Thalamic contributions to psychosis susceptibility: Evidence from co-activation patterns accounting for intra-seed spatial variability (µCAPs).

The temporal variability of the thalamus in functional networks may provide valuable insights into the pathophysiology of schizophrenia. To address the complexity of the role of the thalamic nuclei in psychosis, we introduced micro-co-activation patterns (µCAPs) and employed this method on the human genetic model of schizophrenia 22q11.2 deletion syndrome (22q11.2DS). Participants underwent resting-state functional MRI and a data-driven iterative process resulting in the identification of six whole-brain µCAPs with specific activity patterns within the thalamus. Unlike conventional methods, µCAPs extract dynamic spatial patterns that reveal partially overlapping and non-mutually exclusive functional subparts. Thus, the µCAPs method detects finer foci of activity within the initial seed region, retaining valuable and clinically relevant temporal and spatial information. We found that a µCAP showing co-activation of the mediodorsal thalamus with brain-wide cortical regions was expressed significantly less frequently in patients with 22q11.2DS, and its occurrence negatively correlated with the severity of positive psychotic symptoms. Additionally, activity within the auditory-visual cortex and their respective geniculate nuclei was expressed in two different µCAPs. One of these auditory-visual µCAPs co-activated with salience areas, while the other co-activated with the default mode network (DMN). A significant shift of occurrence from the salience+visuo-auditory-thalamus to the DMN + visuo-auditory-thalamus µCAP was observed in patients with 22q11.2DS. Thus, our findings support existing research on the gatekeeping role of the thalamus for sensory information in the pathophysiology of psychosis and revisit the evidence of geniculate nuclei hyperconnectivity with the audio-visual cortex in 22q11.2DS in the context of dynamic functional connectivity, seen here as the specific hyper-occurrence of these circuits with the task-negative brain networks.

Transient resting-state salience-limbic co-activation patterns in functional neurological disorders.

BACKGROUND: Functional neurological disorders were historically regarded as the manifestation of a dynamic brain lesion which might be linked to trauma or stress, although this association has not yet been directly tested yet. Analysing large-scale brain network dynamics at rest in relation to stress biomarkers assessed by salivary cortisol and amylase could provide new insights into the pathophysiology of functional neurological symptoms. METHODS: Case-control resting-state functional magnetic resonance imaging study of 79 patients with mixed functional neurological disorders (i.e., functional movement disorders, functional seizures, persistent perceptual-postural dizziness) and 74 age- and sex-matched healthy controls. Using a two-step hierarchical data-driven neuroimaging approach, static functional connectivity was first computed between 17 resting-state networks. Second, dynamic alterations in these networks were examined using co-activation pattern analysis. Using a partial least squares correlation analysis, the multivariate pattern of correlation between altered temporal characteristics and stress biomarkers as well as clinical scores were evaluated. RESULTS: Compared to healthy controls, patients presented with functional aberrancies of the salience-limbic network connectivity. Thus, the insula and amygdala were selected as seed-regions for the subsequent analyses. Insular co-(de)activation patterns related to the salience network, the somatomotor network and the default mode network were detected, which patients entered more frequently than controls. Moreover, an insular co-(de)activation pattern with subcortical regions together with a wide-spread co-(de)activation with diverse cortical networks was detected, which patients entered less frequently than controls. In patients, dynamic alterations conjointly correlated with amylase measures and duration of symptoms. CONCLUSION: The relationship between alterations in insular co-activation patterns, stress biomarkers and clinical data proposes inter-related mechanisms involved in stress regulation and functional (network) integration. In summary, altered functional brain network dynamics were identified in patients with functional neurological disorder supporting previously raised concepts of impaired attentional and interoceptive processing.

Ethnicity data resource in population-wide health records: completeness, coverage and granularity of diversity.

Intersectional social determinants including ethnicity are vital in health research. We curated a population-wide data resource of self-identified ethnicity data from over 60 million individuals in England primary care, linking it to hospital records. We assessed ethnicity data in terms of completeness, consistency, and granularity and found one in ten individuals do not have ethnicity information recorded in primary care. By linking to hospital records, ethnicity data were completed for 94% of individuals. By reconciling SNOMED-CT concepts and census-level categories into a consistent hierarchy, we organised more than 250 ethnicity sub-groups including and beyond "White", "Black", "Asian", "Mixed" and "Other, and found them to be distributed in proportions similar to the general population. This large observational dataset presents an algorithmic hierarchy to represent self-identified ethnicity data collected across heterogeneous healthcare settings. Accurate and easily accessible ethnicity data can lead to a better understanding of population diversity, which is important to address disparities and influence policy recommendations that can translate into better, fairer health for all.

