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The development of the kidney involves essential cellular processes, such as cell proliferation and differentiation, which are led by interactions between multiple signaling pathways. Xanthine dehydrogenase (XDH) catalyzes the reaction producing uric acid in the purine catabolism, which plays a multifaceted role in cellular metabolism. Our previous study revealed that the genetic ablation of the Xdh gene in rats leads to smaller kidneys, kidney damage, decline of renal functions, and failure to thrive. Rats, unlike humans, continue their kidney development postnatally. Therefore, we explored whether XDH plays a critical role in kidney development using SS-/- rats during postnatal development phase. XDH expression was significantly increased from postnatal day 5 to 15 in wild-type but not homozygote rat kidneys. The transcriptomic profile of renal tissue revealed several dysregulated pathways due to the lack of Xdh expression with the remodeling in inflammasome, purinergic signaling, and redox homeostasis. Further analysis suggested that lack of Xdh affects kidney development, likely via dysregulation of epidermal growth factor and its downstream STAT3 signaling. The present study showed that Xdh is essential for kidney maturation. Our data, alongside the previous research, suggests that loss of Xdh function leads to developmental issues, rendering them vulnerable to kidney diseases in adulthood.
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Rim , Xantina Desidrogenase , Humanos , Ratos , Animais , Xantina Desidrogenase/genética , Xantina Desidrogenase/metabolismo , Rim/metabolismo , Ácido ÚricoRESUMO
Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.
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Obstrução das Vias Respiratórias , Doença Pulmonar Obstrutiva Crônica , Humanos , Inquéritos Nutricionais , Estudos Transversais , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Dispneia/diagnóstico , Espirometria , Volume Expiratório ForçadoRESUMO
Background: Evaluation for activating mutations in KRAS, NRAS, and BRAF in colorectal cancer (CRC) and in KRAS in pancreatic ductal adenocarcinoma (PDAC) is essential for clinical care. Plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) allows convenient assessment of a tumor's molecular profile, however low tumor DNA shedding limits sensitivity. We investigated mutant allele frequency (MAF) of other oncogenic dominant genes to identify a threshold for accurate detection of KRAS, NRAS, and BRAF (RAS/RAF) mutations in cfDNA. Methods: Molecular and clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA study. Patients with CRC or PDAC and a KRAS, NRAS, or BRAF activating single nucleotide variant (SNV) present on tissue NGS and with available cfDNA assays were included. Recursive partitioning and Wilcoxon-rank statistics methods identified potential cut-points for discriminative MAF values. Results: One hundred and thirty-five CRC and 30 PDAC cases with 198 total cfDNA assays met criteria. Greatest non-RAS/RAF dominant gene MAF of 0.34% provided maximum discrimination for predicting RAS/RAF SNV detection. Sensitivity for RAS/RAF SNVs increased with dominant gene MAF, with MAF ≥1% predicting sensitivity >98%, MAF between 0.34 and 1% predicting sensitivity of 84.0%, and MAF £0.34% predicting sensitivity of 50%. For 43 cfDNA assays that did not detect RAS/RAF SNVs, 18 assays detected 34 other oncogenic variants, of which 80.6% were not also detected on tissue. Conclusions: Non-RAS/RAF dominant oncogenic mutation MAF ≥1% on cfDNA NGS predicts high sensitivity to detect RAS/RAF oncogenic SNVs in CRC and PDAC. MAF £0.34% indicates an assay may not reliably detect RAS/RAF SNVs, despite detection on tissue testing. Most variants from assays that did not detect RAS/RAF had MAF <1% and were not detected on tissue, suggesting potential confounding. These data suggest a practical approach to determining cfDNA assay adequacy, with implications for guiding clinical decisions in CRC and PDAC.
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BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.
