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Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK.
BACKGROUND: Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months. METHODS: We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615. FINDINGS: Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events). INTERPRETATION: Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium. FUNDING: National Institute for Health and Care Research Health Technology Assessment programme.
CRISPR targeting of SNPs associated with age-related macular degeneration in ARPE-19 cells: a potential model for manipulating the complement system.
Age-related Macular degeneration (AMD) is a major cause of vision loss and is linked to several predisposing single nucleotide polymorphisms (SNPs). CRISPR-mediated genome editing offers the potential to target negatively associated SNPs in an allele-specific manner, necessitating the need for a relevant cell model. The ARPE-19 cell line, with its stable monolayer growth and retinal pigment epithelium (RPE) characteristics, serves as an ideal model for AMD studies. Chronic inflammation and complement system dysregulation are implicated in AMD pathogenesis. Most genetic variations associated with AMD are in complement genes, suggesting their regulatory role. In this study, we conducted targeted PCRs to identify AMD-related SNPs in ARPE-19 cells and used CRISPR constructs to assess allele-specific activity. Guide RNA sequences were cloned into an EF-1-driven SpCas9 vector and packaged into lentivirus. Targeting efficiencies were evaluated with TIDE analysis, and allele-specificity was measured with NGS analysis 30 days post-transduction. Our results showed varying targeting efficiencies depending on guide RNA efficacy. For example, TIDE analysis of CFH SNPs rs1061170 and rs1410996 revealed efficiencies of 35.5% and 33.8%, respectively. CFB SNP rs4541862 showed efficiencies from 3% to 36.7%, and rs641153 ranged from 3.4% to 23.8%. Additionally, allele-specific targeting of AMD-related SNPs rs1061170, rs1410996, rs4541862, and rs641153 ranged from 48% to 52% in heterozygous differentiated ARPE-19 cells. These findings demonstrate the potential to manipulate the complement system in an AMD model by targeting disease-associated SNPs in an allele-specific manner, offering a promising therapeutic approach.
Smoking status and vascular risk factors as predictors of disability in AQP4-NMOSD and MOGAD.
BACKGROUND: Smoking and vascular risk factors (VRFs) are reported to have adverse effects in multiple sclerosis but data are limited in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This study aimed to measure their impact on disability. METHODS: Smoking status was defined as never, past or current smokers and VRF comprised of ⩾1: hypertension, dyslipidemia, high body mass index or diabetes. Logistic regression models were fitted to predict their influence on recovery from onset attack and first optic neuritis (ON) attack. RESULTS: A total of 442 patients were included. Current MOGAD smokers had a higher risk of disability from onset attack and first ON attack than never smokers (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.3-6.9; OR 3.3, 95% CI 1.4-7.8). VRF in MOGAD was not predictive of disability. Current AQP4-NMOSD smokers and VRFs had a higher risk of residual disability from onset attacks (OR 7.5, 95% CI 2.1-27.7; OR 1.9, 95% CI 1.0-3.4). VRF was associated with higher risk of visual disability (OR 2.6, 95% CI 1.08-6.46) while smoking status was not. CONCLUSIONS: Current smoking status detrimentally influenced onset attack recovery in AQP4-NMOSD and MOGAD patients, including visual recovery in MOGAD. Non-smoking VRFs influenced clinical and visual outcomes in AQP4-NMOSD.
Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy.
Retinal gene therapy using adeno-associated viral (AAV) vectors has been a groundbreaking step-change in the treatment of inherited retinal diseases (IRDs) and could also be used to treat more common retinal diseases such as age-related macular degeneration and diabetic retinopathy. The delivery and expression of therapeutic transgenes in the eye is limited by innate and adaptive immune responses against components of the vector product, which has been termed gene therapy-associated uveitis (GTAU). This is clinically important as intraocular inflammation could lead to irreversible loss of retinal cells, deterioration of visual function and reduced durability of treatment effect associated with a costly one-off treatment. For retinal gene therapy to achieve an improved efficacy and safety profile for treating additional IRDs and more common diseases, the risk of GTAU must be minimised. We have collated insights from pre-clinical research, clinical trials, and the real-world implementation of AAV-mediated retinal gene therapy to help understand the risk factors for GTAU. We draw attention to an emerging framework, which includes patient demographics, vector construct, vector dose, route of administration, and choice of immunosuppression regime. Importantly, we consider efforts to date and potential future strategies to mitigate the adverse immune response across each of these domains. We advocate for more targeted immunomodulatory approaches to the prevention and treatment of GTAU based on better understanding of the underlying immune response.
