Search results
Found 22531 matches for
New analysis from over 36,000 healthy women in 20 countries suggests that physiological changes during pregnancy may not be as dramatic as traditionally taught. However, blood pressures do appear to be increasing year on year.
Research priorities for the study of atrial fibrillation during acute and critical illness: recommendations from the Symposium on Atrial Fibrillation in Acute and Critical Care
AbstractAtrial fibrillation (AF) is a common arrhythmia encountered in acute and critical illness and is associated with poor short and long-term outcomes. Given the consequences of developing AF, research into prevention, prediction and treatment of this arrhythmia in the critically ill are of great potential benefit, however, study of AF in critically ill patients faces unique challenges, leading to a sparse evidence base to guide management in this population. Major obstacles to the study of AF in acute and critical illness include absence of a common definition, challenges in designing studies that capture complex etiology and assess causality, lack of a clear outcome set, difficulites in recruitment in acute environments with respect to timing, consent, and workflow, and failure to embed studies into clinical care platforms and capitalize on emerging technologies. Collaborative effort by researchers, clinicians, and stakeholders should be undertaken to address these challenges, both through interdisciplinary cooperation for the optimization of research efficiency and advocacy to advance the understanding of this common and complex arrhythmia, resulting in improved patient care and outcomes. The Symposium on Atrial Fibrillation in Acute and Critical Care was convened to address some of these challenges and propose potential solutions.
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.
Cortical evoked activity is modulated by the sleep state in a ferret model of tinnitus. A cross-case study
Subjective tinnitus is a phantom auditory perception in the absence of an actual acoustic stimulus that affects 15% of the global population. In humans, tinnitus is often associated with disturbed sleep and, interestingly, there is an overlap between the brain areas involved in tinnitus and regulation of NREM sleep. We used eight adult ferrets exposed to mild noise trauma as an animal model of tinnitus. We assessed the phantom percept using two operant paradigms sensitive to tinnitus, silent gap detection and silence detection, before and, in a subset of animals, up to six months after the mild acoustic trauma. The integrity of the auditory brainstem was assessed over the same period using auditory brainstem response recordings. Following noise overexposure, ferrets developed lasting, frequency–specific impairments in operant behaviour and evoked brainstem activity. To explore the interaction between sleep and tinnitus, in addition to tracking the behavioural markers of noise–induced tinnitus and hearing impairment after noise overexposure, we evaluated sleep–wake architecture and spontaneous and auditory–evoked EEG activity across vigilance states. Behavioural performance and auditory–evoked activity measurements after noise overexposure suggested distinct degrees of tinnitus and hearing impairment between individuals. Animals that developed signs of tinnitus consistently developed sleep impairments, suggesting a link between the emergence of noise–induced hearing loss and/or tinnitus and sleep disruption. However, neural markers of tinnitus were reduced during sleep, suggesting that sleep may transiently mitigate tinnitus. These results reveal the importance of sleep–wake states in tinnitus and suggest that understanding the neurophysiological link between sleep and tinnitus may provide a new angle for research into the causes of phantom percepts and inform future treatments.
sUPRa is a dual-color reporter for unbiased quantification of the unfolded protein response with cellular resolution.
The unfolded protein response (UPR) maintains proteostasis upon endoplasmic reticulum (ER) stress, and is initiated by a range of physiological and pathological processes. While there have been advances in developing fluorescent reporters for monitoring individual signaling pathways of the UPR, this approach may not capture a cell's overall UPR activity. Here we describe a novel sensor of UPR activity, sUPRa, which is designed to report the global UPR. sUPRa displays excellent response characteristics, outperforms reporters of individual UPR pathways in terms of sensitivity and kinetics, and responds to a range of different ER stress stimuli. Furthermore, sUPRa's dual promoter and fluorescent protein design ensures that both UPR-active and inactive cells are detected, and controls for reporter copy number. Using sUPRa, we reveal UPR activation in layer 2/3 pyramidal neurons of mouse cerebral cortex following a period of sleep deprivation. sUPRa affords new opportunities for quantifying physiological UPR activity with cellular resolution.
Defining an ageing-related pathology, disease or syndrome: International Consensus Statement.
Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.
Provision of peri-operative patient blood management strategies in the UK: a national survey of practice.
INTRODUCTION: In UK hospitals, it is unclear how organisational structures are arranged to support effective implementation of peri-operative blood management practice strategies. The aim of this study was to conduct a national survey of organisations to describe local practices of peri-operative patient blood management and infrastructure availability in the UK. METHODS: A series of benchmarking standards was developed using recommendations informed by national standards, relevant literature and an expert panel. Through the Research and Audit Federation of Trainees networks, 143 hospitals were approached to participate. The pre-piloted survey was conducted online between January and February 2023. RESULTS: Responses were received from 123 hospitals across 74 NHS Trusts and health boards. Formal elective anaemia pathways were not reported in 37/123 (30%) sites. There was considerable inter-site variation in interventional thresholds for anaemia and screening tests. A variety of oral iron regimens were reported, from once-daily dosing in 41/85 (48%) sites, to three times a day dosing in 14/85 (16%). Ferric carboxymaltose was the preparation used most frequently at sites that administered intravenous iron (61/113, 54%). There was variation between hospitals and surgical specialties in the use of tranexamic acid with 49/122 (39%) hospitals reporting a policy for the use of peri-operative tranexamic acid. For sites that performed major surgery routinely (irrespective of specialty), 20/112 (18%) included tranexamic acid in operating theatre safety briefings. Point-of-care coagulation testing was available at 62/123 (50%) sites. DISCUSSION: Our findings show considerable heterogeneity in peri-operative patient blood management strategies and supporting infrastructure availability across the UK. There is a pressing need for hospitals to review pathways of care offered to surgical patients and implement national recommendations.
