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Wenzhen Ge,1 Ning Wu,1 Chieh-I Chen,1 Timothy J Inocencio,1 Patrick R LaFontaine,2 Frank Seebach,3 Matthew Fury,4 James Harnett,1 Emily S Ruiz5 1Department of Health Economics and Outcomes Research, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 2Department of Global Health Economics & Outcomes Research, Sanofi, Cambridge, MA, USA; 3Department of Regulatory Affairs, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 4Department of Clinical Sciences, Oncology, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 5Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA, USACorrespondence: Wenzhen Ge, Regeneron Pharmaceuticals, Inc, 1 Rockwood Road, Sleepy Hollow, NY, 10591, Tel +1 914-847-7000, Email wenzhen.ge@regeneron.comBackground: Prior to the Food and Drug Administration approval of cemiplimab in 2018, the median overall survival (OS) for adult patients with advanced CSCC receiving systemic therapy was approximately 8 to 15 months. Limited real-world data are available on cemiplimab for this indication in the US.Patients and Methods: This retrospective cohort study included US patients with advanced CSCC initiating cemiplimab monotherapy in a real-world database (2018– 2021). A clinical trial–like sub-cohort was identified using select criteria. Time to treatment discontinuation (TTD), time to next treatment (TTNT), and OS were estimated using Kaplan–Meier methods. Cox proportional hazard models were used to examine prognostic factors associated with OS in the main cohort.Results: The main cohort included 622 patients (n = 240 in the trial-like cohort). In the main cohort, the median age was 78 years, 77.8% were male, 21.4% were immunocompromised/immunosuppressed, and 63.8% had metastatic CSCC. Median (95% CI) TTD and TTNT were 8.0 (6.6– 9.0) months and 16.4 (13.3– 21.0) months, respectively, in the main cohort. Median (95% CI) OS was 24.8 (21.8– 29.1) months in the main cohort (not reached in the trial-like cohort). In multivariable analyses, age < 60 years (hazard ratio [HR], 0.37), Eastern Cooperative Oncology Group performance status < 3– 4 (HR range, 0.13– 0.57), and primary CSCC location in the head and neck only versus extremities only (HR, 0.59) were associated with better OS. Similar OS was observed between patients who had immunosuppressing/immunocompromising conditions and those without.Conclusion: These findings confirm the effectiveness of cemiplimab among a heterogenous, real-world advanced CSCC patient population and substantiate the efficacy of cemiplimab observed in clinical trials.Keywords: cutaneous squamous cell carcinoma, cemiplimab, immune checkpoint inhibitor, real-world study, skin cancer

The concept of reward is fundamental in reinforcement learning with a wide range of applications in natural and social sciences. Seeking an interpretable reward for decision-making that largely shapes the system's behavior has always been a challenge in reinforcement learning. In this work, we explore a discrete-time reward for reinforcement learning in continuous time and action spaces that represent many phenomena captured by applying physical laws. We find that the discrete-time reward leads to the extraction of the unique continuous-time decision law and improved computational efficiency by dropping the integrator operator that appears in classical results with integral rewards. We apply this finding to solve output-feedback design problems in power systems. The results reveal that our approach removes an intermediate stage of identifying dynamical models. Our work suggests that the discrete-time reward is efficient in search of the desired decision law, which provides a computational tool to understand and modify the behavior of large-scale engineering systems using the optimal learned decision.

Abstract There are many stars that are rotating spheroids in the Universe, and studying them is of very important significance. Since the times of Newton, many astronomers and physicists have researched gravitational properties of stars by considering the moment equations derived from Eulerian hydrodynamic equations. In this paper we study the scattering of spinors of the Dirac equation, and in particular investigate the scattering issue in the limit case of rotating Maclaurin spheroids. Firstly we give the metric of a rotating ellipsoid star, then write the Dirac equation under this metric, and finally derive the scattering solution to the Dirac equation and establish a relation between differential scattering cross-section, $$\sigma $$ σ , and stellar matter density, $$\mu $$ μ . It is found that the sensitivity of $$\sigma $$ σ to the change in $$\mu $$ μ is proportional to the density $$\mu $$ μ . Because of the weak gravitational field and the constant mass density, our results are reasonable. The results can be applied to white dwarfs, main sequence stars, red giants, supergiant stars and so on, as long as their gravitational fields are so weak that they can be treated in the Newtonan approximations, and the fluid is assumed to be incompressible. Notice that we take the star’s matter density to be its average density and the star is not taken to be compact. Obviously our results cannot be used to study neutron stars and black holes. In particular, our results are suitable for white dwarfs, which have average densities of about $$10^{5}$$ 105 –$$10^{6}$$ 106 g cm$$^{-3}$$ -3 , corresponding to a range of mass of about $$0.21{-}0.61 M_{\bigodot }$$ 0.21-0.61M⨀ and a range of radius of about $$6000{-}10,000$$ 6000-10,000 km.

