Heterogenous brain activations across individuals localize to a common network.

Task functional magnetic resonance imaging research has generally shielded away from studying individuals due to the low reproducibility. Here, we propose that heterogeneous brain activations across individuals localize to a common network. To test this hypothesis, we use working memory (WM) as our example. First, we showed that discrete-brain-based reproducibility of brain activation during WM across individuals was low. Then, we used activation network mapping (ANM) technique to identify each individual's brain network of WM and found that network-based reproducibility was rather high. Prediction analyses using machine learning algorithms indicated that individual WM networks identified via ANM can predict WM behavioral performance. This predictive ability even outperformed that of brain activations. Our study provides a new explanation on the low reproducibility of brain activations across individuals. The results suggest that ANM can be used to identify individual brain networks of cognitive processes, thus promising broad potential applications.

Mapping lesion-related human aggression to a common brain network.

BACKGROUND: Aggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients for which neural mechanisms are unclear and treatment options are limited. METHODS: Using recently validated lesion network mapping technique, we derived an aggression associated network by analyzing 182 patients who had suffered penetrating head injuries during their service in the Vietnam War. To test whether damage to this lesion-derived network would increase the risk of aggression related neuropsychiatric symptoms, we used the Harvard Lesion Repository (N = 928). To explore potential therapeutic relevance of this network, we used an independent Deep brain stimulation dataset of 25 patients with epilepsy, in which irritability and aggression are known potential side effects. RESULTS: We found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific brain network defined by functional connectivity to a hub region in the right prefrontal cortex (PFC). This network involves positive connectivity to the ventromedial PFC, dorsolateral PFC, frontal pole, posterior cingulate cortex, anterior cingulate cortex, temporal-parietal junction, and lateral temporal lobe and negative connectivity to the amygdala, hippocampus, insula, and visual cortex. Among all 25 neuropsychiatric symptoms included in the Harvard Lesion Repository, criminality demonstrated the most alignment with our aggression associated network. DBS site connectivity to this same network was associated with increased irritability. CONCLUSIONS: We conclude that brain lesions associated with aggression map to a specific human brain circuit, and the functionally connected regions in this circuit provide testable targets for therapeutic neuromodulation.

Prediction of stroke severity: systematic evaluation of lesion representations.

OBJECTIVE: To systematically evaluate which lesion-based imaging features and methods allow for the best statistical prediction of poststroke deficits across independent datasets. METHODS: We utilized imaging and clinical data from three independent datasets of patients experiencing acute stroke (N1 = 109, N2 = 638, N3 = 794) to statistically predict acute stroke severity (NIHSS) based on lesion volume, lesion location, and structural and functional disconnection with the lesion location using normative connectomes. RESULTS: We found that prediction models trained on small single-center datasets could perform well using within-dataset cross-validation, but results did not generalize to independent datasets (median R2 N1 = 0.2%). Performance across independent datasets improved using large single-center training data (R2 N2 = 15.8%) and improved further using multicenter training data (R2 N3 = 24.4%). These results were consistent across lesion attributes and prediction models. Including either structural or functional disconnection in the models outperformed prediction based on volume or location alone (P < 0.001, FDR-corrected). INTERPRETATION: We conclude that (1) prediction performance in independent datasets of patients with acute stroke cannot be inferred from cross-validated results within a dataset, as performance results obtained via these two methods differed consistently, (2) prediction performance can be improved by training on large and, importantly, multicenter datasets, and (3) structural and functional disconnection allow for improved prediction of acute stroke severity.

The past, present, and future of the brain imaging data structure (BIDS).

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Treating cancer-associated venous thromboembolism: A practical approach.

Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with cancer. Both cancer and its treatments increase the risk of developing VTE. Specific cancer types and individual patient comorbidities increase the risk of developing cancer-associated VTE, and the risk of bleeding is increased with anticoagulation therapies. The aims of this article are to summarize the latest evidence for treating cancer-associated VTE, discuss the practical considerations involved, and share best practices for VTE treatment in patients with cancer. The article pays particular attention to challenging contexts including patients with brain, lung, gastrointestinal, and genitourinary tumors and those with hematological malignancies. Furthermore, the article summarizes specific clinical scenarios that require additional treatment considerations, including extremes of body weight, nausea and gastrointestinal disturbances, compromised renal function, and anemia, and touches upon the relevance of drug-drug interactions. Historically, vitamin K antagonists and low-molecular-weight heparins (LMWHs) have been used as therapy for cancer-associated VTE. The development of direct oral anticoagulants has provided additional treatment options, which, in certain instances, offer advantages over LMWHs. There are numerous factors that need to be considered when treating cancer-associated VTE, and although various treatment guidelines are helpful, they do not reflect each unique scenario that may arise in clinical practice. This article provides a summary of the latest evidence and a practical approach for treating cancer-associated VTE.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

BACKGROUND: Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. METHODS: A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). RESULTS: A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. CONCLUSIONS: Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals.

Immunization with mosaic-8b (nanoparticles presenting 8 SARS-like betacoronavirus [sarbecovirus] receptor-binding domains [RBDs]) elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated the effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding the greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate mapping, in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19-vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.

Using 30-day modified rankin scale score to predict 90-day score in patients with intracranial hemorrhage: Derivation and validation of prediction model.