CTPS cytoophidia in Drosophila: distribution, regulation, and physiological roles
Intracellular compartmentalization plays a critical role in maintaining cellular homeostasis and regulating metabolic processes. A growing body of evidence suggests that various metabolic enzymes, including CTP synthase (CTPS), can dynamically assemble into membraneless filamentous structures. The formation of these membraneless organelles is precisely regulated by the cellular metabolic state. CTPS, a rate-limiting enzyme in the de novo biosynthesis of CTP, has been shown to assemble into filamentous structures known as cytoophidium. First identified in 2010 by three independent research groups, cytoophidia are evolutionarily conserved across diverse organisms, including bacteria, archaea, yeast, mammals, and plants, suggesting a fundamental biological function. Given the well-established advantages of Drosophila melanogaster as a genetic model, this organism provides a powerful system for investigating the physiological roles of cytoophidia. This review synthesizes current findings on CTPS cytoophidia in Drosophila, with a particular focus on their spatiotemporal distribution in tissues and their regulatory roles in three key biological processes: intestinal homeostasis, lipid metabolism, and reproductive physiology. Furthermore, we discuss the challenges and future directions in cytoophidia research, offering insights into their broader implications in cellular metabolism and physiology.
Clinical neurocardiology: defining the value of neuroscience-based cardiovascular therapeutics - 2024 update.
The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience-based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
The genome sequence of the poplar hawk-moth, Laothoe populi (Linnaeus, 1758).
We present a genome assembly from an individual female Laothoe populi (the poplar hawk-moth; Arthropoda; Insecta; Lepidoptera; Sphingidae). The genome sequence is 576 megabases in span. Most of the assembly is scaffolded into 29 chromosomal pseudomolecules, with the W and Z sex chromosome assembled.
Increased chloroplast area in the rice bundle sheath through cell-specific perturbation of brassinosteroid signalling.
In the leaves of C3 species such as rice (Oryza sativa), mesophyll cells contain the largest compartment of photosynthetically active chloroplasts. In contrast, plants that use the derived and more efficient C4 photosynthetic pathway have a considerable chloroplast compartment in both bundle sheath and mesophyll cells. Accordingly, the evolution of C4 photosynthesis from the ancestral C3 state required an increased chloroplast compartment in the bundle sheath. Here, we investigated the potential to increase chloroplast compartment size in rice bundle sheath cells by manipulating brassinosteroid signalling. Treatment with brassinazole, a brassinosteroid biosynthesis inhibitor, raised leaf chlorophyll content and increased the number but decreased the area of chloroplasts in bundle sheath cells. Ubiquitous overexpression of the transcription factor-encoding BRASSINAZOLE RESISTANT 1 (OsBZR1) increased bundle sheath chloroplast area by up to 45%, but these plants became chlorotic. However, when OsBZR1 expression was driven by a bundle sheath-specific promoter, the negative effects on growth and viability were alleviated whilst chloroplast area still increased. In summary, we report a role for brassinosteroids in controlling chloroplast area and number in rice and conclude that cell-specific manipulation of brassinosteroid signalling can be used to manipulate the chloroplast compartment in rice bundle sheath cells.
Imaging the structural connectome with hybrid MRI-microscopy tractography.
Mapping how neurons are structurally wired into whole-brain networks can be challenging, particularly in larger brains where 3D microscopy is not available. Multi-modal datasets combining MRI and microscopy provide a solution, where high resolution but 2D microscopy can be complemented by whole-brain but lowresolution MRI. However, there lacks unified approaches to integrate and jointly analyse these multi-modal data in an insightful way. To address this gap, we introduce a data-fusion method for hybrid MRI-microscopy fibre orientation and connectome reconstruction. Specifically, we complement precise "in-plane" orientations from microscopy with "through-plane" information from MRI to construct 3D hybrid fibre orientations at resolutions far exceeding that of MRI whilst preserving microscopy's myelin specificity, resulting in superior fibre tracking. Our method is openly available, can be deployed on standard 2D microscopy, including different microscopy contrasts, and is species agnostic, facilitating neuroanatomical investigation in both animal models and human brains.
Deficient synaptic neurotransmission results in a persistent sleep-like cortical activity across vigilance states in mice.
