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The association of insomnia with long COVID: An international collaborative study (ICOSS-II).
OBJECTIVE: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection. METHODS: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety. RESULTS: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p
Fine Tuning of Phosphorothioate Inclusion in 2'-O-Methyl Oligonucleotides Contributes to Specific Cell Targeting for Splice-Switching Modulation.
Splice-switching antisense oligonucleotide- (SSO-) mediated correction of framedisrupting mutation-containing premessenger RNA (mRNA) transcripts using exon skipping is a highly promising treatment method for muscular diseases such as Duchenne muscular dystrophy (DMD). Phosphorothioate (PS) chemistry, a commonly used oligonucleotide modification, has been shown to increase the stability of and improve the pharmacokinetics of SSOs. However, the effect of PS inclusion in 2'-O-methyl SSOs (2OMe) on cellular uptake and splice switching is less well-understood. At present, we demonstrate that the modification of PS facilitates the uptake of 2OMe in H2k-mdx myoblasts. Furthermore, we found a dependency of SSO nuclear accumulation and high splice-switching activity on PS inclusion in 2OMe (2OMePS), as tested in various reporter cell lines carrying pLuc/705. Increased exon-inclusion activity was observed in muscle, neuronal, liver, and bone cell lineages via both the gymnotic uptake and lipofection of 2OMePS. Using the photoactivatable ribonucleoside-enhanced crosslinking and a subsequent proteomic approach, we identified several 2OMePS-binding proteins, which are likely to play a role in the trafficking of 2OMePS to the nucleus. Ablation of one of them, Ncl by small-interfering RNA (siRNA) enhanced 2OMePS uptake in C2C12 myoblasts and upregulated luciferase RNA splicing in the HeLa Luc/705 reporter cell line. Overall, we demonstrate that PS inclusion increases nuclear delivery and splice switching in muscle, neuronal, liver, and bone cell lineages and that the modulation of 2OMePS-binding partners may improve SSO delivery.
A role for pathogenic autoantibodies in small fiber neuropathy?
The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen’s syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.
Changes in sleep and the prevalence of probable insomnia in undergraduate university students over the course of the COVID-19 pandemic: findings from the U-Flourish cohort study.
BACKGROUND: Sleep problems associated with poor mental health and academic outcomes may have been exacerbated by the COVID-19 pandemic. AIMS: To describe sleep in undergraduate students during the COVID-19 pandemic. METHOD: This longitudinal analysis included data from 9523 students over 4 years (2018-2022), associated with different pandemic phases. Students completed a biannual survey assessing risk factors, mental health symptoms and lifestyle, using validated measures. Sleep was assessed with the Sleep Condition Indicator (SCI-8). Propensity weights and multivariable log-binomial regressions were used to compare sleep in four successive first-year cohorts. Linear mixed-effects models were used to examine changes in sleep over academic semesters and years. RESULTS: There was an overall decrease in average SCI-8 scores, indicating worsening sleep across academic years (average change -0.42 per year; P-trend < 0.001), and an increase in probable insomnia at university entry (range 18.1-29.7%; P-trend < 0.001) before and up to the peak of the pandemic. Sleep improved somewhat in autumn 2021, when restrictions loosened. Students commonly reported daytime sleep problems, including mood, energy, relationships (36-48%) and concentration, productivity, and daytime sleepiness (54-66%). There was a consistent pattern of worsening sleep over the academic year. Probable insomnia was associated with increased cannabis use and passive screen time, and reduced recreation and exercise. CONCLUSIONS: Sleep difficulties are common and persistent in students, were amplified by the pandemic and worsen over the academic year. Given the importance of sleep for well-being and academic success, a preventive focus on sleep hygiene, healthy lifestyle and low-intensity sleep interventions seems justified.
Dynamic modulation of subthalamic nucleus activity facilitates adaptive behavior.
Adapting actions to changing goals and environments is central to intelligent behavior. There is evidence that the basal ganglia play a crucial role in reinforcing or adapting actions depending on their outcome. However, the corresponding electrophysiological correlates in the basal ganglia and the extent to which these causally contribute to action adaptation in humans is unclear. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus, a core area of the basal ganglia, in 16 patients with Parkinson's disease (PD) on medication using temporarily externalized deep brain stimulation (DBS) electrodes. Patients as well as 16 age- and gender-matched healthy participants attempted to produce forces as close as possible to a target force to collect a maximum number of points. The target force changed over trials without being explicitly shown on the screen so that participants had to infer target force based on the feedback they received after each movement. Patients and healthy participants were able to adapt their force according to the feedback they received (P < 0.001). At the neural level, decreases in subthalamic beta (13 to 30 Hz) activity reflected poorer outcomes and stronger action adaptation in 2 distinct time windows (Pcluster-corrected < 0.05). Stimulation of the subthalamic nucleus reduced beta activity and led to stronger action adaptation if applied within the time windows when subthalamic activity reflected action outcomes and adaptation (Pcluster-corrected < 0.05). The more the stimulation volume was connected to motor cortex, the stronger was this behavioral effect (Pcorrected = 0.037). These results suggest that dynamic modulation of the subthalamic nucleus and interconnected cortical areas facilitates adaptive behavior.
