Background and Objective
Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in ...adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers.
Methods
This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections.
Results
There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80–125%). Geometric mean C
max
and AUC
last
following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants.
Conclusions
After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals.
Trial Registration
ClinicalTrials.Gov: NCT04988152.
Integrins αvβ5 and αvβ3 are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αvβ5-selective compounds has ...remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αvβ5versus αvβ3 with a pyrrolidine amide linker that confers selectivity for αvβ5 by positioning a key aryl ring in the SDL of αvβ5 with good complementarity; binding in this mode is disfavoured in αvβ3 due to clashes with key residues in the β3-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αvβ5-selective in vitro tool compound.
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•SAR survey of amide containing RGD mimetics for αvβ5 potency & selectivity.•Compounds discovered with high αvβ5 potency & selectivity for αvβ5vs αvβ3.•αvβ5 homology model developed & used to explain selectivity vs αvβ3 seen.•The selective compounds are proposed to elicit steric clashes in αvβ3 active site.•High passive permeability & solubility permit use as αvβ5-selective in vitro tools.
Background
Social media (SoMe) use, in all of its forms, has seen massively increased throughout the past two decades, including academic publishing. Many journals have established a SoMe presence, ...yet the influence of promotion of scientific publications on their visibility and impact remains poorly studied. The European Journal of Neurosurgery «Acta Neurochirurgica» has established its SoMe presence in form of a Twitter account that regularly promotes its publications. We aim to analyze the impact of this initial SoMe campaign on various alternative metrics (altmetrics).
Methods
A retrospective analysis of all articles published in the journal
Acta Neurochirurgica
between May 1st, 2018, and April 30th, 2020, was performed. These articles were divided into a historical control group — containing the articles published between May 1st, 2018, and April 30th, 2019, when the SoMe campaign was not yet established — and into an intervention group. Several altmetrics were analyzed, along with website visits and PDF downloads per month.
Results
In total, 784 articles published during the study period, 128 (16.3%) were promoted via Twitter. During the promotion period, 29.7% of published articles were promoted. Overall, the published articles reached a mean of 31.3 ± 50.5 website visits and 17.5 ± 31.25 PDF downloads per month. Comparing the two study periods, no statistically significant differences in website visits (26.91 ± 32.87 vs. 34.90 ± 61.08,
p
= 0.189) and PDF downloads (17.52 ± 31.25 vs. 15.33 ± 16.07,
p
= 0.276) were detected. However, overall compared to non-promoted articles, promoted articles were visited (48.9 ± 95.0 vs. 29.0 ± 37.0,
p
= 0.005) and downloaded significantly more (25.7 ± 66.7 vs. 16.6 ± 18.0,
p
= 0.045) when compared to those who were not promoted during the promotion period.
Conclusions
We report a 1-year initial experience with promotion of a general neurosurgical journal on Twitter. Our data suggest a clear benefit of promotion on article site visits and article downloads, although no single responsible element could be determined in terms of altmetrics. The impact of SoMe promotion on other metrics, including traditional bibliometrics such as citations and journal impact factor, remains to be determined.
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other ...neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10−8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
This study examines the impact of lifetime blast exposure on white matter integrity in service members and veterans (SMVs). Participants were 227 SMVs, including those with a history of mild ...traumatic brain injury (mTBI;
= 124), orthopedic injury controls (
= 58), and non-injured controls (
= 45), prospectively enrolled in a Defense and Veterans Brain Injury Center (DVBIC)/Traumatic Brain Injury Center of Excellence (TBICoE) study. Participants were divided into three groups based on number of self-reported lifetime blast exposures: none (
= 53); low (i.e., 1-9 blasts;
= 81); and high (i.e., ≥10 blasts;
= 93). All participants underwent diffusion tensor imaging (DTI) at least 11 months post-injury. Tract-of-interest (TOI) analysis was applied to investigate fractional anisotropy and mean, radial, and axial diffusivity (AD) in left and right total cerebral white matter as well as 24 tracts. Benjamini-Hochberg false discovery rate (FDR) correction was used. Regressions investigating blast exposure and mTBI on white matter integrity, controlling for age, revealed that the presence of mTBI history was associated with lower AD in the bilateral superior longitudinal fasciculus and arcuate fasciculus and left cingulum (βs = -0.255 to -0.174;
s < 0.01); however, when non-injured controls were removed from the sample (but orthopedic injury controls remained), these relationships were attenuated and did not survive FDR correction. Regression models were rerun with modified post-traumatic stress disorder (PTSD) diagnosis added as a predictor. After FDR correction, PTSD was not significantly associated with white matter integrity in any of the models. Overall, there was no relationship between white matter integrity and self-reported lifetime blast exposure or PTSD.
