Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.

PURPOSE: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. PATIENTS AND METHODS: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). RESULTS: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. CONCLUSION: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

PET/CT targeted tissue sampling reveals intravenously administered HGN194 IgG1 affects HIV distribution after rectal exposure.

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue two hours after rectal viral challenge. Our results show that IgG1 did not alter the number of virions found throughout the colon or viral penetration into the epithelium of the rectum or descending colon. A minor increase in virions was observed in the transverse colon of IgG1 treated animals. Overall, the number of viral particles found in the mesenteric lymph nodes was low. However, IgG1 administration resulted in a significant reduction of virions found in mesenteric lymph nodes. Taken together, our results show that HGN194 IgG1 does not prevent virions from penetrating into the colorectal mucosa but may perturb HIV virion access to the lymphatic system.

Activation Likelihood Estimation Neuroimaging Meta-Analysis: a Powerful Tool for Emotion Research.

Over the past two decades, functional magnetic resonance imaging (fMRI) has become the primary tool for exploring neural correlates of emotion. To enhance the reliability of results in understanding the complex nature of emotional experiences, researchers combine findings from multiple fMRI studies using coordinate-based meta-analysis (CBMA). As one of the most widely employed CBMA methods worldwide, activation likelihood estimation (ALE) is of great importance in affective neuroscience and neuropsychology. This comprehensive review provides an introductory guide for implementing the ALE method in emotion research, outlining the experimental steps involved. By presenting a case study about the emotion of disgust, with regard to both its core and social processing, we offer insightful commentary as to how ALE can enable researchers to produce consistent results and, consequently, fruitfully investigate the neural mechanisms underpinning emotions, facilitating further progress in this field.

Metabolic Diaschisis in Mild Traumatic Brain Injury.

Neurophysiological diaschisis presents in traumatic brain injury (TBI) as functional impairment distant to the lesion site caused by axonal neuroexcitation and deafferentation. Diaschisis studies in TBI models have evaluated acute phase functional and microstructural changes. Here, in vivo biochemical changes and cerebral blood flow (CBF) dynamics following TBI are studied with magnetic resonance. Behavioral assessments, magnetic resonance spectroscopy (MRS), and CBF measurements on rats followed cortical impact TBI. Data were acquired pre-TBI and 1-3 h, 2-days, 7-days, and 14-days post-TBI. MRS was performed on the ipsilateral and contralateral sides in the cortex, striatum, and thalamus. Metabolites measured by MRS included N-acetyl aspartate (NAA), aspartate (Asp), lactate (Lac), glutathione (GSH), and glutamate (Glu). Lesion volume expanded for 2 days post-TBI and then decreased. Ipsilateral CBF dropped acutely versus baseline on both sides (-62% ipsilateral, -48% contralateral, p < 0.05) but then recovered in cortex, with similar changes in ipsilateral striatum. Metabolic changes versus baseline included increased Asp (+640% by Day 7 post-TBI, p < 0.05) and Lac (+140% on Day 2 post-TBI, p < 0.05) in ipsilateral cortex, while GSH (-67% acutely, p < 0.05) and NAA decreased (-50% on Day 2, p < 0.05). In contralateral cortex Lac decreased (-73% acutely, p < 0.05). Analysis of variance showed significance for Side (p < 0.05), Time after TBI (p < 0.05), and interactions (p < 0.005) for Asp, GSH, Lac, and NAA. Transient decreases of GSH (-30%, p < 0.05, acutely) and NAA (-23% on Day 2, p < 0.05) occurred in ipsilateral striatum with reduced GSH (-42%, p < 0.005, acutely) in the contralateral striatum. GSH was decreased in ipsilateral thalamus (-59% ipsilateral on Day 2, p < 0.05). Delayed increases of total choline were seen in the contralateral thalamus were noted as well (+21% on Day 7 post-TBI, p < 0.05). Both CBF and neurometabolite concentration changes occurred remotely from the TBI site, both ipsilaterally and contralaterally. Decreased Lac levels on the contralateral cortex following TBI may be indicative of reduced anaerobic metabolism during the acute phase. The timing and locations of the changes suggest excitatory and inhibitory signaling processes are affecting post-TBI metabolic fluctuations.

Thermal Nickel-Catalyzed N-Arylation of NH-Sulfoximines with (Hetero)aryl Chlorides Enabled by PhPAd-DalPhos Ligation.

We report a versatile method for cross-coupling of NH-sulfoximines with (hetero)aryl chlorides, as well as bromide and sulfonate electrophiles, that makes use of the air-stable, commercial precatalyst (PhPAd-DalPhos)Ni(o-tol)Cl. Under optimized conditions a diverse electrophile scope is established, including the N-arylation of the pharmaceutical Clozapine. While 5 mol % Ni and 80 °C are commonly employed in this chemistry, successful examples utilizing 1 mol % Ni and/or 25 °C are presented. Competition experiments establish the superiority of NH-sulfoximine over primary sulfonamide as nucleophiles under these conditions.

Riemannian frameworks for the harmonization of resting-state functional MRI scans.

Magnetic Resonance Imaging provides unprecedented images of the brain. Unfortunately, scanners and acquisition protocols can significantly impact MRI scans. The development of statistical methods able to reduce this variability without altering the relevant information in the scans, often coined harmonization methods, has been the topic of an increasing research effort supported by the recent growth of publicly available neuroimaging data sets and new possibilities for combining them to achieve greater statistical power. In this work, we focus on the challenges specifically raised by the harmonization of resting-state functional MRI scans. We propose to harmonize resting-state fMRI scans by reducing the impact of covariates such as scanner differences and scanning protocols on their associated functional connectomes and then propagating the changes back to the rs-fMRI time series. We use Riemannian geometric frameworks to preserve the mathematical properties of functional connectomes during their harmonization, and we demonstrate how state-of-the-art harmonization methods can be embedded within these frameworks to reduce covariates effects while preserving the relevant clinical information associated with aging or brain disorders. During our experiments, a large set of synthetic data was generated and processed to compare eighty variants of the proposed approach. The framework achieving the best harmonization was then applied to three low-dimensional data sets made of 712 sets of fMRI time series provided by the ABIDE consortium and two high-dimensional data sets obtained by processing 1527 rs-fMRI scans provided by the Human Connectome Project, the Framingham Heart Study and the Genetics of Brain Structure and Function study. These experiments established that our new framework could successfully harmonize low-dimensional connectomes and voxelwise functional time series and confirmed the need for preserving connectomes properties during their harmonization.