Sex-specific resting state brain network dynamics in patients with major depressive disorder.

Sex-specific neurobiological changes have been implicated in Major Depressive Disorder (MDD). Dysfunctions of the default mode network (DMN), salience network (SN) and frontoparietal network (FPN) are critical neural characteristics of MDD, however, the potential moderating role of sex on resting-state network dynamics in MDD has not been sufficiently evaluated. Thus, resting-state functional magnetic resonance imaging (fMRI) data were collected from 138 unmedicated patients with first-episode MDD (55 males) and 243 healthy controls (HCs; 106 males). Recurring functional network co-activation patterns (CAPs) were extracted, and time spent in each CAP (the total amount of volumes associated to a CAP), persistence (the average number of consecutive volumes linked to a CAP), and transitions across CAPs involving the SN, DMN and FPN were quantified. Relative to HCs, MDD patients exhibited greater persistence in a CAP involving activation of the DMN and deactivation of the FPN (DMN + FPN-). In addition, relative to the sex-matched HCs, the male MDD group spent more time in two CAPs involving the SN and DMN (i.e., DMN + SN- and DMN-SN + ) and transitioned more frequently from the DMN + FPN- CAP to the DMN + SN- CAP relative to the male HC group. Conversely, the female MDD group showed less persistence in the DMN + SN- CAP relative to the female HC group. Our findings highlight that the imbalance between SN and DMN could be a neurobiological marker supporting sex differences in MDD. Moreover, the dominance of the DMN accompanied by the deactivation of the FPN could be a sex-independent neurobiological correlate related to depression.

Dynamic functional changes upon thalamotomy in essential tremor depend on baseline brain morphometry.

Patients with drug-resistant essential tremor (ET) may undergo Gamma Knife stereotactic radiosurgical thalamotomy (SRS-T), where the ventro-intermediate nucleus of the thalamus (Vim) is lesioned by focused beams of gamma radiations to induce clinical improvement. Here, we studied SRS-T impacts on left Vim dynamic functional connectivity (dFC, n = 23 ET patients scanned before and 1 year after intervention), and on surface-based morphometric brain features (n = 34 patients, including those from dFC analysis). In matched healthy controls (HCs), three dFC states were extracted from resting-state functional MRI data. In ET patients, state 1 spatial stability increased upon SRS-T (F1,22 = 19.13, p = 0.004). More frequent expression of state 3 over state 1 before SRS-T correlated with greater clinical recovery in a way that depended on the MR signature volume (t6 = 4.6, p = 0.004). Lower pre-intervention spatial variability in state 3 expression also did (t6 = - 4.24, p = 0.005) and interacted with the presence of familial ET so that these patients improved less (t6 = 4.14, p = 0.006). ET morphometric profiles showed significantly lower similarity to HCs in 13 regions upon SRS-T (z ≤ - 3.66, p ≤ 0.022), and a joint analysis revealed that before thalamotomy, morphometric similarity and states 2/3 mean spatial similarity to HCs were anticorrelated, a relationship that disappeared upon SRS-T (z ≥ 4.39, p < 0.001). Our results show that left Vim functional dynamics directly relates to upper limb tremor lowering upon intervention, while morphometry instead has a supporting role in reshaping such dynamics.

Problematic social media use is associated with depression and similar to behavioral addictions: Physiological and behavioral evidence.