Given the critical role of pure, organic compound primary reference standards used to characterize and certify chemical Certified Reference Materials (CRMs), it is essential that associated mass ...purity assessments be fit-for-purpose, represented by an appropriate uncertainty interval, and metrologically sound. The mass fraction purities (% g/g) of 25-hydroxyvitamin D (25(OH)D) reference standards used to produce and certify values for clinical vitamin D metabolite CRMs were investigated by multiple orthogonal quantitative measurement techniques. Quantitative ¹H-nuclear magnetic resonance spectroscopy (qNMR) was performed to establish traceability of these materials to the International System of Units (SI) and to directly assess the principal analyte species. The 25(OH)D standards contained volatile and water impurities, as well as structurally-related impurities that are difficult to observe by chromatographic methods or to distinguish from the principal 25(OH)D species by one-dimensional NMR. These impurities have the potential to introduce significant biases to purity investigations in which a limited number of measurands are quantified. Combining complementary information from multiple analytical methods, using both direct and indirect measurement techniques, enabled mitigation of these biases. Purities of 25(OH)D reference standards and associated uncertainties were determined using frequentist and Bayesian statistical models to combine data acquired via qNMR, liquid chromatography with UV absorbance and atmospheric pressure-chemical ionization mass spectrometric detection (LC-UV, LC-ACPI-MS), thermogravimetric analysis (TGA), and Karl Fischer (KF) titration.
The US National Institute of Standards and Technology (NIST) developed a Standard Reference Material® (SRM®) 3949 Folate Vitamers in Frozen Human Serum to replace SRM 1955 Homocysteine and Folate in ...Human Serum. The presence of increased endogenous levels of folic acid and 5-methyltetrahydrofolate (5mTHF) in SRM 3949, enhanced folate stability via addition of ascorbic acid, and inclusion of values for additional minor folates are improvements over SRM 1955 that should better serve the clinical folate measurement community. The new SRM contains folates at three levels. To produce SRM 3949, pilot sera were collected from 15 individual donors, 5 of whom were given a 400-µg folic acid supplement 1 h prior to blood draw to increase serum levels of 5mTHF and folic acid for the high-level material. To stabilize the folates, 0.5% (mass concentration) ascorbic acid was added as soon as possible after preparation of serum. These pilot sera were screened for five folates plus the pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyltetrahydrofolate (MeFox) at the US Centers for Disease Control and Prevention (CDC) by isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC–MS/MS). Based on these results, a blending protocol was specified to obtain the three desired folate concentrations for SRM 3949. ID-LC–MS/MS analysis at the CDC and NIST was utilized to assign values for folic acid and 5mTHF, as well as several minor folates.
Graphical Abstract
β-Amyloid protein (Aβ) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aβ, it is known that Aβ ...oligomers (AβOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AβOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AβOs attach.
An unbiased approach using far western ligand blots has identified three synaptic proteins to which AβOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AβOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AβOs was developed and used to block the toxicity of AβOs. The data were analyzed with one-way analysis of variance.
AβOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aβ inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aβ. α3-Na/K-ATPase protein and synaptic β-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aβ oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3.
We identified three AβO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aβ oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.
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