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Intensive Care Medicine Oct 2021Delirium is the most common manifestation of brain dysfunction in critically ill patients. In the intensive care unit (ICU), duration of delirium is independently... (Review)
Review
Delirium is the most common manifestation of brain dysfunction in critically ill patients. In the intensive care unit (ICU), duration of delirium is independently predictive of excess death, length of stay, cost of care, and acquired dementia. There are numerous neurotransmitter/functional and/or injury-causing hypotheses rather than a unifying mechanism for delirium. Without using a validated delirium instrument, delirium can be misdiagnosed (under, but also overdiagnosed and trivialized), supporting the recommendation to use a monitoring instrument routinely. The best-validated ICU bedside instruments are CAM-ICU and ICDSC, both of which also detect subsyndromal delirium. Both tools have some inherent limitations in the neurologically injured patients, yet still provide valuable information about delirium once the sequelae of the primary injury settle into a new post-injury baseline. Now it is known that antipsychotics and other psychoactive medications do not reliably improve brain function in critically ill delirious patients. ICU teams should systematically screen for predisposing and precipitating factors. These include exacerbations of cardiac/respiratory failure or sepsis, metabolic disturbances (hypoglycemia, dysnatremia, uremia and ammonemia) receipt of psychoactive medications, and sensory deprivation through prolonged immobilization, uncorrected vision and hearing deficits, poor sleep hygiene, and isolation from loved ones so common during COVID-19 pandemic. The ABCDEF (A2F) bundle is a means to facilitate implementation of the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) Guidelines. In over 25,000 patients across nearly 100 institutions, the A2F bundle has been shown in a dose-response fashion (i.e., greater bundle compliance) to yield improved survival, length of stay, coma and delirium duration, cost, and less ICU bounce-backs and discharge to nursing homes.
Topics: Adult; COVID-19; Critical Care; Critical Illness; Delirium; Humans; Intensive Care Units; Pandemics; SARS-CoV-2
PubMed: 34401939
DOI: 10.1007/s00134-021-06503-1 -
Interface Focus Jun 2020Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep... (Review)
Review
Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase in hypothalamic-pituitary-adrenal (HPA) axis activity, leading to a rise in circulating levels of stress hormones (e.g. cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress . This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory-motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep-scoring algorithms.
PubMed: 32382403
DOI: 10.1098/rsfs.2019.0092 -
Science (New York, N.Y.) Apr 2022Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood....
Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch-conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders.
Topics: Animals; Emotions; Humans; Interneurons; Mice; Sensory Receptor Cells; Touch; Touch Perception
PubMed: 35482870
DOI: 10.1126/science.abn2479 -
The Cochrane Database of Systematic... Jul 2021Delirium is an acute neuropsychological disorder that is common in hospitalised patients. It can be distressing to patients and carers and it is associated with serious... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Delirium is an acute neuropsychological disorder that is common in hospitalised patients. It can be distressing to patients and carers and it is associated with serious adverse outcomes. Treatment options for established delirium are limited and so prevention of delirium is desirable. Non-pharmacological interventions are thought to be important in delirium prevention. OBJECTIVES: To assess the effectiveness of non-pharmacological interventions designed to prevent delirium in hospitalised patients outside intensive care units (ICU).
SEARCH METHODS
We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group, with additional searches conducted in MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov and the World Health Organization Portal/ICTRP to 16 September 2020. There were no language or date restrictions applied to the electronic searches, and no methodological filters were used to restrict the search.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of single and multicomponent non-pharmacological interventions for preventing delirium in hospitalised adults cared for outside intensive care or high dependency settings. We only included non-pharmacological interventions which were designed and implemented to prevent delirium. DATA COLLECTION AND ANALYSIS: Two review authors independently examined titles and abstracts identified by the search for eligibility and extracted data from full-text articles. Any disagreements on eligibility and inclusion were resolved by consensus. We used standard Cochrane methodological procedures. The primary outcomes were: incidence of delirium; inpatient and later mortality; and new diagnosis of dementia. We included secondary and adverse outcomes as pre-specified in the review protocol. We used risk ratios (RRs) as measures of treatment effect for dichotomous outcomes and between-group mean differences for continuous outcomes. The certainty of the evidence was assessed using GRADE. A complementary exploratory analysis was undertaker using a Bayesian component network meta-analysis fixed-effect model to evaluate the comparative effectiveness of the individual components of multicomponent interventions and describe which components were most strongly associated with reducing the incidence of delirium.
