RESUMO
BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).
Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Feminino , Humanos , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Canadá , Antígeno Ki-67/biossíntese , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Prognóstico , Pessoa de Meia-Idade , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Receptor ErbB-2/biossíntese , Antineoplásicos Hormonais/uso terapêuticoRESUMO
Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen's κ of at least 0.8. The highest agreement achieved was a Cohen's κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future.
Assuntos
Neoplasias da Mama , Processamento de Imagem Assistida por Computador , Antígeno Ki-67 , Humanos , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Reprodutibilidade dos Testes , Processamento de Imagem Assistida por Computador/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Algoritmos , Imuno-Histoquímica/métodosRESUMO
Here, a scheme for a controllable nonreciprocal phonon laser is proposed in a hybrid photonic molecule system consisting of a whispering-gallery mode (WGM) optomechanical resonator and a χ(2)-nonlinear WGM resonator, by directionally quantum squeezing one of two coupled resonator modes. The directional quantum squeezing results in a chiral photon interaction between the resonators and a frequency shift of the squeezed resonator mode with respect to the unsqueezed bare mode. We show that the directional quantum squeezing can modify the effective optomechanical coupling in the optomechanical resonator, and analyze the impacts of driving direction and squeezing extent on the phonon laser action in detail. Our analytical and numerical results indicate that the controllable nonreciprocal phonon laser action can be effectively realized in this system. The proposed scheme uses an all-optical and chip-compatible approach without spinning resonators, which may be more beneficial for integrating and packaging of the system on a chip. Our proposal may provide a new route to realize integratable phonon devices for on-chip nonreciprocal phonon manipulations, which may be used in chiral quantum acoustics, topological phononics, and acoustical information processing.
RESUMO
In the single-arm, open-label, multicenter, phase II PILOT study, second-line treatment with the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel) in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) for whom hematopoietic stem cell transplantation (HSCT) was not intended resulted in high response rates, durable responses, and a safety profile consistent with previous reports. Here, we analyzed changes in health-related quality of life (HRQOL) in patients who received liso-cel in PILOT. Patients received liso-cel, an autologous, CD19-directed, 4-1BB CAR T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells, for a total target dose of 100×106 CAR+ T cells. HRQOL, a secondary endpoint of PILOT, was assessed as prespecified using three patient-reported outcome instruments (EORTC QLQ-C30; FACT-LymS; EQ-5D-5L). Evaluable datasets for the EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L health utility index, and visual analog scale (EQ-VAS) included 56 (92%), 49 (80%), 55 (90%), and 54 (89%) patients, respectively. Clinically meaningful improvement was achieved across most post-treatment visits for EORTC QLQ-C30 fatigue and FACT-LymS. Overall mean changes from baseline through day 545 showed significant improvements in EORTC QLQ-C30 fatigue, pain, and appetite loss, FACT-LymS, and EQ VAS. In within-patient analyses, clinically meaningful improvements or maintenance in scores were observed in most patients at days 90, 180, 270, and 365. HRQOL was maintained or improved in patients who received liso-cel as second-line therapy in PILOT. These findings support liso-cel as a preferred second-line treatment in patients with R/R LBCL not intended for HSCT (clinicaltrials gov. Identifier: NCT03483103).