While many studies have examined the relationship between problematic social media use (PSMU) and mental health disorders, little is known about reward responsiveness mechanisms that might be driving this relationship and the neurophysiological characteristics of PSMU. We surveyed 96 undergraduate students at a private liberal arts college in upstate NY. PSMU was assessed using the Social Media Disorder Scale. Fourteen Individuals endorsing in five or more and three or less categories on the Social Media Disorder Scale were offered and underwent resting state QEEG. Mental health was assessed with the Center for Epidemiological Studies Depression Scale Short Form, Social Interaction Anxiety Scale, Penn State Worry Questionnaire, the 10-item Perceived Stress Scale, and a locally developed measure of Substance Use Disorder. Reward and motivational systems were studied using the Brief Sensation Seeking Scale, Behavioral Inhibition/Behavioral Activation Scale, and Temporal Experience of Pleasure Scale. SMDS scores were associated with poorer mental health on all measures except substance use. SMDS scores were positively associated with the behavioral inhibition scale, and the anticipatory pleasure scale. QEEG results revealed a negative association of high PSMU and right central and frontal lobeta, right central beta, and a positive association with frontal alpha asymmetry. The study replicates findings that PSMU is associated with mental health issues. Further the pattern of reward response is different compared with other addictive behaviors. QEEG results are consistent with previous work in substance use and depression.

The arrow-of-time in neuroimaging time series identifies causal triggers of brain function.

Moving from association to causal analysis of neuroimaging data is crucial to advance our understanding of brain function. The arrow-of-time (AoT), that is, the known asymmetric nature of the passage of time, is the bedrock of causal structures shaping physical phenomena. However, almost all current time series metrics do not exploit this asymmetry, probably due to the difficulty to account for it in modeling frameworks. Here, we introduce an AoT-sensitive metric that captures the intensity of causal effects in multivariate time series, and apply it to high-resolution functional neuroimaging data. We find that causal effects underlying brain function are more distinctively localized in space and time than functional activity or connectivity, thereby allowing us to trace neural pathways recruited in different conditions. Overall, we provide a mapping of the causal brain that challenges the association paradigm of brain function.

Impact of a post-donation hemoglobin testing strategy on efficiency and safety of whole blood donation in England: A modeling study.

BACKGROUND: Deferrals due to low hemoglobin are time-consuming and costly for blood donors and donation services. Furthermore, accepting donations from those with low hemoglobin could represent a significant safety issue. One approach to reduce them is to use hemoglobin concentration alongside donor characteristics to inform personalized inter-donation intervals. STUDY DESIGN AND METHODS: We used data from 17,308 donors to inform a discrete event simulation model comparing personalized inter-donation intervals using "post-donation" testing (i.e., estimating current hemoglobin from that measured by a hematology analyzer at last donation) versus the current approach in England (i.e., pre-donation testing with fixed intervals of 12-weeks for men and 16-weeks for women). We reported the impact on total donations, low hemoglobin deferrals, inappropriate bleeds, and blood service costs. Personalized inter-donation intervals were defined using mixed-effects modeling to estimate hemoglobin trajectories and probability of crossing hemoglobin donation thresholds. RESULTS: The model had generally good internal validation, with predicted events similar to those observed. Over 1 year, a personalized strategy requiring ≥90% probability of being over the hemoglobin threshold, minimized adverse events (low hemoglobin deferrals and inappropriate bleeds) in both sexes and costs in women. Donations per adverse event improved from 3.4 (95% uncertainty interval 2.8, 3.7) under the current strategy to 14.8 (11.6, 19.2) in women, and from 7.1 (6.1, 8.5) to 26.9 (20.8, 42.6) in men. In comparison, a strategy incorporating early returns for those with high certainty of being over the threshold maximized total donations in both men and women, but was less favorable in terms of adverse events, with 8.4 donations per adverse event in women (7.0, 10,1) and 14.8 (12.1, 21.0) in men. DISCUSSION: Personalized inter-donation intervals using post-donation testing combined with modeling of hemoglobin trajectories can help reduce deferrals, inappropriate bleeds, and costs.

Harmonising electronic health records for reproducible research: challenges, solutions and recommendations from a UK-wide COVID-19 research collaboration.

