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Comprehensive analysis of stroke epidemiology in Vietnam: Insights from GBD 1990–2019 and RES-Q 2017–2023
Background: Stroke is a significant health burden in Vietnam, with substantial impacts on mortality, morbidity, and healthcare resources. An up-to-date report on stroke epidemiology and associated risk factors in Vietnam was missing. Method: We analyzed the data published in the Global Burden of Disease (GBD) 2019, in combination with the first-time analysis of the Registry of Stroke Care Quality Improvement (RES-Q) initiative in Vietnam from 2017 to 2023. Findings: Comparative analysis globally revealed that Vietnam had one of the highest stroke incidence and prevalence rates in Southeast Asia and ranked 4th in stroke mortality among 11 neighbouring countries. In the RES-Q dataset, 95,696 patients (77 %) were ischemic stroke, 23,203 (18 %) were intracerebral haemorrhage, and 2816 (2 %) were subarachnoid haemorrhage. In GBD 2019, stroke was the leading cause of death among cardiovascular diseases in Vietnam, accounting for 135,999 fatalities. The incidence of stroke was 222 (95 % UIs 206–242) per 100,000 population, with a prevalence of 1541 (1430-1679) per 100,000. Results align with the report from the RES-Q dataset in two megacities of Vietnam: Hanoi (incidence rate of 168.9, prevalence rate of 1182.2) and Ho Chi Minh City (incidence rate of 207.1, prevalence rate of 1221.8). Key risk factors for stroke mortality are high systolic blood pressure (79,000 deaths), unhealthy dietary (43,000 deaths), high fasting plasma glucose (35,000 deaths), and air pollution (33,000 deaths). Incidence is lower in rural Vietnam, but availability and quality of care are higher in megacities. Interpretation: The results promote a further understanding of stroke and risk factors for the Vietnamese population and suggest prevention and treatment strategies for the Vietnamese government, including facility and capacity improvement and applications of advanced technologies.
Cognitive and neuropsychiatric profiles distinguish atypical parkinsonian syndromes.
Atypical parkinsonian syndromes are distinguished from Parkinson's disease by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive, and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis. Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may cause cognitive and behavioural manifestations that overlap with frontotemporal dementia, including non-fluent aphasia, apathy and impulsivity. Clinical diagnostic criteria have limited sensitivity, with pathologically confirmed PSP often having presented an initial clinical syndrome other than PSP-Richardson's syndrome. Here we integrate cross-sectional multi-centre baseline data from the PROSPECT and Oxford Discovery cohorts. This allowed us to compare cognitive and psychiatric features across a total of 1138 people with PSP, CBS, multiple-system atrophy (MSA), and idiopathic Parkinson's disease (PD). Data from the different cohorts were harmonised and compared using multiple linear regression. There were five key results. 1. Different syndromes showed distinctive cognitive profiles, using readily applicable 'bedside' screening tools. Frontal executive dysfunction was most evident in PSP, visuospatial deficits in CBS, with milder deficits in memory and executive function in MSA, as compared with PD. 2. The most prevalent neuropsychiatric features were depression and anxiety in CBS, apathy in PSP, with sleep disturbances common in PD. As expected, apathy correlated positively with impulsivity across all disorders. Neuropsychiatric features were generally better at discriminating between atypical parkinsonian syndromes than were the cognitive domains. 3. Both cognitive function and motor severity declined with disease duration, and motor function predicted cognition in PSP, CBS and PD but not in MSA, suggesting that in MSA cognitive and motor dysfunction are decoupled. 4. Plasma neurofilament light chain (NFL) levels, measured in a subset of patients, correlated with cognitive deficits in PSP, but not motor deficits. 5. Cognitive deficits contributed to the impairment in activities of daily living after controlling for motor severity, with every two points on the MoCA worsening the Schwab and England score by one point. In anticipation of future neuroprotective therapies, we present a classifier to improve diagnostic accuracy for atypical parkinsonian syndromes in vivo. Longitudinal cohort studies with resources for neuropathological gold-standard diagnosis remain important to validate better diagnostic tools for people with PSP, CBD, MSA and atypical parkinsonism.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis.
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Biophysical effects and neuromodulatory dose of transcranial ultrasonic stimulation.
Transcranial ultrasonic stimulation (TUS) has the potential to usher in a new era for human neuroscience by allowing spatially precise and high-resolution non-invasive targeting of both deep and superficial brain regions. Currently, fundamental research on the mechanisms of interaction between ultrasound and neural tissues is progressing in parallel with application-focused research. However, a major hurdle in the wider use of TUS is the selection of optimal parameters to enable safe and effective neuromodulation in humans. In this paper, we will discuss the major factors that determine both the safety and efficacy of TUS. We will discuss the thermal and mechanical biophysical effects of ultrasound, which underlie its biological effects, in the context of their relationships with tunable parameters. Based on this knowledge of biophysical effects, and drawing on concepts from radiotherapy, we propose a framework for conceptualising TUS dose.
An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.