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Doença Pulmonar Obstrutiva Crônica , Humanos , Negro ou Afro-Americano , Estudos de Coortes , Estudos Transversais , Volume Expiratório Forçado , Estudos Longitudinais , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Espirometria , Capacidade Vital , Pessoa de Meia-Idade , Brancos , Fumar/efeitos adversosRESUMO
BACKGROUND: Despite institutional perioperative bundles and national infection prevention guidelines, surgical site infection (SSI) after a major abdominal operation remains a significant source of morbidity. Negative pressure therapy (NPT) has revolutionized care for open wounds but the role of closed incision NPT (ciNPT) remains unclear. STUDY DESIGN: We conducted a multi-institutional randomized controlled trial evaluating SSI after major elective colorectal or hepatopancreatobiliary surgery (Clinical Trial Registration: NCT01905397). Patients were randomized to receive conventional wound care vs ciNPT (Prevena Incision Management System, 3M Health Care, San Antonio, TX). The primary endpoint was postoperative incisional SSI. SSI incidence was evaluated at inpatient days 4 or 5 and again at postoperative day 30. With 144 patients studied, the estimated power was 85% for detecting a difference in SSIs between 17% and 5% (conventional vs ciNPT; 1-sided α = 0.1). Secondary endpoints included SSI type, length of stay, 30-day readmission, and mortality. T-tests were used to compare continuous variables between treatments; similarly, chi-square tests were used to compare categorical variables. A p value of <0.05 was considered significant, except in the primary comparison of incisional and organ SSIs. RESULTS: During the 2013 to 2021 time period, 164 patients were randomized, and of those, 138 were evaluable (ciNPT n = 63; conventional n = 75). Incisional SSIs occurred in 9 (14%) patients in the ciNPT group and 13 (17%) patients in the conventional group (p = 0.31). Organ or space SSIs occurred in 7 (11%) patients in the ciNPT group and 10 (13%) in the conventional therapy group (p = 0.35). CONCLUSIONS: In this multi-institutional, randomized controlled trial of patients undergoing colorectal or hepatopancreatobiliary surgery, incidence of incisional SSIs between ciNPT and conventional wound therapy was not statistically significant. Future trials should focus on patient populations undergoing specific procedures types that have the highest risk for SSI.
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Neoplasias Colorretais , Procedimentos Cirúrgicos do Sistema Digestório , Tratamento de Ferimentos com Pressão Negativa , Ferida Cirúrgica , Humanos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Resultado do Tratamento , Ferida Cirúrgica/complicações , Tratamento de Ferimentos com Pressão Negativa/métodosRESUMO
BACKGROUND: Autoimmune (AI) diseases appear to be a product of genetic predisposition and environmental triggers. Disruption of the skin barrier causes exacerbation of psoriasis/eczema. Oxidative stress is a mechanistic pathway for pathogenesis of the disease and is also a primary mechanism for the detrimental effects of air pollution. METHODS: We evaluated the association between autoimmune skin diseases (psoriasis or eczema) and air pollutant mixtures in 9060 subjects from the Personalized Environment and Genes Study (PEGS) cohort. Pollutant exposure data on six criteria air pollutants are publicly available from the Center for Air, Climate, and Energy Solutions and the Atmospheric Composition Analysis Group. For increased spatial resolution, we included spatially cumulative exposure to volatile organic compounds from sites in the United States Environmental Protection Agency Toxic Release Inventory and the density of major roads within a 5 km radius of a participant's address from the United States Geological Survey. We applied logistic regression with quantile g-computation, adjusting for age, sex, diagnosis with an autoimmune disease in family or self, and smoking history to evaluate the relationship between self-reported diagnosis of an AI skin condition and air pollution mixtures. RESULTS: Only one air pollution variable, sulfate, was significant individually (OR = 1.06, p = 3.99E-2); however, the conditional odds ratio for the combined mixture components of PM2.5 (black carbon, sulfate, sea salt, and soil), CO, SO2, benzene, toluene, and ethylbenzene is 1.10 (p-value = 5.4E-3). SIGNIFICANCE: While the etiology of autoimmune skin disorders is not clear, this study provides evidence that air pollutants are associated with an increased prevalence of these disorders. The results provide further evidence of potential health impacts of air pollution exposures on life-altering diseases. SIGNIFICANCE AND IMPACT STATEMENT: The impact of air pollution on non-pulmonary and cardiovascular diseases is understudied and under-reported. We find that air pollution significantly increased the odds of psoriasis or eczema in our cohort and the magnitude is comparable to the risk associated with smoking exposure. Autoimmune diseases like psoriasis and eczema are likely impacted by air pollution, particularly complex mixtures and our study underscores the importance of quantifying air pollution-associated risks in autoimmune disease.
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Poluentes Atmosféricos , Poluição do Ar , Eczema , Psoríase , Humanos , Estados Unidos/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Eczema/induzido quimicamente , Eczema/epidemiologia , Psoríase/induzido quimicamente , Psoríase/epidemiologia , Psoríase/genéticaRESUMO
Purpose of review: We reviewed the exposure assessments of ambient air pollution used in studies of fertility, fecundability, and pregnancy loss. Recent findings: Comprehensive literature searches were performed in the PUBMED, Web of Science, and Scopus databases. Of 168 total studies, 45 met the eligibility criteria and were included in the review. We find that 69% of fertility and pregnancy loss studies have used one-dimensional proximity models or surface monitor data, while only 35% have used the improved models, such as land-use regression models (4%), dispersion/chemical transport models (11%), or fusion models (20%). No published studies have used personal air monitors. Summary: While air pollution exposure models have vastly improved over the past decade from simple, one-dimensional distance or air monitor data, to models that incorporate physiochemical properties leading to better predictive accuracy, precision, and increased spatiotemporal variability and resolution, the fertility literature has yet to fully incorporate these new methods. We provide descriptions of each of these air pollution exposure models and assess the strengths and limitations of each model, while summarizing the findings of the literature on ambient air pollution and fertility that apply each method.
