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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.
CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade
Abstract Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV− patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10−5), with lower incidence of colitis (P = 7.8 × 10−4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10−4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV− patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10−4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.
Structures of the human adult muscle-type nicotinic receptor in resting and desensitized states.
Muscle-type nicotinic acetylcholine receptor (AChR) is the key signaling molecule in neuromuscular junctions. Here, we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states and ACh-bound desensitized states. In addition to identifying the conformational changes during recovery from desensitization, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in patients with congenital myasthenic syndrome (CMS), revealing they cause either slow- or fast-channel CMS characterized by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both the AChR state transition and the pathogenic mechanisms of disease variants.
On brain stimulation in epilepsy.
Brain stimulation has, for many decades, been considered as a potential solution for the unmet needs of the many people living with drug-resistant epilepsy. Clinically, there are several different approaches in use, including vagus nerve stimulation, deep brain stimulation of the thalamus, and responsive neurostimulation. Across populations of patients, all deliver reductions in seizure load and sudden unexpected death in epilepsy risk, yet do so variably, and the improvements seem incremental rather than transformative. In contrast, within the field of experimental neuroscience, the transformational impact of optogenetic stimulation is evident; by providing a means to control subsets of neurons in isolation, it has revolutionized our ability to dissect out the functional relations within neuronal microcircuits. It is worth asking, therefore, how preclinical optogenetics research could advance clinical practice in epilepsy? Here, we review the state of the clinical field, and the recent progress in preclinical animal research. We report various breakthrough results, including the development of new models of seizure initiation, its use for seizure prediction, and for fast, closed-loop control of pathological brain rhythms, and what these experiments tell us about epileptic pathophysiology. Finally, we consider how these preclinical research advances may be translated into clinical practice.
The convergence of neuromodulation and brain–computer interfaces
Neuromodulation and brain–computer interfaces are rapidly evolving fields with distinct origins but with the shared goal of improving the lives of people with neurological and psychiatric disorders or injuries. Their increasing technological overlap provides new opportunities for collaborative work and rapid progress in neurotechnology.
Editor's Choice - Effect of Carotid Endarterectomy on 20 Year Incidence of Recorded Dementia: A Randomised Trial.
OBJECTIVE: Stroke and carotid atherosclerosis are associated with dementia. Carotid endarterectomy (CEA) reduces stroke risk, although its effect on later dementia is uncertain. Participants in the Asymptomatic Carotid Surgery Trial (ACST-1), randomly allocated to immediate vs. deferral of CEA (i.e., no intervention unless or until triggered by ipsilateral transient ischaemic attack or stroke), were followed, to study effects on dementia. METHODS: From 1993 to 2003, ACST-1 included 3 120 participants with asymptomatic tight carotid stenosis. All UK and Swedish patients (n = 1 601; 796 immediate vs. 805 deferral) were followed with trial records, national electronic health record linkage, and (UK only) by post and telephone. Cumulative incidence and competing risk analyses were used to measure the effects of risk factors and CEA on dementia risk. Intention to treat analyses yielded hazard ratios (HRs; immediate vs. deferral) of dementia. RESULTS: The median follow up was 19.4 years (interquartile range 16.9 - 21.7). Dementia was recorded in 107 immediate CEA patients and 115 allocated delayed surgery; 1 290 patients died (1 091 [538 vs. 536] before any dementia diagnosis). Dementia incidence rose with age and with female sex (men: 8.3% aged < 70 years at trial entry vs. 15.1% aged ≥ 70; women: 15.1% aged < 70 years at trial entry vs. 22.4% aged ≥ 70 years) and was higher in those with pre-existing cerebral infarction (silent or with prior symptoms; 20.2% vs. 13.6%). Dementia risk was similar in both randomised groups: 6.7% vs. 6.6% at 10 years and 14.3% vs. 15.5% at 20 years, respectively. The dementia HR was 0.98 (95% confidence interval [CI] 0.75 - 1.28; p = .89), with no heterogeneity in the neutral effect of immediate CEA on dementia related to age, carotid stenosis, blood pressure, diabetes, country of residence, or medical treatments at trial entry (heterogeneity values p > .05). CONCLUSION: CEA was not associated with significant reductions in the long term hazards of dementia, but the CI did not exclude a proportional benefit or hazard of about 25%.