Between-task competition for intentions and actions
People can switch quickly and flexibly from one task to another, but suffer the effects of between-task competition when they do so: After switching, they tend to be distracted by irrelevant stimulus information and hampered by incorrect actions associated with recently performed tasks. This competition results in performance costs of switching, as well as a bias against switching when there is choice over which task to perform, particularly when switching from a difficult task to an easier one. Two experiments investigated the locus of these between-task competition effects in voluntary task switching. Participants switched between an easy location classification and a harder shape classification, making two responses on each trial: the first to register their task choice, the second to perform the chosen task on a subsequently presented stimulus. The results indicated that participants chose to perform the difficult shape task more often than the easier location task, evidence that between-task competition affects intentions that are expressed independently of task-specific actions. The bias was stronger in participants with faster choice speed, suggesting that these influences are relatively automatic. Moreover, even though participants had unlimited time to choose and prepare a task before stimulus presentation, their subsequent performance was nonetheless sensitive to persisting effects of between-task competition. Altogether these results indicate the pervasive influence of between-task competition, which affects both the expression of global task intentions and the production of task-specific actions.
Fornix Microstructure Correlates with Recollection But Not Familiarity Memory
The fornix is the main tract between the medial temporal lobe (MTL) and medial diencephalon, both of which are critical for episodic memory. The precise involvement of the fornix in memory, however, has been difficult to ascertain since damage to this tract in human amnesics is invariably accompanied by atrophy to surrounding structures. We used diffusion-weighted imaging to investigate whether individual differences in fornix white matter microstructure in neurologically healthy participants were related to differences in memory as assessed by two recognition tasks. Higher microstructural integrity in the fornix tail was found to be associated with significantly better recollection memory. In contrast, there was no significant correlation between fornix microstructure and familiarity memory or performance on two non-mnemonic tasks. Our findings support the idea that there are distinct MTL–diencephalon pathways that subserve differing memory processes.
Severe, persistent visual impairment associated with occipital calcification and coeliac disease
While coeliac disease is primarily a disease of the digestive system, there have been several reports of neurological effects, both motor and cognitive. Here, we present the case of a woman with coeliac disease, under dietary control, in whom there is profound long-standing visual disturbance including reduction of visual fields, loss of rapid flicker and colour sensitivity and severe deficits in acuity. Structural magnetic resonance imaging (MRI) indicates large regions of calcification and abnormal tissue that is restricted to the occipital cortex, particularly the posterior region. Functional MRI indicates an absence of normal visual activation in the primary visual cortex, but at least in one hemisphere, there is neural activity to moving stimuli in visual motion area hMT+. White matter microstructure in the pathway between the lateral geniculate nucleus and hMT+ is normal compared to healthy control subjects, but is severely abnormal between the lateral geniculate nucleus and primary visual cortex. This case study illustrates the very specific nature of cortical deficit that can arise in association with coeliac disease, and highlights the importance of early dietary control for the disease.
Novel brain imaging approaches to understand acquired and congenital neuro-ophthalmological conditions
PURPOSE OF REVIEW: The arrival of large datasets and the on-going refinement of neuroimaging technology have led to a number of recent advances in our understanding of visual pathway disorders. This work can broadly be classified into two areas, both of which are important when considering the optimal management strategies. The first looks at the delineation of damage, teasing out subtle changes to (specific components of) the visual pathway, which may help evaluate the severity and extent of disease. The second uses neuroimaging to investigate neuroplasticity, via changes in connectivity, cortical thickness, and retinotopic maps within the visual cortex. RECENT FINDINGS: Here, we give consideration to both acquired and congenital patients with damage to the visual pathway, and how they differ. Congenital disorders of the peripheral visual system can provide insight into the large-scale reorganization of the visual cortex: these are investigated with reference to disorders of the optic chiasm and anophthalmia (absence of the eyes). In acquired conditions, we consider the recent work describing patterns of degeneration, both following single insult and in neurodegenerative conditions. We also discuss the developments in functional neuroimaging, with particular reference to work on hemianopia and the controversial suggestion of cortical reorganization following acquired retinal injury. SUMMARY: Techniques for comparing neuro-ophthalmological conditions with healthy visual systems provide sensitive metrics to uncover subtle differences in grey and white matter structure of the brain. It is now possible to compare the massive reorganization present in congenital conditions with the apparent lack of plasticity following acquired damage. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.