Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with Stimulated Raman Scattering Microscopy.

This study reports the application of stimulated Raman scattering (SRS) microscopy for real-time chemically specific imaging of dynamic phase phenomena in amorphous solid dispersions (ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate) films with different drug loadings (0-100% w/w) as model systems, we employed SRS microscopy with fast spectral focusing to analyze ASD behavior upon contact with a dissolution medium. Multivariate unmixing of the SRS spectra allowed changes in the distributions of the drug, polymer, and water to be (semi)quantitatively imaged in real time, both in the film and the adjacent dissolution medium.

Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion.

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization.

Intramolecular Nucleophilic Vinylic Substitution (SV) by Carbon Nucleophiles: Conformationally Directed Formation of Dienes from N,N'-Diallyl Ureas.

Nucleophilic vinylic substitution (SV) by carbon nucleophiles allows the formation of vinylic C-C bonds without transition metal catalysts. In this paper, we show that tethering two alkenes together through a urea linkage can lead to the formation of a diene by an intramolecular SV reaction. The starting materials are fully substituted N,N'-diallyl ureas; the reaction proceeds in the presence of base, and entails a cascade of deprotonations, reprotonations, and an SV reaction of an allylic carbanion on a rare electrophile: a vinylic urea.

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition.

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity.

Control of sustained attention and impulsivity by G-protein signalling in parvalbumin interneurons of the anterior cingulate cortex.

The anterior cingulate cortex (ACC) has been implicated in attention deficit hyperactivity disorder (ADHD). More specifically, an appropriate balance of excitatory and inhibitory activity in the ACC may be critical for the control of impulsivity, hyperactivity, and sustained attention which are centrally affected in ADHD. Hence, pharmacological augmentation of parvalbumin- (PV) or somatostatin-positive (Sst) inhibitory ACC interneurons could be a potential treatment strategy.

High-dimensional multivariate autoregressive model estimation of human electrophysiological data using fMRI priors.

Multivariate autoregressive (MVAR) model estimation enables assessment of causal interactions in brain networks. However, accurately estimating MVAR models for high-dimensional electrophysiological recordings is challenging due to the extensive data requirements. Hence, the applicability of MVAR models for study of brain behavior over hundreds of recording sites has been very limited.

Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial.

Background: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).

Methods: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands.

Tolerability of concurrent external beam radiotherapy and [Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

Background: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer.

MatchMiner: an open-source platform for cancer precision medicine.

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials.

Nanoparticle-based oral formulation can surprise you with inferior in vivo absorption in humans.

Particle size reduction leads to an increase in the drug dissolution rate, which in turn can lead to a substantial increase in the bioavailability of a poorly soluble compound. To improve bioavailability, a practically insoluble investigational drug, ODM-106, was nanomilled and capsule formulations with three different drug amounts were prepared for the first-in-man study. Fast in vitro dissolution was achieved from all the capsules containing different amounts of drug nanoparticles but in the clinical study, surprisingly, low bioavailability was observed from the highest capsule strength (100 mg) in comparison to a lower strength (10 mg).

Analyzing dynamic species abundance distributions using generalized linear mixed models.

Understanding the mechanisms of ecological community dynamics and how they could be affected by environmental changes is important. Population dynamic models have well known ecological parameters that describe key characteristics of species such as the effect of environmental noise and demographic variance on the dynamics, the long-term growth rate, and strength of density regulation. These parameters are also central for detecting and understanding changes in communities of species; however, incorporating such vital parameters into models of community dynamics is challenging.

A re-analysis of NH sorption on biochar: Have expectations been too high?

Sorption of nutrients such as NH is often quoted as a critical property of biochar, explaining its value as a soil amendment and a filter material. However, published values for NH sorption to biochar vary by more than 3 orders of magnitude, without consensus as to the source of this variability. This lack of understanding greatly limits our ability to use quantitative sorption measurements towards product design.

Multivariate autoregressive model estimation for high-dimensional intracranial electrophysiological data.

Fundamental to elucidating the functional organization of the brain is the assessment of causal interactions between different brain regions. Multivariate autoregressive (MVAR) modeling techniques applied to multisite electrophysiological recordings are a promising avenue for identifying such causal links. They estimate the degree to which past activity in one or more brain regions is predictive of another region's present activity, while simultaneously accounting for the mediating effects of other regions.

Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control.

Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1, might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1-knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice.

A low-cost open-source 5-choice operant box system optimized for electrophysiology and optophysiology in mice.

Operant boxes enable the application of complex behavioural paradigms to support circuit neuroscience and drug discovery research. However, commercial operant box systems are expensive and often not optimised for combining behaviour with neurophysiology. Here we introduce a fully open-source Python-based operant-box system in a 5-choice design (pyOS-5) that enables assessment of multiple cognitive and affective functions.

Modelling temperature-driven changes in species associations across freshwater communities.

Due to global climate change-induced shifts in species distributions, estimating changes in community composition through the use of Species Distribution Models has become a key management tool. Being able to determine how species associations change along environmental gradients is likely to be pivotal in exploring the magnitude of future changes in species' distributions. This is particularly important in connectivity-limited ecosystems, such as freshwater ecosystems, where increased human translocation is creating species associations over previously unseen environmental gradients.

Pre- and Interhospital Workflow Times for Patients With Large Vessel Occlusion Stroke Transferred for Endovasvular Thrombectomy.

Patients with large vessel occlusion (LVO) stroke are often initially admitted to a primary stroke center (PSC) and subsequently transferred to a comprehensive stroke center (CSC) for endovascular thrombectomy (EVT). This interhospital transfer delays initiation of EVT. To identify potential workflow improvements, we analyzed pre- and interhospital time metrics for patients with LVO stroke who were transferred from a PSC for EVT.

How to stop disproportionation of a hydrochloride salt of a very weakly basic compound in a non-clinical suspension formulation.

Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature.

-Methyl Allylic Amines from Allylic Alcohols by Mitsunobu Substitution Using -Boc Ethyl Oxamate.

We report the practical, scalable synthesis of a range of -methyl allylic amines. Primary and secondary allylic alcohols underwent a regioselective Mitsunobu reaction with readily accessible -Boc ethyl oxamate to deliver the corresponding -Boc allylic amines, including in enantiopure form via stereospecific substitution. Subsequent -methylation and Boc deprotection without chromatography yielded the amine products as hydrochloride salts.

Control of impulsivity by G-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity.

Delayed-matching-to-position working memory in mice relies on NMDA-receptors in prefrontal pyramidal cells.

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM).

Synthetic (,-Dimethyl)doxorubicin Glycosyl Diastereomers to Dissect Modes of Action of Anthracycline Anticancer Drugs.

Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase IIα poisoning) and chromatin damage (via eviction of histones). These biological activities can be modulated and toxic side effects can be reduced by separating these two modes of action through alteration of the aminoglycoside moiety of doxorubicin.

Femoral neck strain prediction during level walking using a combined musculoskeletal and finite element model approach.

Recently, coupled musculoskeletal-finite element modelling approaches have emerged as a way to investigate femoral neck loading during various daily activities. Combining personalised gait data with finite element models will not only allow us to study changes in motion/movement, but also their effects on critical internal structures, such as the femur. However, previous studies have been hampered by the small sample size and the lack of fully personalised data in order to construct the coupled model.

A Pilot Study of the Impact of Microwave Ablation on the Dielectric Properties of Breast Tissue.

Percutaneous microwave ablation (MWA) is a promising technology for patients with breast cancer, as it may help treat individuals who have less aggressive cancers or do not respond to targeted therapies in the neoadjuvant or pre-surgical setting. In this study, we investigate changes to the microwave dielectric properties of breast tissue that are induced by MWA. While similar changes have been characterized for relatively homogeneous tissues, such as liver, those prior results are not directly translatable to breast tissue because of the extreme tissue heterogeneity present in the breast.

The association between computed tomography angiography timing and workflow times in patients with acute ischemic stroke.

Background: In most hospitals, computed tomography angiography (CTA) is nowadays routinely performed in patients with acute ischemic stroke. However, it is unclear whether CTA is best performed before or after start of intravenous thrombolysis (IVT), since acquisition of CTA before IVT may prolong door-to-needle times, while acquisition after IVT may prolong door-to-groin times in patients undergoing endovascular treatment.

Methods: We performed a before-versus-after study (CTA following IVT, period I and CTA prior to IVT, period II), consisting of two periods of one year each.