Yi-Che Lee,1–3 Chih-Ting Huang,4 Fong-Yu Cheng,5 Shih-Yuan Hung,3,6 Tsun-Mei Lin,7 Yen-Chang Tsai,4 Chih-I Chen,8 Hao-Kuang Wang,9 Chi-Wei Lin,10 Hung-Hsiang Liou,11 Min-Yu Chang,3 Hsi-Hao Wang,3 Yuan-Yow Chiou4,12 1Division of Nephrology, Department of Internal Medicine, E-DA Dachang Hospital/ I-Shou University, Kaohsiung, Taiwan; 2School of Medicine, College of Medicine; 3Division of Nephrology, Department of Internal Medicine, E-DA Hospital/ I-Shou University, Kaohsiung, Taiwan; 4Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Chemistry, Chinese Culture University, Taipei, Taiwan; 6School of Medicine for International Students; 7Department of Laboratory Medicine; 8Division of Colorectal Surgery, Department of Surgery; 9Department of Neurosurgery; 10Department of Medical Education, E-DA Hospital/ I-Shou University, Kaohsiung, Taiwan; 11Division of Nephrology, Department of Medicine, Hsin-Jen Hospital, New Taipei City, Taiwan; 12Department of Pediatrics, National Cheng Kung University Hospital, Tainan, TaiwanCorrespondence: Yi-Che LeeDivision of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 82445, Taiwan, ROCTel +886-7-6150011 ext. 5121Email pipijer@gmail.com Yuan-Yow ChiouInstitute of Clinical Medicine, Department of Pediatrics, National Cheng Kung University Hospital, Medical College, No. 138, Sheng-Li Road, Tainan City 701, Taiwan, ROCTel +886-6-2353535 ext. 4184Fax +886-6-2753083Email yuanyow@mail.ncku.edu.twPurpose: Vitamin D is a novel potential therapeutic agent for peritoneal dialysis (PD)-related peritoneal fibrosis, but it can induce hypercalcemia and vascular calcification, which limits its applicability. In this study, we create nanotechnology-based drug delivery systems to investigate its therapeutics and side effects.Materials and methods: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) and L-α-phosphatidylcholine (PC), which packages with 1α,25(OH)2D3, were used to construct vitamin D nanoliposomes. To confirm the function and safety of vitamin D nanoliposomes, peritoneal mesothelial cells were treated with TGF-β1 and the reverse was attempted using vitamin D nanoliposomes. Antibodies (Ab) against the peritoneum-glycoprotein M6A (GPM6A) Ab were conjugated with vitamin D nanoliposomes. These particles were implanted into mice by intraperitoneal injection and the animals were monitored for the distribution and side effects induced by vitamin D.Results: Vitamin D nanoliposomes were taken up by the mesothelial cells over time without cell toxicity and it also provided the same therapeutic effect in vitro. In vivo study, fluorescent imaging showed vitamin D nanoliposomes allow specific peritoneum target effect and also ameliorate vitamin D side effect.Conclusion: Nanoliposomes vitamin D delivery systems for the prevention of PD-related peritoneal damage may be a potential clinical strategy in the future.Keywords: peritoneal dialysis, nanoliposome, vitamin D, fibrosis

Background Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes. Results We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol. Conclusion These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.

To address the issue of frequency stability in microgrids with limited communication resources and bandwidth, this paper proposed an event-triggered control method based on a cloud-edge collaborative architecture. Firstly, to address the limited communication resources, event-triggered detector is set up at the edge to upload state variables and update control instructions only when the frequency deviation exceeds a pre-set threshold. Secondly, a fractional-order PI–PD controller is designed at the cloud control center, which achieves higher control degrees of freedom and stronger robustness than traditional integer-order PID control schemes. Additionally, to obtain better control parameters, an optimized design method based on an improved Big Bang-Big Crunch method (BB-BC3) is proposed for the fractional-order PI–PD controller. At last, a simulation example is given to prove the validity of the proposed method. Simulation results show that compared to the integer-order PI–PD controller, the fractional-order PI–PD controller based on the BB-BC3 algorithm proposed in this paper reduces the peak value of the response curve by 5%, and shortens the setting time by 0.14 s. [ABSTRACT FROM AUTHOR]

There are many rotating spheroids in the universe, and many astronomers and physicists have used theoretical methods to study the characteristics of stellar gravity since Newton's time. This paper derives the solutions of eight scattering states (ϕ(0),χ(0),ϕ(1),χ(1),ϕ(2)$$ \Big({\phi}^{(0)},{\chi}^{(0)},{\phi}^{(1)},{\chi}^{(1)},{\phi}^{(2)} $$,χ(2),ϕ(3)$$ {\chi}^{(2)},{\phi}^{(3)} $$, andχ(3))$$ {\chi}^{(3)}\Big) $$ for the Dirac equation with positive‐energy E=im$$ E= im $$, and establishes the relationship between the differential scattering cross section σi(p,θ,φ)$$ {\sigma}_i\left(p,\theta, \varphi \right) $$ and the stellar density μ$$ \mu $$. It is found that: (1) For the eight scattering states, their average scattering cross‐sections σi‾$$ \overline{\sigma_i} $$ are proportional to μ2$$ {\mu}^2 $$, and depend on the star's radius, and the higher the stellar density μ$$ \mu $$, the greater the sensitivity of σi‾$$ \overline{\sigma i} $$ to the change of μ$$ \mu $$; (2) For the four scattering states χ(i),i=0,1,2,3$$ {\chi}^{(i)},i=0,1,2,3 $$, their average scattering amplitudes f‾(p,θ)$$ \overline{f}\left(p,\theta \right) $$ and σ‾(p,θ)$$ \overline{\sigma}\left(p,\theta \right) $$ depend on the mass m$$ m $$ of the particles; while for the other four scattering states ϕ(i)$$ {\phi}^{(i)} $$, i=0,1,2,3$$ i=0,1,2,3 $$, then f‾$$ \overline{f} $$ and σ‾$$ \overline{\sigma} $$ are independent of m$$ m $$. This study links the gravitational characteristics of stars with the scattering cross section, creating a new method for studying the gravitational characteristics, which helps to reveal the mystery of the gravity of rotating ellipsoidal stars. [ABSTRACT FROM AUTHOR]