Assuntos
Linfoma Difuso de Grandes Células B , Qualidade de Vida , Humanos , Projetos Piloto , Linfoma Difuso de Grandes Células B/terapia , Fadiga , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: The clinical relevance of BRAF-V600E alleles in peripheral blood mononuclear cells (PBMCs) and the prognostic impact of the mutants in cell-free (cf) and PBMC DNAs of Langerhans cell histiocytosis (LCH) have not been fully clarified in pediatric LCH. METHODS: We retrospectively determined the levels of BRAF-V600E mutation in paired plasma and PBMC samples at the time of diagnosis of LCH. Subsequently, we performed a separate or combined analysis of the clinical and prognostic impact of the mutants. RESULTS: We assessed BRAF-V600E mutation in peripheral blood from 94 patients of childhood LCH. Our data showed that cfBRAF-V600E was related to young age, multiple-system (MS) disease, involvements of organs with high risk, increased risk of relapse, and worse progression-free survival (PFS) of patients. We also observed that the presence of BRAF-V600E in PBMCs at baseline was significantly associated with MS LCH with risk organ involvement, younger age, and disease progression or relapse. The coexisting of plasma(+)/PBMC(+) identified 36.2% of the patients with the worst outcome, and the hazard ratio was more significant than either of the two alone or neither, indicating that combined analysis of the mutation in plasma and PBMCs was more accurate to predict relapse than evaluation of either one. CONCLUSIONS: Concurrent assessment of BRAF-V600E mutation in plasma and PBMCs significantly impacted the prognosis of children with LCH. Further prospective studies with larger cohorts need to validate the results of this study.
Assuntos
Histiocitose de Células de Langerhans , Leucócitos Mononucleares , Mutação , Proteínas Proto-Oncogênicas B-raf , Humanos , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Masculino , Feminino , Estudos Retrospectivos , Criança , Pré-Escolar , Prognóstico , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/metabolismo , Lactente , Adolescente , Seguimentos , Taxa de SobrevidaRESUMO
Detecting cyanobacteria in environments is an important concern due to their crucial roles in ecosystems, and they can form blooms with the potential to harm humans and nonhuman entities. However, the most widely used methods for high-throughput detection of environmental cyanobacteria, such as 16S rRNA sequencing, typically provide above-species-level resolution, thereby disregarding intraspecific variation. To address this, we developed a novel DNA microarray tool, termed the CyanoStrainChip, that enables strain-level comprehensive profiling of environmental cyanobacteria. The CyanoStrainChip was designed to target 1277 strains; nearly all major groups of cyanobacteria are included by implementing 43,666 genome-wide, strain-specific probes. It demonstrated strong specificity by in vitro mock community experiments. The high correlation (Pearson's R > 0.97) between probe fluorescence intensities and the corresponding DNA amounts (ranging from 1-100 ng) indicated excellent quantitative capability. Consistent cyanobacterial profiles of field samples were observed by both the CyanoStrainChip and next-generation sequencing methods. Furthermore, CyanoStrainChip analysis of surface water samples in Lake Chaohu uncovered a high intraspecific variation of abundance change within the genus Microcystis between different severity levels of cyanobacterial blooms, highlighting two toxic Microcystis strains that are of critical concern for Lake Chaohu harmful blooms suppression. Overall, these results suggest a potential for CyanoStrainChip as a valuable tool for cyanobacterial ecological research and harmful bloom monitoring to supplement existing techniques.
Assuntos
Cianobactérias , Microcystis , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Ribossômico 16S/genética , Ecossistema , Proliferação Nociva de Algas , Cianobactérias/genética , Lagos/microbiologia , Microcystis/genéticaRESUMO
BACKGROUND: The relationship between obstructive sleep apnea (OSA) and the occurrence of arrhythmias and heart rate variability (HRV) in hypertensive patients is not elucidated. Our study investigates the association between OSA, arrhythmias, and HRV in hypertensive patients. METHODS: We conducted a cross-sectional analysis involving hypertensive patients divided based on their apnea-hypopnea index (AHI) into two groups: the AHI ≤ 15 and the AHI > 15. All participants underwent polysomnography (PSG), 24-hour dynamic electrocardiography (DCG), cardiac Doppler ultrasound, and other relevant evaluations. RESULTS: The AHI > 15 group showed a significantly higher prevalence of frequent atrial premature beats and atrial tachycardia (P = 0.030 and P = 0.035, respectively) than the AHI ≤ 15 group. Time-domain analysis indicated that the standard deviation of normal-to-normal R-R intervals (SDNN) and the standard deviation of every 5-minute normal-to-normal R-R intervals (SDANN) were significantly higher in the AHI > 15 group (P = 0.020 and P = 0.033, respectively). Frequency domain analysis revealed that the low-frequency (LF), high-frequency (HF) components, and the LF/HF ratio were also significantly elevated in the AHI > 15 group (P < 0.001, P = 0.031, and P = 0.028, respectively). Furthermore, left atrial diameter (LAD) was significantly larger in the AHI > 15 group (P < 0.001). Both univariate and multivariable linear regression analyses confirmed a significant association between PSG-derived independent variables and the dependent HRV parameters SDNN, LF, and LF/HF ratio (F = 8.929, P < 0.001; F = 14.832, P < 0.001; F = 5.917, P = 0.016, respectively). CONCLUSIONS: Hypertensive patients with AHI > 15 are at an increased risk for atrial arrhythmias and left atrial dilation, with HRV significantly correlating with OSA severity.