BACKGROUND: The CVD-COVID-UK consortium was formed to understand the relationship between COVID-19 and cardiovascular diseases through analyses of harmonised electronic health records (EHRs) across the four UK nations. Beyond COVID-19, data harmonisation and common approaches enable analysis within and across independent Trusted Research Environments. Here we describe the reproducible harmonisation method developed using large-scale EHRs in Wales to accommodate the fast and efficient implementation of cross-nation analysis in England and Wales as part of the CVD-COVID-UK programme. We characterise current challenges and share lessons learnt. METHODS: Serving the scope and scalability of multiple study protocols, we used linked, anonymised individual-level EHR, demographic and administrative data held within the SAIL Databank for the population of Wales. The harmonisation method was implemented as a four-layer reproducible process, starting from raw data in the first layer. Then each of the layers two to four is framed by, but not limited to, the characterised challenges and lessons learnt. We achieved curated data as part of our second layer, followed by extracting phenotyped data in the third layer. We captured any project-specific requirements in the fourth layer. RESULTS: Using the implemented four-layer harmonisation method, we retrieved approximately 100 health-related variables for the 3.2 million individuals in Wales, which are harmonised with corresponding variables for > 56 million individuals in England. We processed 13 data sources into the first layer of our harmonisation method: five of these are updated daily or weekly, and the rest at various frequencies providing sufficient data flow updates for frequent capturing of up-to-date demographic, administrative and clinical information. CONCLUSIONS: We implemented an efficient, transparent, scalable, and reproducible harmonisation method that enables multi-nation collaborative research. With a current focus on COVID-19 and its relationship with cardiovascular outcomes, the harmonised data has supported a wide range of research activities across the UK.

Exploring the latent structure of behavior using the Human Connectome Project's data.

How behavior arises from brain physiology has been one central topic of investigation in neuroscience. Considering the recent interest in predicting behavior from brain imaging using open datasets, there is the need for a principled approach to the categorization of behavioral variables. However, this is not trivial, as the definitions of psychological constructs and their relationships-their ontology-are not always clear. Here, we propose to use exploratory factor analysis (EFA) as a data-driven approach to find robust and interpretable domains of behavior in the Human Connectome Project (HCP) dataset. Additionally, we explore the clustering of behavioral variables using consensus clustering. We find that four and five factors offer the best description of the data, a result corroborated by the consensus clustering. In the four-factor solution, factors for Mental Health, Cognition, Processing Speed, and Substance Use arise. With five factors, Mental Health splits into Well-Being and Internalizing. Clustering results show a similar pattern, with clusters for Cognition, Processing Speed, Positive Affect, Negative Affect, and Substance Use. The factor structure is replicated in an independent dataset using confirmatory factor analysis (CFA). We discuss how the content of the factors fits with previous conceptualizations of general behavioral domains.

Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants.

Metabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy in approximately 121,000 UK Biobank participants has recently been released as a community resource, comprising absolute concentrations and ratios of 249 circulating metabolites, lipids, and lipoprotein sub-fractions. Here we identify and characterise additional sources of unwanted technical variation influencing individual biomarkers in the data available to download from UK Biobank. These included sample preparation time, shipping plate well, spectrometer batch effects, drift over time within spectrometer, and outlier shipping plates. We developed a procedure for removing this unwanted technical variation, and demonstrate that it increases signal for genetic and epidemiological studies of the NMR metabolic biomarker data in UK Biobank. We subsequently developed an R package, ukbnmr, which we make available to the wider research community to enhance the utility of the UK Biobank NMR metabolic biomarker data and to facilitate rapid analysis.

Exploring the heterogeneous morphometric data in essential tremor with probabilistic modelling.

Essential tremor (ET) is a prevalent movement disorder characterized by marked clinical heterogeneity. Here, we explored the morphometric underpinnings of this cross-subject variability on a cohort of 34 patients with right-dominant drug-resistant ET and 29 matched healthy controls (HCs). For each brain region, group-wise morphometric data was modelled by a multivariate Gaussian to account for morphometric features' (co)variance. No group differences were found in terms of mean values, highlighting the limits of more basic group comparison approaches. Variance in surface area was higher in ET in the left lingual and caudal anterior cingulate cortices, while variance in mean curvature was lower in the right superior temporal cortex and pars triangularis, left supramarginal gyrus and bilateral paracentral gyrus. Heterogeneity further extended to the right putamen, for which a mixture of two Gaussians fitted the ET data better than a single one. Partial Least Squares analysis revealed the rich clinical relevance of the ET population's heterogeneity: first, increased head tremor and longer symptoms' duration were accompanied by broadly lower cortical gyrification. Second, more severe upper limb tremor and impairments in daily life activities characterized the patients whose morphometric profiles were more atypical compared to the average ET population, irrespective of the exact nature of the alterations. Our results provide candidate morphometric substrates for two different types of clinical variability in ET. They also demonstrate the importance of relying on analytical approaches that can efficiently handle multivariate data and enable to test more sophisticated hypotheses regarding its organization.

