Background Phase II data suggested that guselkumab, an anti-interleukin-23 monoclonal antibody, was efficacious in psoriasis. Objective We sought to assess efficacy and safety of guselkumab in ...moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. Methods Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. Results At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) ( P < .001). From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance versus withdrawal groups ( P < .001). Of adalimumab nonresponders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient-reported outcomes. Adverse events were comparable among groups. Limitations One-year follow-up limits retreatment data. Conclusions Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.
Abstract
Background
Recent studies have focused on initial clinical and epidemiological characteristics of the coronavirus disease 2019 (COVID-19), which is the mainly revealing situation in Wuhan, ...Hubei.
Aim
This study aims to reveal more data on the epidemiological and clinical characteristics of COVID-19 patients outside of Wuhan, Zhejiang, China.
Design
This study was a retrospective case series.
Methods
Eighty-eight cases of laboratory-confirmed and three cases of clinically confirmed COVID-19 were admitted to five hospitals in Zhejiang province, China. Data were collected from 20 January 2020 to 11 February 2020.
Results and discussion
Of all 91 patients, 88 (96.70%) were laboratory-confirmed COVID-19 with throat swab samples that tested positive for SARS-Cov-2, three (3.30%) cases were clinically diagnosed. The median age of the patients was 50 (36.5–57) years, and female accounted for 59.34%. In this sample, 40 (43.96%) patients had contracted the disease from local cases, 31 (34.07%) patients had been to Wuhan/Hubei, eight (8.79%) patients had contacted with people from Wuhan, and 11 (12.09%) patients were diagnosed after having flown together in the same flight with no passenger that could later be identified as the source of infection. In particular within the city of Ningbo, 60.52% cases can be traced back to an event held in a temple. The most common symptoms were fever (71.43%), cough (60.44%) and fatigue (43.96%). The median of incubation period was 6 (interquartile range 3–8) days and the median time from the first visit to a doctor to the confirmed diagnosis was 1 (1–2) days. According to the chest computed tomography scans, 67.03% cases had bilateral pneumonia.
Conclusions
Social activity cluster, family cluster and flying alongside with persons already infected with COVID-19 were how people got infected with COVID-19 in Zhejiang.
Abstract Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, ...the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.
► Quantified different deformation mechanisms for 304SS at different stages. ► First ones to report detwinning phenomenon for 304SS at late stage of deformation. ► Provided explanations for ...detwinning with the results from open literature.
The microstructure characteristics and deformation behavior of 304L stainless steel during tensile deformation at two different strain rates have been investigated by means of interrupted tensile tests, electron-backscatter-diffraction (EBSD) and transmission electron microscopy (TEM) techniques. The volume fractions of transformed martensite and deformation twins at different stages of the deformation process were measured using X-ray diffraction method and TEM observations. It is found that the volume fraction of martensite monotonically increases with increasing strain but decreases with increasing strain rate. On the other hand, the volume fraction of twins increases with increasing strain for strain level less than 57%. Beyond that, the volume fraction of twins decreases with increasing strain. Careful TEM observations show that stacking faults (SFs) and twins preferentially occur before the nucleation of martensite. Meanwhile, both ɛ-martensite and α′-martensite are observed in the deformation microstructures, indicating the co-existence of stress-induced-transformation and strain-induced-transformation. We also discussed the effects of twinning and martensite transformation on work-hardening as well as the relationship between stacking faults, twinning and martensite transformation.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in ...2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.