Assuntos
Arritmias Cardíacas , Frequência Cardíaca , Hipertensão , Polissonografia , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Hipertensão/fisiopatologia , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/etiologia , Idoso , Fatores de Risco , Prevalência , Eletrocardiografia Ambulatorial , Adulto , Fatores de Tempo , Ecocardiografia Doppler , Complexos Atriais Prematuros/fisiopatologia , Complexos Atriais Prematuros/diagnóstico , Complexos Atriais Prematuros/epidemiologia , Medição de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Hypertension frequently coexists with obstructive sleep apnea (OSA), and their interplay substantially impacts the prognosis of affected individuals. Investigating the influence of OSA on blood pressure variability (BPV) and blood pressure load (BPL) in hypertensive patients has become a focal point of clinical research. METHODS: This cross-sectional study recruited hypertensive patients (n = 265) without discrimination and classified them into four groups based on their apnea-hypopnea index (AHI): control group (n = 40), AHI < 5; mild group (n = 74), 5 ≤ AHI ≤ 15; moderate group (n = 68), 15 < AHI ≤ 30; severe group (n = 83), AHI > 30. All participants underwent comprehensive assessments, including polysomnography (PSG) monitoring, 24-h ambulatory blood pressure (ABP) monitoring, cardiac Doppler ultrasound, and additional examinations when indicated. RESULTS: BPV and BPL exhibited significant elevations in the moderate and severe OSA groups compared to the control and mild OSA groups (P < 0.05). Moreover, interventricular septum thickness and left ventricular end-diastolic volume (LVEDV) demonstrated higher values in the moderate and severe OSA groups (P < 0.05). Multiple stepwise regression analysis identified noteworthy risk factors for elevated BPV in hypertensive patients with OSA, including AHI, maximum apnea time, total times of oxygen reduction, and mean time of apnea. CONCLUSION: Hypertensive patients with moderate to severe OSA exhibited substantially increased BPV and BPL. Moreover, BPV was correlated with AHI, maximum apnea time, total times of oxygen reduction, and mean time of apnea in hypertensive patients with OSA.
Assuntos
Pressão Sanguínea , Hipertensão , Polissonografia , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/fisiopatologia , Hipertensão/fisiopatologia , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Transversais , Pressão Sanguínea/fisiologia , Adulto , Monitorização Ambulatorial da Pressão Arterial , IdosoRESUMO
Low expression levels of E2F3a and caspase 8-associated protein 2 (CASP8AP2) are associated with poor outcomes in children with acute lymphoblastic leukemia. Our previous study showed that a combined assessment of E2F3a and CASP8AP2 expression was more accurate in predicting relapse in children with acute lymphoblastic leukemia. However, the underlying mechanism remains unclear. In this study, the interaction between E2F3a and CASP8AP2 and its role in the regulation of histone expression, cell proliferation, the cell cycle, and chemosensitivity were investigated. Exogenous E2F3a-GST was coprecipitated with CASP8AP2-FLAG in HEK-293T cells. E2F3a was colocalized with CASP8AP2-GFP in the nucleus. The replication-dependent histones H2A and H2B were significantly upregulated when E2F3a or CASP8AP2 was overexpressed in HEK-293T or 697 cells and downregulated by E2F3a or CASP8AP2 knockdown. E2F3a and CASP8AP2 could collaboratively enhance the transcriptional activity of HIST1H2AG and HIST1H2BK . Both CASP8AP2 and E2F3a are involved in S phase progression. E2F3a and CASP8AP2 also affected the sensitivity of leukemic cells to daunorubicin. Therefore, CASP8AP2 and E2F3a collaboratively regulated replication-dependent histone expression, cell cycle progression, and chemosensitivity of leukemic cells.