Using national electronic health records for pandemic preparedness: validation of a parsimonious model for predicting excess deaths among those with COVID-19-a data-driven retrospective cohort study.

OBJECTIVES: To use national, pre- and post-pandemic electronic health records (EHR) to develop and validate a scenario-based model incorporating baseline mortality risk, infection rate (IR) and relative risk (RR) of death for prediction of excess deaths. DESIGN: An EHR-based, retrospective cohort study. SETTING: Linked EHR in Clinical Practice Research Datalink (CPRD); and linked EHR and COVID-19 data in England provided in NHS Digital Trusted Research Environment (TRE). PARTICIPANTS: In the development (CPRD) and validation (TRE) cohorts, we included 3.8 million and 35.1 million individuals aged ≥30 years, respectively. MAIN OUTCOME MEASURES: One-year all-cause excess deaths related to COVID-19 from March 2020 to March 2021. RESULTS: From 1 March 2020 to 1 March 2021, there were 127,020 observed excess deaths. Observed RR was 4.34% (95% CI, 4.31-4.38) and IR was 6.27% (95% CI, 6.26-6.28). In the validation cohort, predicted one-year excess deaths were 100,338 compared with the observed 127,020 deaths with a ratio of predicted to observed excess deaths of 0.79. CONCLUSIONS: We show that a simple, parsimonious model incorporating baseline mortality risk, one-year IR and RR of the pandemic can be used for scenario-based prediction of excess deaths in the early stages of a pandemic. Our analyses show that EHR could inform pandemic planning and surveillance, despite limited use in emergency preparedness to date. Although infection dynamics are important in the prediction of mortality, future models should take greater account of underlying conditions.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Resting state brain dynamics: Associations with childhood sexual abuse and major depressive disorder.

Early life stress (ELS) and major depressive disorder (MDD) share neural network abnormalities. However, it is unclear how ELS and MDD may separately and/or jointly relate to brain networks, and whether neural differences exist between depressed individuals with vs without ELS. Moreover, prior work evaluated static versus dynamic network properties, a critical gap considering brain networks show changes in coordinated activity over time. Seventy-one unmedicated females with and without childhood sexual abuse (CSA) histories and/or MDD completed a resting state scan and a stress task in which cortisol and affective ratings were collected. Recurring functional network co-activation patterns (CAPs) were examined and time in CAP (number of times each CAP is expressed) and transition frequencies (transitioning between different CAPs) were computed. The effects of MDD and CSA on CAP metrics were examined and CAP metrics were correlated with depression and stress-related variables. Results showed that MDD, but not CSA, related to CAP metrics. Specifically, individuals with MDD (N = 35) relative to HCs (N = 36), spent more time in a posterior default mode (DMN)-frontoparietal network (FPN) CAP and transitioned more frequently between posterior DMN-FPN and prototypical DMN CAPs. Across groups, more time spent in a posterior DMN-FPN CAP and greater DMN-FPN and prototypical DMN CAP transition frequencies were linked to higher rumination. Imbalances between the DMN and the FPN appear central to MDD and might contribute to MDD-related cognitive dysfunction, including rumination. Unexpectedly, CSA did not modulate such dysfunctions, a finding that needs to be replicated by future studies with larger sample sizes.

Graph Theoretical Analysis of Structural Covariance Reveals the Relevance of Visuospatial and Attentional Areas in Essential Tremor Recovery After Stereotactic Radiosurgical Thalamotomy.

