transgenic C57Bl/6J mice overexpressing human catalase (TgCAT) were used to test whether limiting excess hydrogen peroxide would protect against EtOH-mediated bone loss. Micro-computed tomography analysis of the skeletons of 6-week-old female chow-fed TgCAT mice revealed a high bone mass phenotype with increased cortical bone area and thickness as well as significantly increased trabecular bone volume (P < 0.05). Six-week-old wild-type (WT) and TgCAT female mice were chow fed or pair fed (PF) liquid diets with or without EtOH, approximately 30% of calories, for 8 weeks. Pair feeding of WT had no demonstrable effect on the skeleton; however, EtOH feeding of WT mice significantly reduced cortical and trabecular bone parameters along with bone strength compared with PF controls (P < 0.05). In contrast, EtOH feeding of TgCAT mice had no effect on trabecular bone compared with PF controls. At 14 weeks of age, there was significantly less trabecular bone and cortical cross-sectional area in TgCAT mice than WT mice (P < 0.05), suggesting impaired normal bone accrual with age. TgCAT mice expressed less collagen1α and higher sclerostin mRNA (P < 0.05), suggesting decreased bone formation in TgCAT mice. In conclusion, catalase overexpression resulted in greater bone mass than in WT mice at 6 weeks and lower bone mass at 14 weeks. EtOH feeding induced significant reductions in bone architecture and strength in WT mice, but TgCAT mice were partially protected. These data implicate ROS signaling in the regulation of bone turnover in an age-dependent manner, and indicate that excess hydrogen peroxide generation contributes to alcohol-induced osteopenia.
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Envejecimiento/metabolismo , Remodelación Ósea/efectos de los fármacos , Catalasa/metabolismo , Etanol/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Envejecimiento/patología , Animales , Fenómenos Biomecánicos , Densidad Ósea/efectos de los fármacos , Catalasa/genética , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Fémur/patología , Peróxido de Hidrógeno/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Tibia/efectos de los fármacos , Tibia/metabolismo , Tibia/patologíaRESUMEN
BACKGROUND: Although many minority patients would prefer a provider of their own race/ethnicity, the influence of this relationship on patient-provider communication remains unknown. This analysis examined the effect of patient-provider race/ethnicity concordance on patient-reported provider communication quality using data from the Medical Expenditure Panel Survey years 2002-2012. METHODS: Ordinary least squares regressions were executed on communication rating, measured by the Consumer Assessment of Health Providers and Systems. RESULTS: Only 13.8% of black, non-Hispanic patients reported their usual source of care provider matched their race/ethnicity, compared with 94.4% of white, non-Hispanic patients and 43.8% of Hispanic patients. Differences in communication ratings were driven by patient race, rather than provider race. Although black, non-Hispanic patients rate their communication significantly higher than their counterparts overall, there was no significant influence of patient-provider racial concordance on ratings of communication when controlling for other sociodemographic variables. CONCLUSIONS: Minorities may seek the services of minority providers, but they are not more satisfied with patient-provider communication experience than when in race-discordant provider arrangements.
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Comunicación , Relaciones Médico-Paciente , Grupos Raciales/psicología , Adolescente , Adulto , Negro o Afroamericano/psicología , Femenino , Hispánicos o Latinos/psicología , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente/etnología , Satisfacción del Paciente/estadística & datos numéricos , Población Blanca/psicología , Adulto JovenRESUMEN
PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.
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Lesión Renal Aguda , Compuestos Organometálicos , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Anciano , Cisplatino/farmacología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Superóxidos , Ratones Endogámicos C57BL , Riñón , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND: Shifts from in-person learning to virtual and hybrid learning modes in response to the coronavirus pandemic potentially impacted children's physical, emotional, social, and academic development. This study examined the association between virtual, in-person, and hybrid learning modality with parent-reported quality of life among US students (kindergarten-12th) in early 2021. METHODS: Parents reported current learning modality and physical, emotional, social, and school quality of life for children (aged 5-11, n = 1381) and adolescents (aged 12-17, n = 640). Multivariable logistic regression models assessed the odds of impaired quality of life by learning modality. RESULTS: Among children, hybrid and virtual learners had greater odds of impaired quality of life (adjusted odds ratio [aOR] 1.79, 95% confidence interval [CI] 1.22, 2.64 and aOR 1.57, 95% CI 1.17, 2.12, respectively) relative to in-person learners. Among adolescents, virtual learners had greater odds impaired physical (aOR 2.06, 95% CI 1.26, 3.38) and school function (aOR 2.23, 95% CI 1.38, 3.61) relative to in-person learners. CONCLUSIONS: Learning modality was associated with student well-being, and appropriate alternative learning modalities may differ for younger and older students in terms of educational quality and quality of life.
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Coronavirus , Calidad de Vida , Adolescente , Humanos , Niño , Calidad de Vida/psicología , Pandemias , Instituciones Académicas , EscolaridadRESUMEN
In the United States, much has been learned about the determinants of longevity from survey data and aggregated tabulations. However, the lack of large-scale, individual-level administrative mortality records has proven to be a barrier to further progress. We introduce the CenSoc datasets, which link the complete-count 1940 U.S. Census to Social Security mortality records. These datasets-CenSoc-DMF (N = 4.7 million) and CenSoc-Numident (N = 7.0 million)-primarily cover deaths among individuals aged 65 and older. The size and richness of CenSoc allows investigators to make new discoveries into geographic, racial, and class-based disparities in old-age mortality in the United States. This article gives an overview of the technical steps taken to construct these datasets, validates them using external aggregate mortality data, and discusses best practices for working with these datasets. The CenSoc datasets are publicly available, enabling new avenues of research into the determinants of mortality disparities in the United States.
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Mortalidad , Grupos Raciales , Humanos , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Negative pressure pulmonary edema (NPPE) may result in respiratory failure refractory to conventional management strategies. Venovenous extracorporeal membrane oxygenation (VV ECMO) can serve as a rescue therapy in cases of severe respiratory failure. Rapid initiation of VV ECMO can decrease morbidity and mortality while facilitating early liberation from mechanical ventilation and promoting early rehabilitation. We describe the successful utilization of VV ECMO as rescue therapy for severe NPPE-induced hypoxic respiratory failure and peri-arrest state in the postanesthesia care unit (PACU) in a patient with postextubation airway obstruction after undergoing patellar tendon repair.
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Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.