Assuntos
Histonas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Proteínas Reguladoras de Apoptose , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas de Ligação ao CálcioRESUMO
BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Mutação/genética , Superóxido Dismutase-1/genéticaRESUMO
BACKGROUND: Post-vaccination myopericarditis is reported after immunization with coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines. The effect of inadvertent intravenous injection of this vaccine on the heart is unknown. METHODS: We compared the clinical manifestations, histopathological changes, tissue mRNA expression, and serum levels of cytokine/chemokine and troponin in Balb/c mice at different time points after intravenous (IV) or intramuscular (IM) vaccine injection with normal saline (NS) control. RESULTS: Although significant weight loss and higher serum cytokine/chemokine levels were found in IM group at 1-2 days post-injection (dpi), only IV group developed histopathological changes of myopericarditis as evidenced by cardiomyocyte degeneration, apoptosis, and necrosis with adjacent inflammatory cell infiltration and calcific deposits on visceral pericardium, although evidence of coronary artery or other cardiac pathologies was absent. Serum troponin level was significantly higher in IV group. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen expression by immunostaining was occasionally found in infiltrating immune cells of the heart or injection site, in cardiomyocytes and intracardiac vascular endothelial cells, but not skeletal myocytes. The histological changes of myopericarditis after the first IV-priming dose persisted for 2 weeks and were markedly aggravated by a second IM- or IV-booster dose. Cardiac tissue mRNA expression of interleukin (IL)-1ß, interferon (IFN)-ß, IL-6, and tumor necrosis factor (TNF)-α increased significantly from 1 dpi to 2 dpi in the IV group but not the IM group, compatible with presence of myopericarditis in the IV group. Ballooning degeneration of hepatocytes was consistently found in the IV group. All other organs appeared normal. CONCLUSIONS: This study provided in vivo evidence that inadvertent intravenous injection of COVID-19 mRNA vaccines may induce myopericarditis. Brief withdrawal of syringe plunger to exclude blood aspiration may be one possible way to reduce such risk.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Animais , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Quimiocinas , Citocinas , Células Endoteliais , Humanos , Injeções Intravenosas , Camundongos , RNA Mensageiro , SARS-CoV-2 , Troponina , Vacinas Sintéticas , Vacinas de mRNARESUMO
BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.