Cortical layer 6 neurons are the only projection neuron population in the cortical mantle known to electrophysiologically respond to orexin-a neuropeptide involved in cortical arousal and emotive behaviour. These neurons exhibit extensive intercortical and thalamic projections, yet the exact mechanisms underlying these responses are not fully understood. We hypothesize that cortical circuits activated by orexin sensitive L6 neurons in the medial prefrontal cortex (mPFC) are responsible for detecting salient features of sensory stimuli and are therefore involved in regulating emotional states. Here, we show that Drd1a-Cre+ neurons in the mPFC are selectively sensitive to orexin and gate the activation of the prefrontal network in vivo. Moreover, we demonstrated that chronically "silencing" this subpopulation of L6 neurons (Drd1a-Cre+/+:Snap25fl/fl) across the cortical mantle from birth abolishes the orexin-induced prefrontal activation. Consequently, the chronic silencing of these neurons had strong anxiolytic effects on several anxiety-related behavioural paradigms, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.
Association of cholesterol and glycemic state biomarkers with phenotypic variation and Parkinson's disease progression: The Oxford Discovery cohort.
BackgroundParkinson's disease (PD) has marked phenotypic variability. Increased lipids have been suggested as being neuroprotective whilst hyperglycemia may increase α-synuclein aggregation.ObjectiveWe have tested whether high total cholesterol and high-density lipoprotein cholesterol (HDL-C) and low levels of fructosamine are associated with better PD phenotypes and predict less rapid progressionMethodsNon-fasting serum HDL-C, total cholesterol, and fructosamine were measured at baseline in 866 patients with early PD (median duration, 0.96; IQR, 0.43-1.98 years) from the Oxford Discovery cohort. These biomarkers were compared against our data-derived PD subtypes using multinomial logistic regression. We used multilevel models to predict longitudinal motor and non-motor outcomes (e.g., cognition, mood).ResultsHDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behavior disorder, and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (e.g., UPDRS-II score with 1 SD increase in HDL-C -0.74, 95%CI -1.22 to -0.26, p = 0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression. Fructosamine levels were not associated with phenotypic variability or rate of disease progression.ConclusionsHypercholesterolemia was associated with a better motor/non-motor disease subtype and daily living impairment at presentation, but did not predict longitudinal change. Future research needs to determine if these associations are causally related or secondary to disease onset by examining prodromal subjects.
Efficacy of digital cognitive behavioral therapy for treating insomnia in adults aged 65 and older: a secondary analysis using individual participant data from three randomized controlled trials.
OBJECTIVES: Insomnia prevalence increases with age. Although cognitive behavioral therapy (CBT) for insomnia is the first-line treatment, limited accessibility leaves many older adults with few effective treatment options. This study assessed the efficacy of digital CBT (dCBT) for treating insomnia, anxiety, and depression symptoms in adults aged 65 and older. METHOD: Data from three published randomized controlled trials of dCBT for insomnia (Sleepio) versus controls were combined for those aged 65+ with insomnia disorder (N = 315). Insomnia, anxiety, and depression scores were standardized into z-scores for comparison. Mixed-effects models estimated the treatment effect on insomnia, depression, and anxiety outcomes at post-treatment (8-10 wk) and follow-up (24 wk). Chi-squared tests of Sleep Condition Indicator (SCI-8) scores evaluated post-treatment insomnia remission rates between groups. RESULTS: Compared with controls, dCBT generated significantly greater improvements at post-treatment and follow-up in insomnia (gs ≤ -1.88, ps < 0.001) and depression (gs ≤ -0.44, ps ≤ 0.001) and significantly greater improvements in anxiety at post-treatment (g = -0.33, p
Reducing inequalities through greater diversity in clinical trials – As important for medical devices as for drugs and therapeutics
In medicine and public health, the randomised controlled trial (RCT) is generally considered the key generator of ‘gold standard’ evidence. However, basic and clinical research and trials are often unrepresentative of real-world populations. Recruiting insufficiently diverse cohorts of participants in trials (e.g. in terms of socioeconomic status, racial and ethnic background, or sex and gender) may not only overstate the general effectiveness of a technology; it may also actively increase health inequalities. We highlight some general issues in this domain, before discussing several specific illustrative examples in the context of medical devices. High quality evidence on factors that would improve trial recruitment is extremely limited. There is a clear need for research on candidate strategies for improving recruitment of under-represented groups in RCTs. These could include, for example, offering various forms of financial incentives; non-monetary incentives, such as preferential access to the technologies that are being tested if they are found to be effective; and various types of informational messages and nudges; as well as involvement of community partners and champions in the recruitment process. Ideally, recruitment practices should ultimately be based on evidence generated from RCTs. Studies Within a Trial (SWAT), where randomised experiments are built into the actual recruitment processes in RCTs, are an ideal way to gain this evidence. SWAT studies are seeing an increase in traction, as indicated by funding streams in bodies such as the UK-based NIHR. Making greater funding available for studies of this kind is needed to improve the evidence base on how best to improve diversity in trial recruitment.