Safety and Effectiveness of Regdanvimab for COVID-19 Treatment: A Phase 4 Post-marketing Surveillance Study Conducted in South Korea

Introduction Regdanvimab, a neutralising monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), received approval for the treatment of coronavirus disease 2019 (COVID-19) in South Korea in 2021. The Ministry of Food and Drug Safety in South Korea mandate that new medications be re-examined for safety and effectiveness post-approval in at least 3000 individuals. This post-marketing surveillance (PMS) study was used to evaluate the safety and effectiveness of regdanvimab in real-world clinical care. Methods This prospective, multicentre, phase 4 PMS study was conducted between February 2021 and March 2022 in South Korea. Eligible patients were aged ≥ 18 years with confirmed mild COVID-19 at high risk of disease progression or moderate COVID-19. Patients were hospitalised and treated with regdanvimab (40 mg/kg, day 1) and then monitored until discharge, with a follow-up call on day 28. Adverse events (AEs) were documented, and the COVID-19 disease progression rate was used to measure effectiveness. Results Of the 3123 patients with COVID-19 infection identified, 3036 were eligible for inclusion. Approximately 80% and 5% of the eligible patients were diagnosed with COVID-19 during the delta- and omicron-dominant periods, respectively. Median (range) age was 57 (18–95) years, and 50.6% of patients were male. COVID-19 severity was assessed before treatment, and high-risk mild and moderate COVID-19 was diagnosed in 1030 (33.9%) and 2006 (66.1%) patients, respectively. AEs and adverse drug reactions (ADRs) were experienced by 684 (22.5%) and 363 (12.0%) patients, respectively. The most common ADR was increased liver function test (n = 62, 2.0%). Nine (0.3%) patients discontinued regdanvimab due to ADRs. Overall, 378 (12.5%) patients experienced disease progression after regdanvimab infusion, with extended hospitalisation/re-admission (n = 300, 9.9%) as the most common reason. Supplemental oxygen was required by 282 (9.3%) patients. Ten (0.3%) patients required intensive care monitoring and 3 (0.1%) died due to COVID-19. Conclusion This large-scale PMS study demonstrated that regdanvimab was effective against COVID-19 progression and had an acceptable safety profile when used in real-world clinical practice.This study and the journals Rapid Service fee was funded by Celltrion Inc. (Incheon, Republic of Korea)

Baseline Renal Function Predicts Hyponatremia in Liver Cirrhosis Patients Treated with Terlipressin for Variceal Bleeding

Objectives. Terlipressin is safely used for acute variceal bleeding. However, side effects, such as hyponatremia, although very rare, can occur. We investigated the development of hyponatremia in cirrhotic patients who had acute variceal bleeding treated with terlipressin and the identification of the risk factors associated with the development of hyponatremia. Design and Methods. This retrospective, case-control study investigated 88 cirrhotic patients who developed hyponatremia and 176 controls that did not develop hyponatremia and were matched in terms of age and gender during the same period following terlipressin administration. Results. The overall change in serum sodium concentration and the mean lowest serum sodium concentration were 3.44 ± 9.55 and 132.44 ± 8.78 mEq/L during treatment, respectively. Multivariate analysis revealed that baseline serum sodium was an independent positive predictor, and the presence of baseline serum creatinine, HBV, DM, creatinine, and shock on admission was independent negative predictors of hyponatremia (P<0.05). Conclusion. The presence of HBV, DM, the baseline serum sodium, shock on admission, and especially baseline creatinine may be predictive of the development of hyponatremia after terlipressin treatment. Therefore, physicians conduct vigilant monitoring associated with severe hyponatremia when cirrhotic patients with preserved renal function are treated with terlipressin for variceal bleeding

Eculizumab as rescue therapy in a kidney transplant recipient with atypical hemolytic uremic syndrome: a case report

A 61-year-old female patient with chronic kidney disease due to diabetes mellitus and hypertension–induced nephropathy received a deceased donor kidney transplant in March 2020. In July 2020, she was transferred from a local hospital due to the exacerbation of general weakness and diarrhea. Upon her arrival, we noticed a high level of serum creatinine (sCr) of 1.5 mg/dL and a decrease in urine output. Her laboratory results indicated significant hemolysis, with a hemoglobin level of 7.0 g/dL, platelet count of 20 ×103/µL, and a lactate dehydrogenase level of 3,207 IU/L. Kidney biopsy showed severe thrombotic microangiopathy without any evidence of acute rejection. Under the impression of atypical hemolytic uremic syndrome (aHUS), we immediately started plasmapheresis and hemodialysis for anuria. Eculizumab was considered as a kidney graft rescue therapy since her sCr level was not effectively decreased, and her anuria continued despite hemodialysis and plasmapheresis. Eculizumab (900 mg) was administered weekly for 4 weeks. An additional 600 mg of eculizumab was administered on the day of plasmapheresis. Since the patient’s laboratory data gradually improved, hemodialysis and plasmapheresis were ceased on admission day 37. After that, eculizumab was administered biweekly (1,200 mg) two more times. The patient’s sCr and platelet count normalized after 2 months of eculizumab treatment. Based on our experience, a shorter interval between the clinical diagnosis of aHUS and administration of eculizumab increases the likelihood of rescuing the kidney

