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Sang-Hyun Ihm,1 Hui-Kyung Jeon,1 Tae-Joon Cha,2 Taek-Jong Hong,3 Sang-Hyun Kim,4 Nae-Hee Lee,5 Jung Han Yoon,6 Namsik Yoon,7 Kyung-Kuk Hwang,8 Sang-Ho Jo,9 Ho-Joong Youn1 1Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 2Division of Cardiology, Department of Internal Medicine, Kosin University College of Medicine, 3Division of Cardiology, Department of Internal Medicine, Pusan National University Hospital, Busan, 4Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, 5Department of Cardiology, Soonchunhyang University Hospital, Bucheon, 6Division of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, 7Department of Cardiology, Chonnam National University Hospital, Gwangju, 8Department of Internal Medicine, Chungbuk National University, College of Medicine, Cheongju, 9Division of Cardiology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea Purpose: To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy.Patients and methods: Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] ≥90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings.Results: After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were -9.67±6.50/-12.89±11.78, -10.72±6.19/-13.79±9.41, and -4.93±7.26/-4.55±11.27 mmHg in the CKD-828 2.5/40 mg (P

ABSTRACT With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss of neutralization of newer variants. The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible variants. Virological efficacy and impact on pathogenicity was assessed in K18-hACE2 mice inoculated with either the Delta or BA.1 Omicron variants. Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post-infection, for the Delta variant but not the Omicron variant. It also blocked brain infection, which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a multifocal granulomatous inflammation in which the virus appeared to be confined. The current study provides evidence of an altered tissue response to SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data demonstrate that experimental designs that reflect treatment use cases are achievable in animal models for monoclonal antibodies. Extreme caution should be taken when interpreting prophylactic experimental designs that may not be representative of treatment.IMPORTANCEFollowing the emergence of the SARS-CoV-2 Omicron variant, the WHO recommended against the use of Ronapreve in its COVID-19 treatment guidelines due to a lack of efficacy based on current pharmacokinetic-pharmacodynamic understanding. However, the continued use of Ronapreve, specifically in vulnerable patients, was advocated by some based on in vitro neutralization data. Here, the virological efficacy of Ronapreve was demonstrated in both the lung and brain compartments using Delta as a paradigm for a susceptible variant. Conversely, a lack of virological efficacy was demonstrated for the Omicron variant. Comparable concentrations of both monoclonal antibodies were observed in the plasma of Delta- and Omicron-infected mice. This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection (‘twinfection’) is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

Abstract COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

This paper presents a comprehensive assessment of the performance of on-chip circularly polarized (CP) circular loop antennas that have been designed and fabricated to operate in the Q/V frequency band. The proposed antenna design incorporates two concentric loops, with the outer loop as the active element and the inner loop enhancing the CP bandwidth. The study utilizes gallium arsenide (GaAs) and silicon carbide (4H-SiC) semiconductor wafer substrates. The measured results highlight the successful achievement of impedance matching at 40 GHz and 44 GHz for the 4H-SiC and GaAs substrates, respectively. Furthermore, both cases yield an axial ratio (AR) of less than 3 dB, with variations in bandwidths and frequency bands contingent upon the dielectric constant of the respective substrate material. Moreover, the outcomes confirm that utilizing 4H-SiC substrates results in a significantly higher radiation efficiency of 95%, owing to lower substrate losses. In pursuit of these findings, a 4-element circularly polarized loop array antenna has been fabricated for operation at 40 GHz, employing a 4H-SiC wafer as a low-loss substrate. The results underscore the antenna’s remarkable performance, exemplified by a broadside gain of approximately 9.7 dBic and a total efficiency of circa 92%. A close agreement has been achieved between simulated and measured results.