Assuntos
Doença de Parkinson , Idade de Início , Povo Asiático/genética , China , Proteínas de Ligação a DNA/genética , Humanos , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Air pollution has been associated with metabolic disease and obesity. Adipokines are potential mediators of these effects, but studies of air pollution-adipokine relationships are inconclusive. Macrophage and T cells in adipose tissue (AT) and blood modulate inflammation; however, the role of immune cells in air pollution-induced dysregulation of adipokines has not been studied. We examined the association between air pollution exposure and circulating and AT adipokine concentrations, and whether these relationships were modified by macrophage and T cell numbers in the blood and AT. METHODS: Fasting blood and abdominal subcutaneous AT biopsies were collected from 30 overweight/obese 18-26 year-old volunteers. Flow cytometry was used to quantify T effector (Teff, inflammatory) and regulatory (Treg, anti-inflammatory) lymphocytes and M1 [inflammatory] and M2 [anti-inflammatory]) macrophage cell number. Serum and AT leptin and adiponectin were measured using enzyme-linked immunosorbent assay (ELISA). Exposure to near-roadway air pollution (NRAP) from freeway and non-freeway vehicular sources and to regional particulate matter, nitrogen dioxide and ozone were estimated for the year prior to biopsy, based on participants' residential addresses. Linear regression models were used to examine the association between air pollution exposures and adipokines and to evaluate effect modification by immune cell counts. RESULTS: An interquartile increase in non-freeway NRAP exposure during 1 year prior to biopsy was associated with higher leptin levels in both serum [31.7% (95% CI: 10.4, 52.9%)] and AT [19.4% (2.2, 36.6%)]. Non-freeway NRAP exposure effect estimates were greater among participants with greater than median Teff/Treg ratio and M1/M2 ratio in blood, and with greater M1 counts in AT. No adipokine associations with regional air pollutants were found. DISCUSSION: Our results suggest that NRAP may increase serum leptin levels in obese young adults, and this association may be promoted in a pro-inflammatory immune cell environment in blood and AT.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Adipocinas/análise , Adolescente , Adulto , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Humanos , Leptina/análise , Obesidade/epidemiologia , Material Particulado/análise , Material Particulado/toxicidade , Adulto JovemRESUMO
BACKGROUND: Rapid ethical access to personal health information (PHI) to support research is extremely important during pandemics, yet little is known regarding patient preferences for consent during such crises. This follow-up study sought to ascertain whether there were differences in consent preferences between pre-pandemic times compared to during Wave 1 of the COVID-19 global pandemic, and to better understand the reasons behind these preferences. METHODS: A total of 183 patients in the pandemic cohort completed the survey via email, and responses were compared to the distinct pre-pandemic cohort (n = 222); all were patients of a large Canadian cancer center. The survey covered (a) broad versus study-specific consent; (b) opt-in versus opt-out contact approach; (c) levels of comfort sharing with different recipients; (d) perceptions of commercialization; and (e) options to track use of information and be notified of results. Four focus groups (n = 12) were subsequently conducted to elucidate reasons motivating dominant preferences. RESULTS: Patients in the pandemic cohort were significantly more comfortable with sharing all information and biological samples (90% vs. 79%, p = 0.009), sharing information with the health care institution (97% vs. 83%, p < 0.001), sharing information with researchers at other hospitals (85% vs. 70%, p < 0.001), sharing PHI provincially (69% vs. 53%, p < 0.002), nationally (65% vs. 53%, p = 0.022) and internationally (48% vs. 39%, p = 0.024) compared to the pre-pandemic cohort. Discomfort with sharing information with commercial companies remained unchanged between the two cohorts (50% vs. 51% uncomfortable, p = 0.58). Significantly more pandemic cohort patients expressed a wish to track use of PHI (75% vs. 61%, p = 0.007), and to be notified of results (83% vs. 70%, p = 0.012). Thematic analysis uncovered that transparency was strongly desired on outside PHI use, particularly when commercialization was involved. CONCLUSIONS: In pandemic times, patients were more comfortable sharing information with all parties, except with commercial entities, where levels of discomfort (~ 50%) remained unchanged. Focus groups identified that the ability to track and receive results of studies using one's PHI is an important way to reduce discomfort and increase trust. These findings meaningfully inform wider discussions on the use of personal health information for research during global crises.
Assuntos
COVID-19 , Registros de Saúde Pessoal , COVID-19/epidemiologia , Canadá , Seguimentos , Humanos , Consentimento Livre e Esclarecido , Pandemias , Preferência do PacienteRESUMO
While the importance of physician involvement in organizational quality and safety (Q&S) activities has been well established, a paucity of information exists on tangible supports needed to effectively execute this role. Interviews with 13 MD Q&S leads uncovered common enablers, including valuing Q&S work academically, hiring skilled collaborators, ensuring appropriate power and authority to advance Q&S initiatives, facilitating connections, emphasizing culture change and strong action by leadership. To operationalize these enablers and drive quality innovation, organizations should prioritize the identification and appointment of MD Q&S leads for each department/division and facilitate their assembly as a formal physician Q&S committee.