Growing evidence suggests that brain activity during sleep, as well as sleep regulation, are tightly linked with synaptic function and network excitability at the local and global levels. We previously reported that a mutation in synaptobrevin 2 (Vamp2) in restless (rlss) mice results in a marked increase of wakefulness and suppression of sleep, in particular REM sleep (REMS), as well as increased consolidation of sleep and wakefulness. In this study, using finer-scale in vivo electrophysiology recordings, we report that spontaneous cortical activity in rlss mice during NREM sleep (NREMS) is characterized by an occurrence of abnormally prolonged periods of complete neuronal silence (OFF-periods), often lasting several seconds, similar to the burst suppression pattern typically seen under deep anesthesia. Increased incidence of prolonged network OFF-periods was not specific to NREMS but also present in REMS and wake in rlss mice. Slow-wave activity (SWA) was generally increased in rlss mice relative to controls, while higher frequencies, including theta-frequency activity, were decreased, further resulting in diminished differences between vigilance states. The relative increase in SWA after sleep deprivation was attenuated in rlss mice, suggesting either that rlss mice experience persistently elevated sleep pressure or, alternatively, that the intrusion of sleep-like patterns of activity into the wake state attenuates the accumulation of sleep drive. We propose that a deficit in global synaptic neurotransmitter release leads to "state inertia," reflected in an abnormal propensity of brain networks to enter and remain in a persistent "default state" resembling coma or deep anesthesia.
Hypotheses in light detection by vertebrate ancient opsin in the bird brain.
Extra-retinal photoreception is common across fish and avian species. In birds, the hypothalamus contains non-visual photoreceptors that detect light and regulate multiple endocrine systems. To date, light-dependent control of seasonal reproduction is one of the most well-studied systems that require deep brain photoreception. However, the precise photoreceptor(s) that detect light and the neuroendocrine connection between opsin-expressing cells and the gonadotropin-releasing hormone-1 (GnRH1) system remain poorly defined. In the past couple of decades, two opsin molecules have been proposed to link light detection with seasonal reproduction in birds: neuropsin (Opn5) and vertebrate ancient opsin (VA opsin). Only VA opsin is expressed in GnRH1 cells and has an absorption spectrum that matches the action spectrum of the avian photoperiodic reproductive response. This perspective describes how the annual change in daylength, referred to as photoperiod, regulates the neuroendocrine control of seasonal reproduction. The opsin genes are then outlined, and the cellular phototransduction cascade is described, highlighting the common feature of hyperpolarization in response to light stimulation. We then discuss the latest evidence using short-hairpin RNA to temporarily knock down VA opsin and Opn5 on transcripts involved in the neuroendocrine regulation of reproduction. Based on emerging data, we outline three theoretical scenarios in which VA opsin might regulate GnRH1 synthesis and release in birds. The models proposed provide a series of testable hypotheses that can be used to improve our understanding of avian light detection by VA opsin or other opsin-expressing cells in the brain.
Photoreceptors and Circadian Clocks
The possession of a circadian timing system allows an organism to anticipate rhythmic phenomena. Rather than passively responding to 24h changes in the environment, an internal clock allows an organism to anticipate these changes. Thus physiology and behavior can be fine-tuned in advance of the altered conditions and no time will be lost in the adjustment process. In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus are the site of a master circadian pacemaker, coordinating rhythms throughout the body, including sleep–wake cycles. The primary input into the SCN is light, and the light–dark cycle produced by the rotation of the Earth provides a robust signal enabling internal and external cycles to be synchronized (entrained). The influence of light upon this central clock is mediated by photoreceptors within the eye, but until recently it remained unclear which ocular cells provided dawn/dusk information for photoentrainment. Research into the mechanisms of mammalian photoentrainment resulted in the identification of a third class of ocular photoreceptor, quite different from the rods and cones. This system is composed of a subset of ‘blue-light’-photosensitive retinal ganglion cells expressing the photopigment melanopsin. Subsequent studies have shown that these cells not only regulate the circadian system but also mediate a broad range of other irradiance-detection tasks, including pineal melatonin suppression and pupil constriction.
Enabling SENSE accelerated 2D CSI for hyperpolarized carbon-13 imaging.
As hyperpolarized (HP) carbon-13 (13C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium (23Na) sensitivity maps for SENSE reconstructed 13C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique's ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data.
The Nuffield Early Language Intervention (NELI) programme is associated with lasting improvements in children's language and reading skills.