Inhibitory Effect of Corn Silk on Skin Pigmentation

In this study, the inhibitory effect of corn silk on melanin production was evaluated. This study was performed to investigate the inhibitory effect of corn silk on melanin production in Melan-A cells by measuring melanin production and protein expression. The corn silk extract applied on Melan-A cells at a concentration of 100 ppm decreased melanin production by 37.2% without cytotoxicity. This was a better result than arbutin, a positive whitening agent, which exhibited a 26.8% melanin production inhibitory effect at the same concentration. The corn silk extract did not suppress tyrosinase activity but greatly reduced the expression of tyrosinase in Melan-A cells. In addition, corn silk extract was applied to the human face with hyperpigmentation, and skin color was measured to examine the degree of skin pigment reduction. The application of corn silk extract on faces with hyperpigmentation significantly reduced skin pigmentation without abnormal reactions. Based on the results above, corn silk has good prospects for use as a material for suppressing skin pigmentation

De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans

Defects in the mitochondrial genome (mitochondrial DNA (mtDNA)) are associated with both congenital and acquired disorders in humans. Nuclear-encoded DNA polymerase subunit gamma (POLG) plays an important role in mtDNA replication, and proofreading and mutations in POLG have been linked with increased mtDNA deletions. SSBP1 is also a crucial gene for mtDNA replication. Here, we describe a patient diagnosed with Pearson syndrome with large mtDNA deletions that were not detected in the somatic cells of the mother. Exome sequencing was used to evaluate the nuclear factors associated with the patient and his family, which revealed a paternal POLG mutation (c.868C > T) and a maternal SSBP1 mutation (c.320G > A). The patient showed lower POLG and SSBP1 expression than his healthy brothers and the general population of a similar age. Notably, c.868C in the wild-type allele was highly methylated in the patient compared to the same site in both his healthy brothers. These results suggest that the co- deficient expression of POLG and SSBP1 genes could contribute to the development of mtDNA deletion

Mitochondrial DNA Haplogroup Related to the Prevalence of Helicobacter pylori

Mitochondria are essential organelles that are not only responsible for energy production but are also involved in cell metabolism, calcium homeostasis, and apoptosis. Targeting mitochondria is a key strategy for bacteria to subvert host cells’ physiology and promote infection. Helicobacter (H.) pylori targets mitochondria directly. However, mitochondrial genome (mtDNA) polymorphism (haplogroup) is not yet considered an important factor for H. pylori infection. Here, we clarified the association of mitochondrial haplogroups with H. pylori prevalence and the ability to perform damage. Seven mtDNA haplogroups were identified among 28 H. pylori-positive subjects. Haplogroup B was present at a higher frequency and haplotype D at a lower one in the H. pylori population than in that of the H. pylori-negative one. The fibroblasts carrying high-frequency haplogroup displayed a higher apoptotic rate and diminished mitochondrial respiration following H. pylori infection. mtDNA mutations were accumulated more in the H. pylori-positive population than in that of the H. pylori-negative one in old age. Among the mutations, 57% were located in RNA genes or nonsynonymous protein-coding regions in the H. pylori-positive population, while 35% were in the H. pylori-negative one. We concluded that gastric disease caused by Helicobacter virulence could be associated with haplogroups and mtDNA mutations

Gene regulatory cascade of senescence-associated NAC transcription factors activated by ETHYLENE-INSENSITIVE2-mediated leaf senescence signalling in Arabidopsis

Leaf senescence is a finely tuned and genetically programmed degeneration process, which is critical to maximize plant fitness by remobilizing nutrients from senescing leaves to newly developing organs. Leaf senescence is a complex process that is driven by extensive reprogramming of global gene expression in a highly coordinated manner. Understanding how gene regulatory networks involved in controlling leaf senescence are organized and operated is essential to decipher the mechanisms of leaf senescence. It was previously reported that the trifurcate feed-forward pathway involving EIN2, ORE1, and miR164 in Arabidopsis regulates age-dependent leaf senescence and cell death. Here, new components of this pathway have been identified, which enhances knowledge of the gene regulatory networks governing leaf senescence. Comparative gene expression analysis revealed six senescence-associated NAC transcription factors (TFs) (ANAC019, AtNAP, ANAC047, ANAC055, ORS1, and ORE1) as candidate downstream components of ETHYLENE-INSENSITIVE2 (EIN2). EIN3, a downstream signalling molecule of EIN2, directly bound the ORE1 and AtNAP promoters and induced their transcription. This suggests that EIN3 positively regulates leaf senescence by activating ORE1 and AtNAP, previously reported as key regulators of leaf senescence. Genetic and gene expression analyses in the ore1 atnap double mutant revealed that ORE1 and AtNAP act in distinct and overlapping signalling pathways. Transient transactivation assays further demonstrated that ORE1 and AtNAP could activate common as well as differential NAC TF targets. Collectively, the data provide insight into an EIN2-mediated senescence signalling pathway that coordinates global gene expression during leaf senescence via a gene regulatory network involving EIN3 and senescence- associated NAC TFs. © 2014 The Author.

Germline and somatic mtDNA mutations in mouse aging.

The accumulation of acquired mitochondrial genome (mtDNA) mutations with aging in somatic cells has been implicated in mitochondrial dysfunction and linked to age-onset diseases in humans. Here, we asked if somatic mtDNA mutations are also associated with aging in the mouse. MtDNA integrity in multiple organs and tissues in young and old (2-34 months) wild type (wt) mice was investigated by whole genome sequencing. Remarkably, no acquired somatic mutations were detected in tested tissues. However, we identified several non-synonymous germline mtDNA variants whose heteroplasmy levels (ratio of normal to mutant mtDNA) increased significantly with aging suggesting clonal expansion of inherited mtDNA mutations. Polg mutator mice, a model for premature aging, exhibited both germline and somatic mtDNA mutations whose numbers and heteroplasmy levels increased significantly with age implicating involvement in premature aging. Our results suggest that, in contrast to humans, acquired somatic mtDNA mutations do not accompany the aging process in wt mice