Objective To investigate the risk factors attributable to tuberculosis-related deaths in areas with human immunodeficiency virus（HIV） infection epidemics. Methods A prospective cohort study of newly ...registered patients in tuberculosis（TB） dispensaries in six representative Chinese provinces was conducted from September 1, 2009 to August 31, 2011. Risk factors for TB-associated death were identified through logistic regression analysis. Results Of 19,103 newly registered pulmonary TB patients, 925（4.8%） were found to be HIV-positive. Miliary TB and acid-fast bacillus smear-negative TB were more common among these patients. Out of a total of 322（1.7%） deaths that occurred during TB treatment, 85（26%） of the patients were co-infected with HIV. Multivariate analysis revealed that HIV infection was the strongest predictor of death adjusted odds ratio（aO R） 7.86. Other significant mortality risk factors included presentation with miliary TB（aO R 4.10; 95% confidence interval： 2.14-7.88）, ≥35 years of age（aO R 3.04）, non-Han ethnicity（aO R 1.67）, and farming as an occupation（aO R 1.59）. For patients with TB/HIV co-infection, miliary TB was the strongest risk factor for death（aO R 5.48）. A low CD4 count（≤ 200 cells/μL）（aO R 3.27） at the time of TB treatment initiation and a lack of antiretroviral therapy（ART） administration（aO R 3.78） were also correlated with an increased risk of death. Conclusion Infection with HIV was independently associated with increased mortality during TB treatment. Offering HIV testing at the time of diagnosis with TB, early TB diagnosis among HIV/acquired immunodeficiency syndrome patients, and the timely provision of ART were identified as the key approaches that could reduce the number of HIV-associated TB deaths.
Objectives. The purpose of the study was to evaluate whether movement performance in Parkinson's disease (PD) is facilitated by having a visuotemporal cue (VTC) or by having a more purposeful ...activity (PA). Methods. Seventeen subjects with idiopathic PD participated. They were asked to reach and grasp a bottle that was swung back and forth or fixed in front of them for the VTC or non-VTC conditions, respectively. PA or non-PA conditions were represented by the presence or absence of money in the bottle, respectively. Kinematic measurements of the reaching movement were performed in order to evaluate the temporal and spatial characteristics. Results . In the VTC conditions, the wrist path appeared straighter and the maximal values of wrist velocity, acceleration and deceleration were lower than in the non-VTC conditions. There were no differences between the PA and non-PA conditions. Discussion. PD subjects appeared to benefit from the VTC condition for the spatial characteristics of movement. However, they showed deficits in the temporal characteristics, possibly related to a visual perception problem in PD. The lack of effect of the PA condition may have been due to an insufficient difference between the PA and non-PA conditions used. Alternatively, it may be related to impaired incentive learning in PD. Conclusion. The present design of external information led to no improvement of the movement in people with PD. The reason for this absence of improvement may be that the external information was not suitably designed in relation to the deficits of people with PD.
Electrochemical water splitting offers an attractive approach for hydrogen production. However, the lack of high‐performance cost‐effective electrocatalyst severely hinders its applications. Here, a ...multinary high‐entropy intermetallic (HEI) that possesses an unusual periodically ordered structure containing multiple non‐noble elements is reported, which can serve as a highly efficient electrocatalyst for hydrogen evolution. This HEI exhibits excellent activities in alkalinity with an overpotential of 88.2 mV at a current density of 10 mA cm−2 and a Tafel slope of 40.1 mV dec−1, which are comparable to those of noble catalysts. Theoretical calculations reveal that the chemical complexity and surprising atomic configurations provide a strong synergistic function to alter the electronic structure. Furthermore, the unique L12‐type ordered structure enables a specific site‐isolation effect to further stabilize the H2O/H* adsorption/desorption, which dramatically optimizes the energy barrier of hydrogen evolution. Such an HEI strategy uncovers a new paradigm to develop novel electrocatalyst with superior reaction activities.
Novel multinary high‐entropy intermetallic compounds (HEIs) with an unusual periodically ordered structure and multiple non‐noble elements are prepared by low‐cost and scalable metallurgical technique. The HEIs present superior water splitting performance in both efficiency and stability when compared to the state‐of‐the‐art. The excellent performance for water splitting is mainly owing to their chemical complexity, unique site‐isolation effect, and dendrite‐like porous morphology.