Assuntos
Liderança , Médicos , Hospitais , Humanos , Cultura Organizacional , Inovação OrganizacionalRESUMO
BACKGROUND: Mass vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing amidst widespread transmission during the coronavirus disease-2019 (COVID-19) pandemic. Disease phenotypes of SARS-CoV-2 exposure occurring around the time of vaccine administration have not been described. METHODS: Two-dose (14 days apart) vaccination regimen with formalin-inactivated whole virion SARS-CoV-2 in golden Syrian hamster model was established. To investigate the disease phenotypes of a 1-dose regimen given 3 days prior (D-3), 1 (D1) or 2 (D2) days after, or on the day (D0) of virus challenge, we monitored the serial clinical severity, tissue histopathology, virus burden, and antibody response of the vaccinated hamsters. RESULTS: The 1-dose vaccinated hamsters had significantly lower clinical disease severity score, body weight loss, lung histology score, nucleocapsid protein expression in lung, infectious virus titers in the lung and nasal turbinate, inflammatory changes in intestines, and a higher serum neutralizing antibody or IgG titer against the spike receptor-binding domain or nucleocapsid protein when compared to unvaccinated controls. These improvements were particularly noticeable in D-3, but also in D0, D1, and even D2 vaccinated hamsters to varying degrees. No increased eosinophilic infiltration was found in the nasal turbinate, lung, and intestine after virus challenge. Significantly higher serum titer of fluorescent foci microneutralization inhibition antibody was detected in D1 and D2 vaccinated hamsters at day 4 post-challenge compared to controls despite undetectable neutralizing antibody titer. CONCLUSIONS: Vaccination just before or soon after exposure to SARS-CoV-2 does not worsen disease phenotypes and may even ameliorate infection.
Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Cricetinae , Humanos , Mesocricetus , Vacinas de Produtos InativadosRESUMO
BACKGROUND: Accurate classification of coronary artery abnormalities (CAAs) is essential for clinical decision-making and long-term management in Kawasaki disease (KD) patients. To date, there are several echocardiographic criteria of CAA assessment. MATERIALS AND METHODS: The Japanese Ministry of Health (JMH) criteria and the Z-score criteria from 2004 American Heart Association guidelines were adopted and their detective efficacies for CAAs were compared in 251 Chinese patients with KD Z scores were calculated by 6 published methods. RESULTS: According to the JMH criteria, 19 (7.57%) KD patients were classified as CAAs during the acute KD episode. However, the detective number of CAAs was highest and had a 0.68-fold increase by the Dallaire et al method with a Z-score cut point of ≥2.5 as compared with the JMH criteria; in contrast, more than 78.95% of patients with CAAs identified by the JMH criteria had a coronary artery Z score ≥2.5. All 6 different Z-score methods had satisfactory accuracies with a range from 93.23% to 97.61% in screening CAAs. For the 19 patients with CAAs identified by the JMH criteria, their Z scores presented the widest variation calculated by the McCrindle et al method. CONCLUSIONS: The JMH criteria underestimate the prevalence of CAAs as compared with the Z-score criteria. Quantitative assessment of coronary artery luminal dimensions, normalized as Z scores adjusted for body surface, should be recommended. The larger coronary artery luminal dimensions vary, the more heterogeneous Z scores calculated by different methods have.
Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Síndrome de Linfonodos Mucocutâneos/diagnóstico por imagem , Pré-Escolar , China , Doença da Artéria Coronariana/diagnóstico , Ecocardiografia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Guias de Prática Clínica como Assunto , Estudos RetrospectivosRESUMO
Nitrogen (N) fixation in soils is closely linked to microbially mediated molybdenum (Mo) cycling. Therefore, elucidating the mechanisms and factors that affect Mo bioavailability is crucial for understanding N fixation. Here, we demonstrate that long-term (26 years) manure fertilization increased microbial diversity and content of short-range ordered iron (oxyhydr)oxides that raised Mo bioavailability (by 2.8 times) and storage (by â¼30%) and increased the abundance of nifH genes (by â¼14%) and nitrogenase activity (by â¼60%). Nanosized iron (oxyhydr)oxides (ferrihydrite, goethite, and hematite nanoparticles) play a dual role in soil Mo cycling: (i) in concert with microorganisms, they raise Mo bioavailability by catalyzing hydroxyl radical (HOâ¢) production via the Fenton reactions and (ii) they increase Mo retention by association with the nanosized iron (oxyhydr)oxides. In summary, long-term manure fertilization raised the stock and bioavailability of Mo (and probably also of other micronutrients) by increasing iron (oxyhydr)oxide reactivity and intensified asymbiotic N fixation through an increased abundance of nifH genes and nitrogenase activity. This work provides a strategy for increasing biological N fixation in agricultural ecosystems.
Assuntos
Molibdênio , Fixação de Nitrogênio , Disponibilidade Biológica , Ecossistema , Radicais Livres , Ferro , Óxidos , SoloRESUMO
BACKGROUND: Immense volumes of personal health information (PHI) are required to realize the anticipated benefits of artificial intelligence in clinical medicine. To maintain public trust in medical research, consent policies must evolve to reflect contemporary patient preferences. METHODS: Patients were invited to complete a 27-item survey focusing on: (a) broad versus specific consent; (b) opt-in versus opt-out approaches; (c) comfort level sharing with different recipients; (d) attitudes towards commercialization; and (e) options to track PHI use and study results. RESULTS: 222 participants were included in the analysis; 83% were comfortable sharing PHI with researchers at their own hospital, although younger patients (≤ 49 years) were more uncomfortable than older patients (50 + years; 13% versus 2% uncomfortable, p < 0.05). While 56% of patients preferred broad consent, 38% preferred specific consent; 6% preferred not sharing at all. The majority of patients (63%) preferred to be asked for permission before entry into a contact pool. Again, this trend was more pronounced for younger patients (≤ 49 years: 76%). Approximately half of patients were uncomfortable sharing PHI with commercial enterprises (51% uncomfortable, 27% comfortable, 22% neutral). Most patients preferred to track PHI usage (61%), with the highest proportion once again reported by the youngest patients (≤ 49 years: 71%). A majority of patients also wished to be notified regarding study results (70%). CONCLUSIONS: While most patients were willing to share their PHI with researchers within their own institution, many preferred a transparent and reciprocal consent process. These data also suggest a generational shift, wherein younger patients preferred more specific consent options. Modernizing consent policies to reflect increased autonomy is crucial in fostering sustained public engagement with medical research.
Assuntos
Inteligência Artificial , Registros de Saúde Pessoal , Humanos , Consentimento Livre e Esclarecido , Preferência do Paciente , ConfiançaRESUMO
Ion transport in an artificial asymmetric nanoporous membrane, which is similar to biological ion channels, can be used for biosensing. Here, a dendrimer-Au nanoparticle network (DAN) is in situ assembled on a nanoporous anodic aluminum oxide (AAO) surface, forming a DAN/AAO hybrid membrane. Benefiting from the high surface area and anion selectivity of DAN, the prepared DAN/AAO hybrid presents selective ion transport. Under a bias potential, a diode-like current-potential (I-V) response is observed. The obtained ionic current rectification (ICR) property can be tuned by the ion valence and pH value of the electrolyte. The rectified ionic current endows the as-prepared DAN/AAO hybrid with the ability of enhanced bioanalysis. Sensitive capture and detection of circulating tumor cells (CTCs) with a detection limit of 80 cells mL-1 as well as excellent reusability can be achieved.