Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
Background. Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. Methods. A retrospective cohort study was ...conducted on all adults (≥18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009–2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. Results. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. Conclusions. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.
The genetic basis of major depression Kendall, K M; Van Assche, E; Andlauer, T F M ...
Psychological medicine,
10/2021, Letnik:
51, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high ...prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
•The optimal decisions considering the platform-enabled power and remanufacturing are explored.•Marketplace mode and reselling mode are considered in our work.•Whether to adopt blockchain for the ...manufacturer is analyzed.•The quantity and social welfare coordination challenges are discussed.
Blockchain technology has been widely used in many industries. One current application is in remanufacturing. In this paper we consider the combination of remanufacturing and blockchain, and model a supply chain composed of a manufacturer, a third-party firm, and an online platform. Among them, the manufacturer faces the cap-and-trade regulation and adopts blockchain to record the information on the used products and then remanufactures products. The platform has the power to expand the potential market size and can operate in the marketplace or reselling mode. The third-party firm collects used products for the manufacturer. We conduct a Stackelberg game analysis and obtain the following major findings: First, the optimal production quantities and optimal collection rates with and without blockchain in the marketplace and reselling modes increase with the allocated cap and platform-enabled power. Second, in the reselling or marketplace mode, the manufacturer should not adopt blockchain if the emissions intensity is low; otherwise, it should adopt blockchain. Third, selecting the reselling (marketplace) mode is more profitable for the manufacturer if the platform-enabled power is low (high). Fourth, for quantity coordination, the reselling mode under the wholesale price contract can always coordinate the manufacturer and platform, and the manufacturer, online platform, and third-party firm. However, the marketplace mode with a commission rate can only coordinate the manufacturer, online platform, and third-party firm. For social welfare coordination, the manufacturer, online platform, and third-party firm can achieve coordination in the marketplace or reselling mode. Finally, extending the work to consider the cross-channel effect, we find that the major findings for both quantity coordination and social welfare coordination in the reselling and marketplace modes still hold.
Nanoindentation measurements were obtained on eight commercially-produced DP980 dual-phase steels to quantify the hardness of the individual constituents, ferrite and martensite, in each steel. Each ...microstructure was also evaluated to determine grain size, martensite volume fraction (MVF), and retained austenite content. Nanoindentation hardnesses and quantitative microstructural measurements were correlated with tensile properties and performance in hole expansion tests to assess the importance of the individual constituent properties. Hole expansion samples were prepared with both sheared edges produced by mechanical punching, and non-deformed edges produced by electric discharge machining (EDM). Average material hardness based on nanoindentation data correlated directly to Vickers hardness measurements, verifying the capability of the nanoindentation technique to produce data consistent with traditional hardness measurements. Yield strength (YS) correlated directly to ferrite hardness indicating that, for a similar MVF and microstructural morphology, the YS is controlled by the strength of the softer matrix phase (ferrite). Hole expansion ratios (HER) on EDM samples decreased with an increase in both martensite and ferrite hardness, indicating that EDM HER values can be enhanced by softening both constituents. Punched-hole HER values decreased with increasing martensite hardness and martensite-to-ferrite hardness ratio, but were independent of ferrite hardness, indicating that softening the martensite while increasing the ferrite hardness could produce a higher HER.
Livedo racemosa in lymphocytic vasculitis Toh, C; Choi, E C E; Tan, C L
QJM : An International Journal of Medicine,
12/2022, Letnik:
115, Številka:
12
Journal Article
The major research methodologies deployed for operations management (OM) research include analytical modeling research (e.g., optimization, computational, and simulation models), quantitative ...empirical research (e.g., surveys, and event studies), and case study research. In recent years, there is an emerging trend toward employing a multi‐methodological approach (MMA) to address complex and intriguing OM issues. The MMA helps derive solid research results and boost the scientific merit of OM research. We examine this research trend and present some MMAs germane to the pursuit of rigorous and scientific OM research. We also discuss the strengths and weaknesses of such MMAs.