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.
Radiofrequency thalamotomy for tremor outcomes correlate with dentorubrothalamic tract distance.
BACKGROUND: Thalamotomy was the main surgical treatment for medically refractory tremor before deep brain stimulation (DBS). While DBS is now preferred, it has drawbacks such as hardware failure, infection risk, frequent battery replacements, and multiple programming adjustments. Radiofrequency (RF) thalamotomy avoids these issues, can be performed under local anaesthesia, and suits patients in poor health. This study examines long-term outcomes of RF thalamotomy. METHODS: We reviewed 14 consecutive RF thalamotomies performed in Oxford from 2016 to 2021. Three patients died from unrelated causes, leaving eight for long-term assessment. We recorded Bain and Findlay (BF) tremor scores, Clinical Global Impression of Severity (CGI-S), Clinical Global Impression of Change (CGI-C), Patient's Global Impression of Change (PGI-C), and Efficacy Index (EI). The median follow-up was 39 months (range 12-126). Post-operative tractography was correlated with clinical outcomes. RESULTS: Six patients had essential tremor and eight had Parkinson's disease. Reasons for choosing thalamotomy over DBS included medical comorbidities, patient preference, age, and previous DBS failure. Ten patients (71%) reported significant tremor improvement, with relapse in two after six months. The mean BF tremor score decreased from 16.1 preoperatively to 8.5 postoperatively (p = 0.0043). Adverse events occurred in seven patients (50%), resolving completely in three, partially in three, and persisting in one. Sustained outcomes correlated with a wider distance of residual dentrorubrothalamic tract (DRTT) fibres from the lesion. CONCLUSIONS: RF thalamotomy is an effective long-term treatment for medication-refractory tremor and should be considered for select patients needing unilateral tremor control.
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.
CRISPR targeting of SNPs associated with age-related macular degeneration in ARPE-19 cells: a potential model for manipulating the complement system
Abstract 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.
Process evaluation in a randomised controlled trial of DREAMS-START (dementia related manual for sleep; strategies for relatives) for sleep disturbance in people with dementia and their carers.
INTRODUCTION: DREAMS-START is a multicomponent intervention targeting sleep disturbance in people with dementia. To enhance understanding of the DREAMS-START randomised controlled trial, which showed improved sleep in the intervention compared to the control arm, we conducted a process evaluation exploring (i) DREAMS-START delivery, (ii) behaviour change mechanisms and (iii) contextual factors impacting outcomes. METHODS: Mixed-methods design. We measured intervention adherence, fidelity and additional therapeutic process measures. We interviewed a sub-sample of intervention arm family carers and facilitators delivering DREAMS-START. We analysed data thematically guided by a prespecified theory of change logic model informed by the Theoretical Domains Framework. We measured movement using an actigraph worn by the person with dementia at baseline and at four- and eight-month follow-ups to explore potential mechanisms of action. RESULTS: Attendance was good (82.8% attended ≥4/6 sessions). Mean fidelity score (95.4%; SD 0.08) and median score for all four process measures assessed (5/5; IQR 5-5) were high. We interviewed 43/188 family carers and 9/49 DREAMS-START facilitators. We identified three overarching themes aligned with our model: (i) knowledge and facilitation enable behaviour change, (ii) increasing sleep pressure and developing skills to manage sleep disturbances and (iii) Establishing a routine and sense of control. We were unable to collect sufficient data for pre-specified actigraphy analyses. CONCLUSION: Despite competing demands, carers attended DREAMS-START. It promoted behaviour change through supportive in-session reflection, increasing carer knowledge and skills. This was embedded between sessions and actions were positively reinforced as carers experienced changes. Results will inform future implementation in clinical services.
Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals.
With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.
Traumatic Brain Injury and Alzheimer’s Disease: A Shared Neurovascular Hypothesis
Traumatic brain injury (TBI) is a modifiable risk factor for Alzheimer’s disease (AD). TBI and AD share several histopathological hallmarks: namely, beta-amyloid aggregation, tau hyperphosphorylation, and plasma protein infiltration. The relative contributions of these proteinopathies and their interplay in the pathogenesis of both conditions remains unclear although important differences are emerging. This review synthesises emerging evidence for the critical role of the neurovascular unit in mediating protein accumulation and neurotoxicity in both TBI and AD. We propose a shared pathogenic cascade centred on a neurovascular unit, in which increased blood-brain barrier permeability induces a series of noxious mechanisms leading to neuronal loss, synaptic dysfunction and ultimately cognitive dysfunction in both conditions. We explore the application of this hypothesis to outstanding research questions and potential treatments for TBI and AD, as well as other neurodegenerative and neuroinflammatory conditions. Limitations of this hypothesis, including the challenges of establishing a causal relationship between neurovascular damage and proteinopathies, are also discussed.