Essential tremor (ET) is the most common movement disorder. Its pathophysiology is only partially understood. Here, we leveraged graph theoretical analysis on structural covariance patterns quantified from morphometric estimates for cortical thickness, surface area, and mean curvature in patients with ET before and one year after (to account for delayed clinical effect) ventro-intermediate nucleus (Vim) stereotactic radiosurgical thalamotomy. We further contrasted the observed patterns with those from matched healthy controls (HCs). Significant group differences at the level of individual morphometric properties were specific to mean curvature and the post-/pre-thalamotomy contrast, evidencing brain plasticity at the level of the targeted left thalamus, and of low-level visual, high-level visuospatial and attentional areas implicated in the dorsal visual stream. The introduction of cross-correlational analysis across pairs of morphometric properties strengthened the presence of dorsal visual stream readjustments following thalamotomy, as cortical thickness in the right lingual gyrus, bilateral rostral middle frontal gyrus, and left pre-central gyrus was interrelated with mean curvature in the rest of the brain. Overall, our results position mean curvature as the most relevant morphometric feature to understand brain plasticity in drug-resistant ET patients following Vim thalamotomy. They also highlight the importance of examining not only individual features, but also their interactions, to gain insight into the routes of recovery following intervention.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.

BACKGROUND: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. METHODS AND FINDINGS: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. CONCLUSIONS: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

Investigating Genetic and Other Determinants of First-Onset Myocardial Infarction in Malaysia: Protocol for the Malaysian Acute Vascular Events Risk Study.

BACKGROUND: Although the burden of premature myocardial infarction (MI) is high in Malaysia, direct evidence on the determinants of MI in this multi-ethnic population remains sparse. OBJECTIVE: The Malaysian Acute Vascular Events Risk (MAVERIK) study is a retrospective case-control study established to investigate the genomic, lipid-related, and other determinants of acute MI in Malaysia. In this paper, we report the study protocol and early results. METHODS: By June 2019, we had enrolled approximately 2500 patients with their first MI and 2500 controls without cardiovascular disease, who were frequency-matched by age, sex, and ethnicity, from 17 hospitals in Malaysia. For each participant, serum and whole blood have been collected and stored. Clinical, demographic, and behavioral information has been obtained using a 200-item questionnaire. RESULTS: Tobacco consumption, a history of diabetes, hypertension, markers of visceral adiposity, indicators of lower socioeconomic status, and a family history of coronary disease were more prevalent in cases than in controls. Adjusted (age and sex) logistic regression models for traditional risk factors indicated that current smoking (odds ratio [OR] 4.11, 95% CI 3.56-4.75; P<.001), previous smoking (OR 1.34, 95% CI 1.12-1.60; P=.001), a history of high blood pressure (OR 2.13, 95% CI 1.86-2.44; P<.001), a history of diabetes mellitus (OR 2.72, 95% CI 2.34-3.17; P<.001), a family history of coronary heart disease (OR 1.28, 95% CI 1.07-1.55; P=.009), and obesity (BMI >30 kg/m2; OR 1.19, 95% CI 1.05-1.34; P=.009) were associated with MI in age- and sex-adjusted models. CONCLUSIONS: The MAVERIK study can serve as a useful platform to investigate genetic and other risk factors for MI in an understudied Southeast Asian population. It should help to hasten the discovery of disease-causing pathways and inform regionally appropriate strategies that optimize public health action. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/31885.

Morphometric features of drug-resistant essential tremor and recovery after stereotactic radiosurgical thalamotomy.

Essential tremor (ET) is the most common movement disorder. Its neural underpinnings remain unclear. Here, we quantified structural covariance between cortical thickness (CT), surface area (SA), and mean curvature (MC) estimates in patients with ET before and 1 year after ventro-intermediate nucleus stereotactic radiosurgical thalamotomy, and contrasted the observed patterns with those from matched healthy controls. For SA, complex rearrangements within a network of motion-related brain areas characterized patients with ET. This was complemented by MC alterations revolving around the left middle temporal cortex and the disappearance of positive-valued covariance across both modalities in the right fusiform gyrus. Recovery following thalamotomy involved MC readjustments in frontal brain centers, the amygdala, and the insula, capturing nonmotor characteristics of the disease. The appearance of negative-valued CT covariance between the left parahippocampal gyrus and hippocampus was another recovery mechanism involving high-level visual areas. This was complemented by the appearance of negative-valued CT/MC covariance, and positive-valued SA/MC covariance, in the right inferior temporal cortex and bilateral fusiform gyrus. Our results demonstrate that different morphometric properties provide complementary information to understand ET, and that their statistical cross-dependences are also valuable. They pinpoint several anatomical features of the disease and highlight routes of recovery following thalamotomy.