The classical newsvendor problem seeks to minimize the expected inventory cost or maximize the expected profit. But optimizing an expected value alone does not fully capture the stochastic nature of ...the newsvendor problem. Inspired by the higher‐moment analyses explored in finance literature, we conduct a mean‐variance‐skewness‐kurtosis (MVSK) analysis for the newsvendor problem. We first derive the analytical expressions for the profit’s mean, variance, skewness, and kurtosis in the standard newsvendor setting, and reveal their structural properties. We then establish various MVSK optimization problems and find the solution to each of them. We show that kurtosis aversion always induces the newsvendor to order less, while skewness seeking can induce the newsvendor to order either more or less depending on the specific structure of the profit’s skewness, which is affected by the symmetric and asymmetric properties of the demand distribution. Finally, based on the Pareto‐optimality concept, we address the challenge of supply chain coordination (SCC) in the presence of MVSK agents in two specific cases: (i) each agent maximizes its MVSK‐objective‐function and (ii) each agent maximizes its expected profit function, subject to given constraints on the profit’s variance, skewness, and kurtosis. In each case, we explore whether and how the supply chain can be coordinated. We find that considering the MVSK preferences of supply chain agents will affect the achievability of SCC and flexibility of the coordinating contract. We also uncover that if we assume an individual MVSK agent to be an MV one, the achievability of SCC by contracts will be very much negatively affected.
Abstract
We report the discovery of six ultra-faint Milky Way satellites identified through matched-filter searches conducted using Dark Energy Camera (DECam) data processed as part of the second ...data release of the DECam Local Volume Exploration (DELVE) survey. Leveraging deep Gemini/GMOS-N imaging (for four candidates) as well as follow-up DECam imaging (for two candidates), we characterize the morphologies and stellar populations of these systems. We find that these candidates all share faint absolute magnitudes (
M
V
≥ −3.2 mag) and old, metal-poor stellar populations (
τ
> 10 Gyr, Fe/H < −1.4 dex). Three of these systems are more extended (
r
1/2
> 15 pc), while the other three are compact (
r
1/2
< 10 pc). From these properties, we infer that the former three systems (Boötes V, Leo Minor I, and Virgo II) are consistent with ultra-faint dwarf galaxy classifications, whereas the latter three (DELVE 3, DELVE 4, and DELVE 5) are likely ultra-faint star clusters. Using data from the Gaia satellite, we confidently measure the proper motion of Boötes V, Leo Minor I, and DELVE 4, and tentatively detect a proper-motion signal from DELVE 3 and DELVE 5; no signal is detected for Virgo II. We use these measurements to explore possible associations between the newly discovered systems and the Sagittarius dwarf spheroidal, the Magellanic Clouds, and the Vast Polar Structure, finding several plausible associations. Our results offer a preview of the numerous ultra-faint stellar systems that will soon be discovered by the Vera C. Rubin Observatory and highlight the challenges of classifying the faintest stellar systems.
In recent years, research on supply chain coordination (SCC) with risk‐averse agents has received much attention. Previous studies are primarily concerned with the coordination of a single ...manufacturer–single retailer supply chain using different definitions of SCC. What is lacking is a comprehensive analysis of the achievability of SCC. In this paper, we provide a systematic analysis of SCC with risk‐averse agents. We see that three definitions of SCC have been proposed in the literature to investigate SCC with risk‐averse agents, among which the one based on Pareto optimality (PO) stands out. Here we explore the challenges of using the PO criterion. Specifically, we first examine the standard two‐agent supply chain under the mean–variance (MV) and mean‐downside‐risk (MDR) objectives. What we find is that the achievability of PO depends on the contract type. The wholesale price contract even with a side payment may not lead to PO. Also, unlike under MV where risk sharing is Pareto optimal, we observe that the least risk‐averse agent must take all the risk to achieve SCC under MDR. Importantly, we extend our analysis to multiretailer, multimanufacturer, and multitier supply chains. In each case, we characterize the efficient Pareto‐optimal manifold in the multidimensional space and design coordinating contracts that result in Pareto‐optimal actions acceptable to all agents. We also discover that identifying PO across all the contract forms is difficult when some other risk‐aversion criteria are considered. We conclude by providing suggestions and methods for SCC when we are unable to identify PO.
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