Objectives The purpose of this study was to compare the efficiency, cost, and safety of a diagnostic strategy employing early coronary computed tomographic angiography (CCTA) to a strategy employing ...rest-stress myocardial perfusion imaging (MPI) in the evaluation of acute low-risk chest pain. Background In the United States, >8 million patients require emergency department evaluation for acute chest pain annually at an estimated diagnostic cost of >$10 billion. Methods This multicenter, randomized clinical trial in 16 emergency departments ran between June 2007 and November 2008. Patients were randomly allocated to CCTA (n = 361) or MPI (n = 338) as the index noninvasive test. The primary outcome was time to diagnosis; the secondary outcomes were emergency department costs of care and safety, defined as freedom from major adverse cardiac events in patients with normal index tests, including 6-month follow-up. Results The CCTA resulted in a 54% reduction in time to diagnosis compared with MPI (median 2.9 h 25th to 75th percentile: 2.1 to 4.0 h vs. 6.3 h 25th to 75th percentile: 4.2 to 19.0 h, p < 0.0001). Costs of care were 38% lower compared with standard (median $2,137 25th to 75th percentile: $1,660 to $3,077 vs. $3,458 25th to 75th percentile: $2,900 to $4,297, p < 0.0001). The diagnostic strategies had no difference in major adverse cardiac events after normal index testing (0.8% in the CCTA arm vs. 0.4% in the MPI arm, p = 0.29). Conclusions In emergency department acute, low-risk chest pain patients, the use of CCTA results in more rapid and cost-efficient safe diagnosis than rest-stress MPI. Further studies comparing CCTA to other diagnostic strategies are needed to optimize evaluation of specific patient subsets. (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment CT-STAT; NCT00468325 )
Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such ...correlation is unclear in sorafenib resistance of HCC.
Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.
The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R(2)=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg(-1) per day) plus DCA (100 mg kg(-1) per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: -87% vs -36%, P<0.001).
The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.
Al/SiC nanolaminates possess an excellent combination of mechanical strength and flexibility. While nanoindentation provides a reasonable estimate of the mechanical properties such as Young’s modulus ...and hardness of these materials, the stress state under nanoindentation is extremely complex. Micropillar compression has become an attractive method of studying the mechanical properties of materials at small length scales in a nominally homogeneous stress state. In this work, micropillars of Al/SiC nanolaminate were fabricated using focused ion beam milling. Compression testing was carried out using a flat-end nanoindenter head. The actual displacement of the pillar during micropillar compression was deconvoluted by subtracting the “extraneous” displacements of the system. Fractographic analysis showed that Al squeezes out between the SiC layers and that a mutual constraint is observed between the hard and soft layers. Numerical finite element modeling was also employed to provide physical insight into the deformation features of the multilayered pillar structure and agreed well with the experimental observations.
With a suite of multi-modal and multi-scale characterization techniques, the present study unambiguously proves that a substantially-improved combination of ultrahigh strength and good ductility can ...be achieved by tailoring the volume fraction, morphology, and carbon content of the retained austenite (RA) in a transformation-induced-plasticity (TRIP) steel with the nominal chemical composition of 0.19C–0.30Si–1.76Mn–1.52Al (weight percent, wt%). After intercritical annealing and bainitic holding, a combination of ultimate tensile strength (UTS) of 1100MPa and true strain of 50% has been obtained, as a result of the ultrafine RA lamellae, which are alternately arranged in the bainitic ferrite around junction regions of ferrite grains. For reference, specimens with a blocky RA, prepared without the bainitic holding, yield a low ductility (35%) and a low UTS (800MPa). The volume fraction, morphology, and carbon content of RA have been characterized using various techniques, including the magnetic probing, scanning electron microscopy (SEM), electron-backscatter-diffraction (EBSD), and transmission electron microscopy (TEM). Interrupted tensile tests, mapped using EBSD in conjunction with the kernel average misorientation (KAM) analysis, reveal that the lamellar RA is the governing microstructure component responsible for the higher mechanical stability, compared to the blocky one. By coupling these various techniques, we quantitatively demonstrate that in addition to the RA volume fraction, its morphology and carbon content are equally important in optimizing the strength and ductility of TRIP-assisted steels.
Although randomized control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, a randomized study is not feasible in certain disease ...settings. When a randomized design is not possible, incorporating external control data into the study design can be an effective way to expand the interpretability of the results of an experimental arm by introducing the ability to carry out a formal or an informal comparative analysis. This paper provides an introduction to the concepts of external controls in oncology trials, followed by a review of relevant and current research on this topic. The paper also focuses on general considerations for designing a trial that may incorporate external control data, followed by case studies of the marketing applications submitted to the Food and Drug Administration that included external control data.
•Considerations for the use of external controls in oncology clinical trials are multifaceted and depend on the intended use.•Review of recent research and some marketing applications describe current usage of external control data in oncology.•Including external controls for primary evidence of efficacy requires careful pre-specification of study design elements.
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