Developing highly efficient and durable electrocatalysts for hydrogen evolution reaction (HER) under both alkaline and acidic media is crucial for the future development of a hydrogen economy. ...However, state‐of‐the‐art high‐performance electrocatalysts recently developed are based on carbon carriers mediated by binding noble elements and their complicated processing methods are a major impediment to commercialization. Here, inspired by the high‐entropy alloy concept with its inherent multinary nature and using a glassy alloy design with its chemical homogeneity and tunability, we present a scalable strategy to alloy five equiatomic elements, PdPtCuNiP, into a high‐entropy metallic glass (HEMG) for HER in both alkaline and acidic conditions. Surface dealloying of the HEMG creates a nanosponge‐like architecture with nanopores and embedded nanocrystals that provides abundant active sites to achieve outstanding HER activity. The obtained overpotentials at a current density of 10 mA cm−2 are 32 and 62 mV in 1.0 m KOH and 0.5 m H2SO4 solutions, respectively, outperforming most currently available electrocatalysts. Density functional theory reveals that a lattice distortion and the chemical complexity of the nanocrystals lead to a strong synergistic effect on the electronic structure that further stabilizes hydrogen proton adsorption/desorption. This HEMG strategy establishes a new paradigm for designing compositionally complex alloys for electrochemical reactions.
A high‐entropy metallic glass with multinary nature and chemical homogeneity is developed by a scalable metallurgical technique. Dealloying creates a nanosponge‐like architecture with embedded nanocrystals that provides abundant active sites to achieve outstanding hydrogen evolution activity in both alkaline and acidic conditions. This work will provide a roadmap for designing alloy catalysts for many years to come.
Single-cell RNA sequencing has enabled the decomposition of complex tissues into functionally distinct cell types. Often, investigators wish to assign cells to cell types through unsupervised ...clustering followed by manual annotation or via 'mapping' to existing data. However, manual interpretation scales poorly to large datasets, mapping approaches require purified or pre-annotated data and both are prone to batch effects. To overcome these issues, we present CellAssign, a probabilistic model that leverages prior knowledge of cell-type marker genes to annotate single-cell RNA sequencing data into predefined or de novo cell types. CellAssign automates the process of assigning cells in a highly scalable manner across large datasets while controlling for batch and sample effects. We demonstrate the advantages of CellAssign through extensive simulations and analysis of tumor microenvironment composition in high-grade serous ovarian cancer and follicular lymphoma.
Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may ...reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation.
We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression.
Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001).
Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.
Platinum-based electrocatalysts possess high water electrolysis activity and are essential components for hydrogen evolution reaction (HER). A major challenge, however, is how to break the ...cost-efficiency trade-off. Here, a novel defect engineering strategy is presented to construct a nanoporous (FeCoNiB
)
Pt
(atomic %) high-entropy metallic glass (HEMG) with a nanocrystalline surface structure that contains large amounts of lattice distortion and stacking faults to achieve excellent electrocatalytic performance using only 3 at% of Pt. The defect-rich HEMG achieves ultralow overpotentials at ampere-level current density of 1000 mA cm
for HER (104 mV) and oxygen evolution reaction (301 mV) under alkaline conditions, while retains a long-term durability exceeding 200 h at 100 mA cm
. Moreover, it only requires 81 and 122 mV to drive the current densities of 1000 and 100 mA cm
for HER under acidic and neutral conditions, respectively. Modelling results reveal that lattice distortion and stacking fault defects help to optimize atomic configuration and modulate electronic interaction, while the surface nanoporous architecture provides abundant active sites, thus synergistically contributing to the reduced energy barrier for water electrolysis. This defect engineering approach combined with a HEMG design strategy is expected to be widely applicable for development of high-performance alloy catalysts.
COVID-19 in patients with lung cancer Luo, J.; Rizvi, H.; Preeshagul, I.R. ...
Annals of oncology,
10/2020, Letnik:
31, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of ...COVID-19 may inform optimal cancer care during this pandemic.
We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate (ICU/intubation/DNI a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166).
COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07–9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35–9.68, respectively. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes.
COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.
•COVID-19 is associated with high burden of severity in patients with lung cancer.•Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.
Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and ...biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood.
We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37 °C or 6 °C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37 °C), which are minimized by dissociation with a cold active protease (6 °C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues.
The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.
Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization ...of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking
PRNP
, and (2) aqueous extracts from brains of individuals who died with Alzheimer’s disease, dementia with Lewy bodies, and Pick’s disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrP
C
. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.
PDF
