Safety and immunogenicity of NVX-CoV2373 (TAK-019) vaccine in healthy Japanese adults: Interim report of a phase I/II randomized controlled trial

BackgroundWe evaluated the safety and immunogenicity of NVX-CoV2373, a recombinant SARS-CoV-2 nanoparticle vaccine, in healthy Japanese participants.MethodsThis phase 1/2, randomized, observer-blind, placebo-controlled trial conducted in Japan (two sites), enrolled healthy Japanese adults aged ≥ 20 years with no history/risk of SARS-CoV-2 infection and no prior exposure to other approved/investigational SARS-CoV-2 vaccines or treatments. Participants were stratified by age (< 65 or ≥ 65 years) and randomized to receive two doses of either NVX-CoV2373 (5 μg SARS-CoV-2 rS; 50 μg Matrix-M1) or placebo, 21 days apart. Primary outcomes were safety and immunogenicity assessed by serum IgG antibody levels against SARS-CoV-2 rS protein on day 36. Herein, we report the primary data analysis at 4 weeks after the second dose, ahead of 12-month follow-up completion (data cut-off: 8 May 2021).ResultsBetween 12 February 2021 and 17 March 2021, 326 subjects were screened, and 200 participants enrolled and randomized: NVX-CoV2373, n = 150; placebo, n = 50. Solicited adverse events (AEs) through 7 days after each injection occurred in 121/150 (80.7%) and 11/50 (22.0%) participants in the NVX-CoV2373 and placebo arms, respectively. In the NVX-CoV2373 arm, tenderness and injection site pain were the most frequently reported solicited AEs after each vaccination, irrespective of age. Robust immune responses occurred with NVX-CoV2373 (n = 150) by day 36: IgG geometric mean fold rise (95% confidence interval) 259 (219, 306); seroconversion rate 100% (97.6, 100). No such response occurred with placebo (n = 49).ConclusionTwo doses of NVX-CoV2373 given with a 21-day interval demonstrated acceptable safety and induced robust anti-SARS-CoV-2 immune responses in healthy Japanese adults. Funding: Takeda Pharmaceutical Company Limited and Japan Agency for Medical Research and Development (AMED). ClinicalTrials.gov identifier: NCT04712110.     

Long‐term therapy of multiple basal cell carcinomas: Clinicodermoscopic score for monitoring of intermittent vismodegib treatment

Vismodegib treatment of multiple basal cell carcinomas (BCCs) is limited by adverse effects and high relapse rates: intermittent regimens are therefore preferred for long‐term administration. The objective of this study was to investigate clinical and dermoscopic changes in BCCs during long‐term intermittent treatment and to identify those most indicative of tumor persistence/clearing. Clinical and dermoscopic images (n = 380 each) of 38 BCCs were acquired at 10 observation times (t0–t9). Biopsies were performed at baseline (t0) and after 72 weeks of treatment (t9). All images were evaluated retrospectively by experts who assessed the presence/absence of 12 clinical and 14 dermoscopic features: clinical scores (CScs) and dermoscopic scores (DScs) were then calculated.     

Cognitive interference as a possible therapeutic strategy to prevent expression of benzodiazepine withdrawal

Benzodiazepines are usually prescribed for anxiety and sleep disorders in long‐term schedules that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. The context‐dependent associative learning process that underlies diazepam dependence can be interfered by pre‐exposure to the drug administration context, an effect known as latent inhibition. Considering this background, the primary aim of the present investigation is to develop a therapeutic strategy to prevent diazepam withdrawal in male Wistar rats by interfering with this learning process. Nitric oxide is a crucial player in learning and memory, hippocampal synaptic transmission and in diazepam withdrawal. Then, a secondary goal is to determine how latent inhibition could alter functional plasticity and neuronal nitric oxide synthase enzyme (NOS‐1) expression within the hippocampus, by using multi‐unitary cell recordings and Western blot, respectively. Our results indicate that chronic diazepam treated animals under latent inhibition did not show anxiety, or changes in hippocampal synaptic transmission, but a significant reduction in NOS‐1 expression was observed. Accordingly, pharmacological NOS‐1 inhibition resembles behavioral and electrophysiological changes induced by latent inhibition. Contrary, diazepam treated animals under Control protocol expressed anxiety and evidenced an increased hippocampal‐plasticity, without alterations in NOS‐1 expression. In conclusion, manipulation of the contextual cues presented during diazepam administration may be considered as an effective non‐pharmacological tool to prevent the withdrawal syndrome. This behavioral strategy may influence hippocampal synaptic transmission, probably by alterations in nitric oxide signaling pathways in this structure.     

Where is the “where” in the brain? A meta‐analysis of neuroimaging studies on spatial cognition

Spatial representations are processed in the service of several different cognitive functions. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta‐analysis to identify: (a) the shared neural activations among spatial functions to reveal the “core” network of spatial processing; (b) the specific neural activations associated with each of these functions. Following PRISMA guidelines, a total of 133 fMRI and PET studies were included in the meta‐analysis. The overall analysis showed that the core network of spatial processing comprises regions that are symmetrically distributed on both hemispheres and that include dorsal frontoparietal regions, presupplementary motor area, anterior insula, and frontal operculum. The specific analyses revealed the brain regions that are selectively recruited for each spatial function, such as the right temporoparietal junction for shift of spatial attention, the right parahippocampal gyrus, and the retrosplenial cortex for navigation and spatial long‐term memory. The findings are integrated within a systematic review of the neuroimaging literature and a new neurocognitive model of spatial cognition is proposed.     

Autism‐associated Shank3 mutations alter mGluR expression and mGluR‐dependent but not NMDA receptor‐dependent long‐term depression

SHANK3 is a postsynaptic structural protein localized at excitatory glutamatergic synapses in which deletions and mutations have been implicated in patients with autism spectrum disorders (ASD). The expression of Shank3 ASD mutations causes impairments in ionotropic glutamate receptor‐mediated synaptic responses in neurons, which is thought to underlie ASD‐related behaviors, thereby indicating glutamatergic synaptopathy as one of the major pathogenic mechanisms. However, little is known about the functional consequences of ASD‐associated mutations in Shank3 on another important set of glutamate receptors, group I metabotropic glutamate receptors (mGluRs). Here, we further assessed how Shank3 mutations identified in patients with ASD (one de novo InsG mutation and two inherited point mutations, R87C and R375C) disrupt group I mGluR (mGluR1 and mGluR5) expression and function. To identify potential isoform‐specific deficits induced by ASD‐associated Shank3 mutations on group I mGluRs, we surface immunolabeled mGluR1 and mGluR5 independently. We also induced mGluR‐dependent synaptic plasticity (R,S‐3,5‐dihydroxyphenylglycine [DHPG]‐induced long‐term depression [LTD]) as well as N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent LTD. ASD‐associated mutations in Shank3 differentially interfered with the ability of cultured hippocampal neurons to express mGluR5 and mGluR1 at synapses. Intriguingly, all ASD Shank3 mutations impaired mGluR‐dependent LTD without altering NMDAR‐dependent LTD. Our data show that the specific perturbation in mGluR‐dependent synaptic plasticity occurs in neurons expressing ASD‐associated Shank3 mutations, which may underpin synaptic dysfunction and subsequent behavioral deficits in ASD.