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Preclinical evidence indicates that the endocannabinoid system is involved in neural responses to reward. This study aimed to investigate associations between basal serum concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) with brain functional reward processing. Additionally, a personality measure of reward dependence was obtained. Brain functional data were obtained of 30 right-handed adults by conducting fMRI at 3 Tesla using a reward paradigm. Reward dependence was obtained using the subscale reward dependence of the Tridimensional Personality Questionnaire (TPQ). Basal concentrations of AEA and 2-AG were determined in serum. Analyzing the fMRI data, for AEA and 2-AG ANCOVAs were calculated using a full factorial model, with condition (reward > control, loss > control) and concentrations for AEA and 2-AG as factors. Regression analyses were conducted for AEA and 2-AG on TPQ-RD scores. A whole-brain analysis showed a significant interaction effect of AEA concentration by condition (positive vs. negative) within the putamen (x = 26, y = 16, z = −8, F13.51, TFCE(1, 54) = 771.68, k = 70, PFWE = 0.044) resulting from a positive association of basal AEA concentrations and putamen activity to rewarding stimuli, while this association was absent in the loss condition. AEA concentrations were significantly negatively correlated with TPQ reward dependence scores (rspearman = −0.56, P = 0.001). These results show that circulating AEA may modulate brain activation during reward feedback and that the personality measure reward dependence is correlated with AEA concentrations in healthy human volunteers. Future research is needed to further characterize the nature of the lipids’ influence on reward processing, the impact on reward anticipation and outcome, and on vulnerability for psychiatric disorders.

This multiplex PCR enrichment protocol enables sequencing of Zika and other viral genomes of low abundance from clinical samples using the Illumina platform, or the portable MinION sequencer, facilitating direct application in field situations. Genome sequencing has become a powerful tool for studying emerging infectious diseases; however, genome sequencing directly from clinical samples (i.e., without isolation and culture) remains challenging for viruses such as Zika, for which metagenomic sequencing methods may generate insufficient numbers of viral reads. Here we present a protocol for generating coding-sequence-complete genomes, comprising an online primer design tool, a novel multiplex PCR enrichment protocol, optimized library preparation methods for the portable MinION sequencer (Oxford Nanopore Technologies) and the Illumina range of instruments, and a bioinformatics pipeline for generating consensus sequences. The MinION protocol does not require an Internet connection for analysis, making it suitable for field applications with limited connectivity. Our method relies on multiplex PCR for targeted enrichment of viral genomes from samples containing as few as 50 genome copies per reaction. Viral consensus sequences can be achieved in 1–2 d by starting with clinical samples and following a simple laboratory workflow. This method has been successfully used by several groups studying Zika virus evolution and is facilitating an understanding of the spread of the virus in the Americas. The protocol can be used to sequence other viral genomes using the online Primal Scheme primer designer software. It is suitable for sequencing either RNA or DNA viruses in the field during outbreaks or as an inexpensive, convenient method for use in the lab.

Background Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. Results We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis -acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. Conclusions We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.

Abstract Rationale Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear. Objectives To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults. Methods This two-center, double-blind, placebo-controlled trial randomized 100 delirium-free critically ill adults receiving sedatives to receive nocturnal (9:30 p.m. to 6:15 a.m.) intravenous dexmedetomidine (0.2 μg/kg/h, titrated by 0.1 μg /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of −1 or maximum rate of 0.7 μg/kg/h was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire. Measurements and Main Results Nocturnal dexmedetomidine (vs. placebo) was associated with a greater proportion of patients who remained delirium-free during the ICU stay (dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients]; relative risk, 0.44; 95% confidence interval, 0.23–0.82; P = 0.006). The average Leeds Sleep Evaluation Questionnaire score was similar (mean difference, 0.02; 95% confidence interval, 0.42–1.92) between the 34 dexmedetomidine (average seven assessments per patient) and 30 placebo (six per patient) group patients able to provide one or more assessments. Incidence of hypotension, bradycardia, or both did not differ significantly between groups. Conclusions Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient-reported sleep quality appears unchanged. Clinical trial registered with www.clinicaltrials.gov (NCT01791296).

Abstract Rationale Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them. Objectives Elucidate the pharmacological limitations of NAC and test a novel mucin-reducing agent, P3001, in preclinical settings. Methods The study used biochemical (e.g., Western blotting, mass spectrometry) and biophysical assays (e.g., microrheology/macrorheology, spinnability, mucus velocity measurements) to test compound efficacy and toxicity in in vitro and in vivo models and patient sputa. Measurements and Main Results Dithiothreitol and P3001 were directly compared with NAC in vitro and both exhibited superior reducing activities. In vivo, P3001 significantly decreased lung mucus burden in βENaC-overexpressing mice, whereas NAC did not (n = 6–24 mice per group). In NAC-treated CF subjects (n = 5), aerosolized NAC was rapidly cleared from the lungs and did not alter sputum biophysical properties. In contrast, P3001 acted faster and at lower concentrations than did NAC, and it was more effective than DNase in CF sputum ex vivo. Conclusions These results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P3001 class mucolytic agents.