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Nontuberculous mycobacteria (NTM) are environmental organisms that can cause opportunistic pulmonary disease with species diversity showing significant regional variation. In the United States, Hawai'i shows the highest rate of NTM pulmonary disease. The need for improved understanding of NTM reservoirs led us to identify NTM from patient respiratory specimens and compare NTM diversity between outdoor and indoor locations in Hawai'i. A total of 545 water biofilm samples were collected from 357 unique locations across Kaua'i (n = 51), O'ahu (n = 202), Maui (n = 159), and Hawai'i Island (n = 133) and divided into outdoor (n = 179) or indoor (n = 366) categories. rpoB sequence analysis was used to determine NTM species and predictive modeling applied to develop NTM risk maps based on geographic characteristics between environments. M. chimaera was frequently identified from respiratory and environmental samples followed by M. chelonae and M. abscessus; yet significantly less NTM were consistently recovered from outdoor compared to indoor biofilms, as exemplified by showerhead biofilm samples. While the frequency of M. chimaera recovery was comparable between outdoor and indoor showerhead biofilms, phylogenetic analyses demonstrate similar rpoB gene sequences between all showerhead and respiratory M. chimaera isolates, supporting outdoor and indoor environments as possible sources for pulmonary M. chimaera infections.
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Esquizofrenia/complicações , Situs Inversus/complicações , Adolescente , Humanos , MasculinoRESUMO
INTRODUCTION: Superior semi-circular canal dehiscence (SSCD) is a known cause of hearing loss. This study quantifies hearing loss in SSCD ears in a frequency-specific fashion. METHODS: A meta-analysis of English language literature pertaining to SSCD was performed, with extraction and evaluation of available human audiometric data. Our own institution's case series of SSCD patients was also similarly analysed. Hearing loss in SSCD ears was compared to same patient control ears and to age-matched normative audiometric data. RESULTS: Ears with SSCD had statistically significant worse hearing as compared to both normative data and to own normal ear controls at 2000 Hz and below. The effect appears to diminish with increasing frequency. DISCUSSION: The presence of statistically significant conductive hearing loss in the low frequencies was confirmed for SSCD ears. SSCD may also predispose ears to high frequency sensorineural hearing loss.
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Percepção Auditiva , Limiar Auditivo/fisiologia , Perda Auditiva Condutiva/diagnóstico , Canais Semicirculares/fisiopatologia , Idoso , Audiometria de Tons Puros , Condução Óssea/fisiologia , Feminino , Perda Auditiva Condutiva/etiologia , Humanos , Doenças do Labirinto/complicações , Doenças do Labirinto/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiografia , Valores de Referência , Medição de Risco , Canais Semicirculares/diagnóstico por imagem , Índice de Gravidade de DoençaAssuntos
Administração de Caso/organização & administração , Serviços Comunitários de Saúde Mental/organização & administração , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/mortalidade , Adulto , Idoso , Centros Comunitários de Saúde Mental/organização & administração , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The development of otoconia in the utricular and saccular maculae from initial embryonic formation to adult stages was examined in Japanese quails. Both the morphology and size of the otoconia were quantified at different developmental stages. It was observed that the otoconia were initially formed on embryologic stage E5 in the saccule and E6 in the utricle. Otolith mass areas increased in a sigmoidal growth pattern, with saccular otolith areas being smaller than the utricular mass areas. Saccular otolith masses reached adult values at embryonic stage E12 and utricular areas reached adult values at post-hatch day 7. Mature individual otoconia were characterized by a barrel shape with two trihedral faceted ends. However, initial formation of otoconia at E5 (saccular) and E6 (utricular) maculae was characterized by a double fluted morphology that consisted of an hourglass shape with extended fins forming trihedral angles of 120 degrees. Double fluted otoconia rapidly filled, so that by embryonic day 8 mature otoconia dominated the maculae for the remainder of development through adulthood. Thus, a progression from double fluted to mature forms was noted. Mature utricular otoconia in adult quails averaged 11 microm in length and 5 microm in width, with length/width ratios of approximately 2.5:1, for all size ranges. Saccular otoconia were smaller, having about 70% the size of utricular otoconia in both length and width. During development, the average size and range of individual otoconia increased nearly linearly for both otolith organs. In the utricular macula, large otoconia were concentrated in the lateral regions of the epithelium. In contrast, otoconia of various sizes were distributed uniformly across the surface of the saccular macula.