Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Brain impedance variation of directional leads implanted in subthalamic nuclei of Parkinsonian patients

ObjectiveConventional deep brain stimulation (DBS) systems with ring-shaped leads generate spherical electrical fields. In contrast, novel directional leads use segmented electrodes. Aim of this study was to quantify the impedance variations over time in subjects with the directional Cartesia-Boston® system.MethodsImpedance records, programming settings, and clinical data of 11 consecutive Parkinsonian patients implanted with DBS directional leads in two Italian centers (Udine and Vicenza) were retrospectively evaluated. Data were collected before starting stimulation (in the operating room and at days 5 and 40) and after switching stimulation on at the successive follow-up visits (1, 6 and 12 months).ResultsDirectional leads have significantly higher impedance than ring leads. Stimulated contacts had always lower impedance compared to non-stimulated contacts. Before DBS-on, all contacts had higher impedance in the operating room, with an initial decrease five days post-surgery and a subsequent increase at day 40, more evident for directional contacts. The impedance of directional leads increased post-implantation at 1 and 6 months with a plateau at 12 months.ConclusionsThere was a significant difference between the directional and ring leads at baseline (before activation of DBS) and during follow-up (chronic DBS).SignificanceOur study reveals new information about the impedance of segmented electrodes that is useful for patient management during the initial test period, as well as during long-term DBS follow-up.     

Steep Decrease of Gender Difference in DSM-IV Alcohol Use Disorder: A Comparison of Two Nation-wide Surveys Conducted 10 Years Apart in Korea

While decreasing trend in gender differences in alcohol use disorders was reported in Western countries, the change in Asian countries is unknown. This study aims to explore the shifts in gender difference in alcohol abuse (AA) and dependence (AD) in Korea. We compared the data from two nation-wide community surveys to evaluate gender differences in lifetime AA and AD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Face-to-face interviews using the Composite International Diagnostic Interview (CIDI) were applied to all subjects in 2001 (n=6,220) and 2011 (n=6,022). Male-to-female ratio of odds was decreased from 6.41 (95% CI, 4.81-8.54) to 4.37 (95% CI, 3.35-5.71) for AA and from 3.75 (95% CI, 2.96-4.75) to 2.40 (95% CI, 1.80-3.19) for AD. Among those aged 18-29, gender gap even became statistically insignificant for AA (OR, 1.59; 95% CI, 0.97-2.63) and AD (OR, 1.18; 95% CI, 0.80-2.41) in 2011. Men generally showed decreased odds for AD (0.55; 95% CI, 0.45-0.67) and women aged 30-39 showed increased odds for AA (2.13; 95% CI 1.18-3.84) in 2011 compared to 2001. Decreased AD in men and increased AA in women seem to contribute to the decrease of gender gap. Increased risk for AA in young women suggests needs for interventions.     

Ocular changes in the mouse embryo following acute maternal ethanol intoxication

The development of the eye was investigated in the mouse embryo following a single administration of ethanol plus [3H]thymidine to the dam on day 13 of gestation. After 1 hr there was no difference in the number of labelled cells/100 micron 2 in the neural layer of the retina compared to controls, but there was an alcohol-related reduction in labelling density. After 24 hr there was an increase in the numbers of both pyknotic cells and mitotic figures, breaks occurred in the inner surface of the retina and cell debris was being extruded into the posterior chamber. At 48 hr the increase in pyknotic cells persisted, but there was less evidence of cell debris and the borders had been repaired. The estimated cell cycle time in the neural progenitor cells following maternal alcohol administration was increased 7-fold compared to controls. Morphometric analysis revealed that after 48 hr there were significant alcohol-related reductions in the width and depth of the eye, in the thickness of the neural layer and in the interocular distance. It appears that many of the ophthalmic abnormalities reported in human fetal alcohol syndrome can be produced in the mouse embryo following a single episode of acute maternal intoxication during a critical period of ocular ontogeny, and that they evolve primarily from disturbances in the normal patterns of recruitment and loss of neural progenitor cells in the developing retina.     

Enhancing Nurse Assessment of Alcohol and Drug Dependency: A Preliminary Study

The purpose of this project was to prepare nurses to provide brief interventions for clients with alcohol or other drug (AOD) dependency in order to reduce hospitalization, morbidity, and mortality. The project was a collaborative process between a major medical center and a school of nursing. Nurses were surveyed for understanding of alcohol and other drug assessment, and a day long training was provided to teach techniques of brief interventions. The short-term results included increased knowledge of nurses about AOD assessment. Long-term results indicated that 95% of patients referred to the AOD team were confirmed to have AOD problems (Dunn & Ries, 1997). This project documents the need for nurses to have more knowledge about AOD problems and brief intervention techniques.