Education Levels and Poststroke Cognitive Trajectories.
IMPORTANCE: Acute stroke is associated with accelerated, years-long cognitive decline. Whether education levels are associated with faster cognitive decline after stroke is unclear. OBJECTIVE: To evaluate the association of education level with poststroke cognitive decline and to determine whether age at stroke modifies the association. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data meta-analysis of 4 US cohort studies (January 1971 to December 2019). Analysis began August 2022 and was completed in January 2024. EXPOSURES: Education level (less than high school, completed high school, some college, and college graduate). MAIN OUTCOMES AND MEASURES: Harmonized cognitive outcomes were global cognition (primary outcome), memory, and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition, with higher score representing better function. Linear mixed-effect models estimated the trajectory of cognitive decline after incident stroke. RESULTS: The analysis included 2019 initially dementia-free stroke survivors (1048 female [51.9%]; median [IQR] age at stroke, 74.8 [69.0-80.4] years; 339 with less than a high school education [16.7%]; 613 who completed high school [30.4%]; 484 with some college [24.0%]; 583 with a college degree or higher [28.9%]). Median (IQR) follow-up time after stroke was 4.1 (1.8-7.2) years. Compared with those with less than a high school degree, college graduates had higher initial poststroke performance in global cognition (1.09 points higher; 95% CI, 0.02 to 2.17 points higher), executive function (1.81 points higher; 95%CI, 0.38 to 3.24 points higher), and memory (0.99 points higher; 95% CI, 0.02 to 1.96 points higher). Compared with stroke survivors with less than a high school education, there was a faster decline in executive function among college graduates (-0.44 points/y faster; 95% CI, -0.69 to -0.18 points/y faster) and those with some college education(-0.30 points/y faster; 95% CI, -0.57 to -0.03 points/y faster). Education level was not associated with declines in global cognition or memory. Age did not modify the association of education with cognitive decline. CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the trajectory of cognitive decline after stroke varied by education level and cognitive domain, suggesting that stroke survivors with a higher education level may have greater cognitive reserve but steeper decline in executive function than those with a lower education level.
Oxford Case Histories in TIA and Stroke
Based around the core curriculum for specialist trainees, Oxford Case Histories in TIA and Stroke features 51 well-structured, peer-reviewed cases from the Oxford Hospitals giving detailed coverage of the specialty, including diagnostic and management dilemmas. Each case comprises a brief clinical history and the relevant examination findings; details of investigations undertaken, followed by questions on differential diagnosis and management; and detailed answers and discussion. The question-and-answer format is designed to enhance the reader's diagnostic ability and clinical understanding. As part of the Oxford Case Histories series, this book is aimed at post-membership trainees and consultants and will be a useful resource for those preparing for exit examinations or revalidation. It will also be of interest to those who wish to improve their skills in diagnosis and management of a broad range of stroke disorders.
Track-and-Trigger System: Identifying and Predicting Patient Deterioration through Scores and Algorithms
A track-and-trigger system (TTS) is a key component of the afferent limb of a rapid response system (RRS), alerting teams to deteriorating patients. Most TTSs identify deterioration through measurements of vital sign abnormalities (e.g. heart rate, oxygen saturations, temperature), but may incorporate additional criteria such as seizure or clinical concern. Traditional TTSs either alert on extreme values in one vital sign (e.g. tachycardia) or aggregate vital sign abnormalities into a composite early warning score (EWS). Both approaches have the advantage of simple implementation and provide a common language in which to communicate patient risk in clinical environments. However, this simplicity comes at the expense of high numbers of false alerts, generating unnecessary demand on limited RRS resources. Evidence that TTSs improve patients’ outcomes in hospital is limited. In this chapter, we will summarise TTSs used internationally and the development of more sophisticated TTSs to improve early detection of patient deterioration.
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.