MAIN RESULTS
We included 22 RCTs that recruited a total of 5718 adult participants. Fourteen trials compared a multicomponent delirium prevention intervention with usual care. Two trials compared liberal and restrictive blood transfusion thresholds. The remaining six trials each investigated a different non-pharmacological intervention. Incidence of delirium was reported in all studies. Using the Cochrane risk of bias tool, we identified risks of bias in all included trials. All were at high risk of performance bias as participants and personnel were not blinded to the interventions. Nine trials were at high risk of detection bias due to lack of blinding of outcome assessors and three more were at unclear risk in this domain. Pooled data showed that multi-component non-pharmacological interventions probably reduce the incidence of delirium compared to usual care (10.5% incidence in the intervention group, compared to 18.4% in the control group, risk ratio (RR) 0.57, 95% confidence interval (CI) 0.46 to 0.71, I = 39%; 14 studies; 3693 participants; moderate-certainty evidence, downgraded due to risk of bias). There may be little or no effect of multicomponent interventions on inpatient mortality compared to usual care (5.2% in the intervention group, compared to 4.5% in the control group, RR 1.17, 95% CI 0.79 to 1.74, I = 15%; 10 studies; 2640 participants; low-certainty evidence downgraded due to inconsistency and imprecision). No studies of multicomponent interventions reported data on new diagnoses of dementia. Multicomponent interventions may result in a small reduction of around a day in the duration of a delirium episode (mean difference (MD) -0.93, 95% CI -2.01 to 0.14 days, I = 65%; 351 participants; low-certainty evidence downgraded due to risk of bias and imprecision). The evidence is very uncertain about the effect of multicomponent interventions on delirium severity (standardised mean difference (SMD) -0.49, 95% CI -1.13 to 0.14, I=64%; 147 participants; very low-certainty evidence downgraded due to risk of bias and serious imprecision). Multicomponent interventions may result in a reduction in hospital length of stay compared to usual care (MD -1.30 days, 95% CI -2.56 to -0.04 days, I=91%; 3351 participants; low-certainty evidence downgraded due to risk of bias and inconsistency), but little to no difference in new care home admission at the time of hospital discharge (RR 0.77, 95% CI 0.55 to 1.07; 536 participants; low-certainty evidence downgraded due to risk of bias and imprecision). Reporting of other adverse outcomes was limited. Our exploratory component network meta-analysis found that re-orientation (including use of familiar objects), cognitive stimulation and sleep hygiene were associated with reduced risk of incident delirium. Attention to nutrition and hydration, oxygenation, medication review, assessment of mood and bowel and bladder care were probably associated with a reduction in incident delirium but estimates included the possibility of no benefit or harm. Reducing sensory deprivation, identification of infection, mobilisation and pain control all had summary estimates that suggested potential increases in delirium incidence, but the uncertainty in the estimates was substantial. Evidence from two trials suggests that use of a liberal transfusion threshold over a restrictive transfusion threshold probably results in little to no difference in incident delirium (RR 0.92, 95% CI 0.62 to 1.36; I = 9%; 294 participants; moderate-certainty evidence downgraded due to risk of bias). Six other interventions were examined, but evidence for each was limited to single studies and we identified no evidence of delirium prevention. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence regarding the benefit of multicomponent non-pharmacological interventions for the prevention of delirium in hospitalised adults, estimated to reduce incidence by 43% compared to usual care. We found no evidence of an effect on mortality. There is emerging evidence that these interventions may reduce hospital length of stay, with a trend towards reduced delirium duration, although the effect on delirium severity remains uncertain. Further research should focus on implementation and detailed analysis of the components of the interventions to support more effective, tailored practice recommendations.
Topics: Aged; Aged, 80 and over; Bias; Blood Transfusion; Combined Modality Therapy; Delirium; Hospital Mortality; Humans; Incidence; Inpatients; Length of Stay; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 34280303
DOI: 10.1002/14651858.CD013307.pub2 -
Cell Reports May 2023Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional...
Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional mechanisms of cross-modal plasticity can indicate how the brain recovers from various forms of injury and how different sensory modalities are integrated. Here, we demonstrate that rewiring of the microglia-mediated local circuit synapse is crucial for cross-modal plasticity induced by visual deprivation (monocular deprivation [MD]). MD relieves the usual inhibition of functional connectivity between the somatosensory cortex and secondary lateral visual cortex (V2L). This results in enhanced excitatory responses in V2L neurons during whisker stimulation and a greater capacity for vibrissae sensory discrimination. The enhanced cross-modal response is mediated by selective removal of inhibitory synapse terminals on pyramidal neurons by the microglia in the V2L via matrix metalloproteinase 9 signaling. Our results provide insights into how cortical circuits integrate different inputs to functionally compensate for neuronal damage.
Topics: Animals; Microglia; Neurons; Synapses; Pyramidal Cells; Visual Cortex; Neuronal Plasticity; Vibrissae; Somatosensory Cortex
PubMed: 37086724
DOI: 10.1016/j.celrep.2023.112383 -
Indian Journal of Ophthalmology Jul 2023The optimal method of treatment for a child depends on the patient's age at the time of diagnosis, the onset and type of amblyopia, and the degree of compliance... (Review)
Review
The optimal method of treatment for a child depends on the patient's age at the time of diagnosis, the onset and type of amblyopia, and the degree of compliance attainable. In deprivation amblyopia, the cause of visual impairment (e.g., cataract, ptosis) needs to be treated first, and then the disorder can be treated such as other types of amblyopia. Anisometropic amblyopia needs glasses first. In strabismic amblyopia, conventionally amblyopia should be treated first, and then strabismus corrected. Correction of strabismus will have little if any effect on the amblyopia, although the timing of surgery is controversial. Best outcomes are achieved if amblyopia is treated before the age of 7 years. The earlier the treatment, the more efficacious it is. In selected cases of bilateral amblyopia, the more defective eye must be given a competitive advantage over the comparatively good eye. Glasses alone can work when a refractive component is present, but occlusion might make the glasses work faster. The gold standard therapy for amblyopia remains occlusion of the better eye although penalization is also evidenced to achieve equal results. Pharmacotherapy has been shown to achieve suboptimal outcomes. Newer monocular and binocular therapies based on neural tasks and games are adjuncts to patching and can also be used in adults.
Topics: Child; Adult; Humans; Amblyopia; Visual Acuity; Sensory Deprivation; Strabismus; Refraction, Ocular; Treatment Outcome
PubMed: 37417105
DOI: 10.4103/IJO.IJO_338_23 -
Cell Feb 2020The cerebral vasculature is a dense network of arteries, capillaries, and veins. Quantifying variations of the vascular organization across individuals, brain regions,...
The cerebral vasculature is a dense network of arteries, capillaries, and veins. Quantifying variations of the vascular organization across individuals, brain regions, or disease models is challenging. We used immunolabeling and tissue clearing to image the vascular network of adult mouse brains and developed a pipeline to segment terabyte-sized multichannel images from light sheet microscopy, enabling the construction, analysis, and visualization of vascular graphs composed of over 100 million vessel segments. We generated datasets from over 20 mouse brains, with labeled arteries, veins, and capillaries according to their anatomical regions. We characterized the organization of the vascular network across brain regions, highlighting local adaptations and functional correlates. We propose a classification of cortical regions based on the vascular topology. Finally, we analysed brain-wide rearrangements of the vasculature in animal models of congenital deafness and ischemic stroke, revealing that vascular plasticity and remodeling adopt diverging rules in different models.
Topics: Adaptation, Physiological; Animals; Brain; Capillaries; Cerebral Arteries; Cerebral Veins; Female; Male; Mice; Mice, Inbred C57BL; Sensory Deprivation; Stress, Psychological; Stroke; Vascular Remodeling
PubMed: 32059781
DOI: 10.1016/j.cell.2020.01.028 -
Nature Metabolism Mar 2023Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based...
Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
Topics: Glutamine; Aspartate-Ammonia Ligase; Cilia; Signal Transduction
PubMed: 36879119
DOI: 10.1038/s42255-023-00754-6