Antibiotic treatment failure in Pseudomonas aeruginosa chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors in vitro , is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant in vitro condition that recapitulates antibiotic tolerance observed in ex vivo treated sputum. Ultimately, this study revealed a dominant effect of in vivo evolved bacterial populations in defining inter-subject ex vivo antibiotic tolerance and establishes a robust and translatable in vitro model for therapeutic development.

ObjectiveThis study has two objectives: first, to explore the diagnostic experiences of black/African American (BAA) patients with lung cancer to pinpoint pitfalls, suboptimal experiences and instances of discrimination leading to disparities in outcomes compared with patients of other ethnic backgrounds, especially white patients. The second objective is to identify the underlying causes contributing to health disparities in the diagnosis of lung cancer among BAA patients.MethodsWe employed a phenomenological research approach, guiding in-depth interviews with patients self-identifying as BAA diagnosed with lung cancer, as well as caregivers, healthcare professionals and community advocates knowledgeable about BAA experiences with lung cancer. We performed thematic analysis to identify experiences at patient, primary care and specialist levels. Contributing factors were identified using the National Institute of Minority Health and Health Disparities (NIMHD) health disparity model.ResultsFrom March to November 2021, we conducted individual interviews with 19 participants, including 9 patients/caregivers and 10 providers/advocates. Participants reported recurring and increased pain before seeking treatment, treatment for non-cancer illnesses, delays in diagnostic tests and referrals, poor communication and bias when dealing with specialists and primary care providers. Factors contributing to suboptimal experiences included reluctance by insurers to cover costs, provider unwillingness to conduct comprehensive testing, provider bias in recommending treatment, high healthcare costs, and lack of healthcare facilities and qualified staff to provide necessary support. However, some participants reported positive experiences due to their insurance, availability of services and having an empowered support structure.ConclusionsBAA patients and caregivers encountered suboptimal experiences during their care. The NIMHD model is a useful framework to organise factors contributing to these experiences that may be leading to health disparities. Additional research is needed to fully capture the extent of these experiences and identify ways to improve BAA patient experiences in the lung cancer diagnosis pathway.

Virtual reality (VR) provides an immersive environment in which a participant can experience a feeling of presence in a virtual world. Such environments generate strong emotional and physical responses and have been used for wide-ranging applications. The ability to collect functional neuroimaging data whilst a participant is immersed in VR would represent a step change for experimental paradigms; unfortunately, traditional brain imaging requires participants to remain still, limiting the scope of naturalistic interaction within VR. Recently however, a new type of magnetoencephalography (MEG) device has been developed, that employs scalp-mounted optically-pumped magnetometers (OPMs) to measure brain electrophysiology. Lightweight OPMs, coupled with precise control of the background magnetic field, enables participant movement during data acquisition. Here, we exploit this technology to acquire MEG data whilst a participant uses a virtual reality head-mounted display (VRHMD). We show that, despite increased magnetic interference from the VRHMD, we were able to measure modulation of alpha-band oscillations, and the visual evoked field. Moreover, in a VR experiment in which a participant had to move their head to look around a virtual wall and view a visual stimulus, we showed that the measured MEG signals map spatially in accordance with the known organisation of primary visual cortex. This technique could transform the type of neuroscientific experiment that can be undertaken using functional neuroimaging. •Virtual reality (VR) offers an immersive environment in which to evoke brain activity.•For the first time, we combine VR with a newly developed OPM-MEG system.•Despite increased interference from the VR headset, usable OPM-MEG data were measured.•Alpha oscillations and visual evoked fields were detected in the presence of VR.•OPM-MEG signals, evoked by VR stimulation, map topologically to primary visual cortex.

Cover crops can improve soil health by increasing soil organic matter, soil porosity, permeability, and crop yield. Yet, land planted to cover crops are often limited by economic constraints. Perennial living mulch (LM) cover crops may provide better benefits to soil health because they are actively growing throughout the year and self‐regenerate without reseeding. The objective of this study was to compare the impact of a white clover (Trifolium repens L.) LM vs. annual cover crops on soil health traits. Treatments were established on a Cecil sandy loam soil in the fall of 2014 and annual cover crop treatments re‐established each fall of the following 3 yr. White clover re‐established in the LM without reseeding. Corn (Zea mays L.) was planted into the treatments in the spring of each year. Soils were sampled at the V4/V5, V12, and R5 stages of corn development and analyzed for chemical traits. Surface soil characteristics were measured after corn harvest in 2018. Soils in the LM system had lower lime buffering capacity and greater pH, base saturation, cation exchange capacity (CEC), Ca, K2O, Mg, P2O5, and total organic C concentrations than other treatments. Soil NH3 and NO3 had seasonal fluctuations associated with mineral N fertilizer and were lower in the LM treatment. After 3 yr, the soil bulk density was lower and porosity, water infiltration, and labile C were greater in surface soils from the LM treatment than in the surface soils of the other treatments. Use of a perennial LM cover crops expedited soil health regeneration compared to other treatments. Core Ideas Cover crops improve soil quality. Living mulch cover crops are perennial and do not require annual re‐seeding. Soil physical characteristics improve faster in living mulch than annual cover crop systems. Mineral nutrients are retained in living mulch soils compared to annual cover crops. The living mulch system reduced yield.

In response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network.