BACKGROUND: Oral language skills are a critical foundation for education and psychosocial development. Learning to read, in particular, depends heavily on oral language skills. The Nuffield Early Language Intervention (NELI) has been shown to improve the language of 4-5-year-old children entering school with language weaknesses in four robust trials. To date, however, there is limited evidence on the durability of the gains produced by the intervention, and some have argued that the effects of such educational interventions typically fade-out quite rapidly. METHODS: A large-scale effectiveness trial of the NELI intervention implemented under real-world conditions produced educationally meaningful improvements in children's language and reading abilities. Here, we report follow-up testing of children from this study conducted approximately 2 years after the completion of the intervention. RESULTS: At 2-year follow-up, children who had received NELI had better oral language (d = 0.22 or d = 0.33 for children with lower language ability), reading comprehension (d = 0.16 or d = 0.24 for children with lower language ability) and single-word reading skills (d = 0.16 or d = 0.22 for children with lower language ability) than the control group. CONCLUSIONS: Our data show that, although fade-out effects are common in educational research, a widely used language intervention produces durable improvements in language and reading skills, with educationally important effect sizes. These findings have important theoretical and practical implications.
Adopting Quality for School Readiness (AQSR): A Heuristic Framework using Recommended Practice and Professional Knowledge to Support Oral Language in Multilingual Classrooms
Quality oral language interventions support children’s readiness for formal literacy instruction and yet a framework for multilingual classrooms is not available. To address this gap, we drew on the empirical literature on linguistically diverse learners, classroom linguistic environments, and usage-based theories to identify principles for recommended pedagogical practices. We next examined how teachers explained their oral language teaching and what they said after delivering an intervention based on recommended practice. Using a reflexive approach to qualitative interview and questionnaire data, we found some convergence but also areas of limited overlap between recommended practice and teacher professional knowledge. Supporting child talk was seen to serve a motivational-affective purpose more than the cognitive-linguistic purposes implicit in research-informed recommended practices. Based on insights from specialized literature and distillations of professional knowledge, we propose a heuristic framework named Adopting Quality for School Readiness (AQSR). We also discuss uses for the AQSR framework and outstanding questions for future research.
Harmonising flavours: How arousing music and sound influence food perception and emotional responses
This study aims to provide a novel understanding of how music and sound varying in arousal can affect temporal changes in food perception and the corresponding emotional responses, measured through both subjective and objective (i.e., electrophysiological) methods. Exciting conditions are associated with low valence and high arousal, whereas calm conditions are associated with high valence and low arousal. Calm music (CM), calm sound (CS), and a combination of calm music and sound (CMCS) evoked emotions such as joy, relaxation, calmness, pleasantness, and at ease, and were correlated with the perception of sweetness and creaminess. Conversely, exciting music (EM) increased arousal, evoked emotions such as, activity, enthusiasm, energy, and excitement, and amplified the perception of roasted and bitter flavours. Exciting sounds (ES) and combined exciting music and exciting sound (EMES) conditions were positively correlated with anxiety, fatigue, unease, unhappiness, difficulty concentrating, irritation, and restlessness, as well as enhancing the perception of roasted and bitter flavours. Furthermore, the EM and EMES conditions gave rise to significantly higher skin conductance and respiration rate, with corresponding correlations with the perception of roasted and bitter flavours. The ES and EMES conditions demonstrated significantly higher heart rate and respiration rate. The CM condition showed significantly higher heart rate and emotional responses while the CS condition showed significantly higher skin conductance. The findings of this study indicate that sensory attributes are closely associated with the emotions and physiological responses evoked when consuming ice cream under different music and sound conditions.
Audiovisual Associations in Saint-Saëns’ Carnival of the Animals: A Cross-Cultural Investigation on the Role of Timbre
Several studies have investigated crossmodal associations involving audiovisual stimuli. To date, however, far fewer studies have explored the relationship between musical timbre and visual features (e.g., soft/harsh timbres with blue/red colours). To fill this gap in the literature, 249 participants were invited to judge the match between different coloured images and musical excerpts. The images depicted seven characters from Saint-Saëns’ “Carnival of the Animals”; the audio stimuli consisted of the music the composer created to represent each character. To test the effect of timbre and culture, the audio stimuli were presented either in the original orchestral version or in the piano transcription, while the participants were recruited from various countries, encompassing both Western and non-Western nationalities. The results demonstrate that timbre influences crossmodal associations between musical excerpts and drawings, while these associations remain consistent across cultures, languages, and levels of musical background.