Whether 30-day modified Rankin Scale (mRS) scores can predict 90-day scores is unclear. This study derived and validated a model to predict ordinal 90-day mRS score in an intracerebral hemorrhage (ICH) population using 30-day mRS values and routinely available baseline variables. Adults enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) trial between May 2011 and September 2015 with acute ICH, who were alive at 30 days and had mRS scores reported at both 30 and 90 days were included in this post-hoc analysis. A proportional odds regression model for predicting ordinal 90-day mRS scores was developed and internally validated using bootstrapping. Variables in the model included: mRS score at 30 days, age (years), hematoma volume (cm3), hematoma location (deep [basal ganglia, thalamus], lobar, or infratentorial), presence of intraventricular hemorrhage (IVH), baseline Glasgow Coma Scale (GCS) score, and National Institutes of Health Stroke Scale (NIHSS) score at randomization. We assessed model fit, calibration, discrimination, and agreement (ordinal, dichotomized functional independence), and EuroQol-5D ([EQ-5D] utility weighted) between predicted and observed 90-day mRS. A total of 898/1000 participants were included. Following bootstrap internal validation, our model (calibration slope = 0.967) had an optimism-corrected c-index of 0.884 (95% CI = 0.873-0.896) and R2 = 0.712 for 90-day mRS score. The weighted ĸ for agreement between observed and predicted ordinal 90-day mRS score was 0.811 (95% CI = 0.787-0.834). Agreement between observed and predicted functional independence (mRS score of 0-2) at 90 days was 74.3% (95% CI = 69.9-78.7%). The mean ± SD absolute difference between predicted and observed EQ-5D-weighted mRS score was negligible (0.005 ± 0.145). This tool allows practitioners and researchers to utilize clinically available information along with the mRS score 30 days after ICH to reliably predict the mRS score at 90 days.

Localization of stuttering based on causal brain lesions.

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.

Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses.

Defending against future pandemics requires vaccine platforms that protect across a range of related pathogens. Nanoscale patterning can be used to address this issue. Here, we produce quartets of linked receptor-binding domains (RBDs) from a panel of SARS-like betacoronaviruses, coupled to a computationally designed nanocage through SpyTag/SpyCatcher links. These Quartet Nanocages, possessing a branched morphology, induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented in the vaccine. Equivalent antibody responses are raised to RBDs close to the nanocage or at the tips of the nanoparticle's branches. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increase the strength and breadth of an otherwise narrow immune response. A Quartet Nanocage including the Omicron XBB.1.5 'Kraken' RBD induced antibodies with binding to a broad range of sarbecoviruses, as well as neutralizing activity against this variant of concern. Quartet nanocages are a nanomedicine approach with potential to confer heterotypic protection against emergent zoonotic pathogens and facilitate proactive pandemic protection.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Network localization of pediatric lesion-induced dystonia.

Objective: Dystonia is a movement disorder defined by involuntary muscle contractions leading to abnormal postures or twisting and repetitive movements. Classically dystonia has been thought of as a disorder of the basal ganglia, but newer results in idiopathic dystonia and lesion-induced dystonia in adults point to broader motor network dysfunction spanning the basal ganglia, cerebellum, premotor cortex, sensorimotor, and frontoparietal regions. It is unclear whether a similar network is shared between different etiologies of pediatric lesion-induced dystonia. Methods: Three cohorts of pediatric patients with lesion-induced dystonia were identified. The lesion etiologies included hypoxia, kernicterus, and stroke versus comparison subjects with acquired lesions not associated with dystonia. Multivariate lesion-symptom mapping and lesion network mapping were used to evaluate the anatomy and networks associated with dystonia. Results: Multivariate lesion-symptom mapping showed that lesions of the putamen (stroke: r = 0.50, p <0.01; hypoxia, r = 0.64, p <0.001) and globus pallidus (kernicterus, r = 0.61, p <0.01) were associated with dystonia. Lesion network mapping using normative connectome data from healthy children demonstrated that these regional findings occurred within a common brain-wide network that involves the basal ganglia, anterior and medial cerebellum, and cortical regions that overlap the cingulo-opercular and somato-cognitive-action networks. Interpretation: We interpret these findings as novel evidence for a unified dystonia brain network that involves the somato-cognitive-action network, which is involved in higher order coordination of movement. Elucidation of this network gives insight into the functional origins of dystonia and provides novel targets to investigate for therapeutic intervention.

The Role of Direct Oral Anticoagulants in the Treatment of Cancer-Associated Venous Thromboembolism: Review by Middle East and North African Experts.

Venous thromboembolism is a leading cause of morbidity and mortality in patients with active cancer who require anticoagulation treatment. Choice of anticoagulant is based on careful balancing of the risks and benefits of available classes of treatment: vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Results from randomized controlled trials have shown the consistent efficacy of DOACs versus LMWH in the treatment of cancer-associated venous thromboembolism (VTE). However, increased major gastrointestinal bleeding was observed for edoxaban and rivaroxaban, but not apixaban, compared with LMWH dalteparin. Most guidelines recommend DOACs for the treatment of cancer-associated VTE in patients without gastrointestinal or genitourinary cancer, and with considerations for renal impairment and drug-drug interactions. These updates represent a major paradigm shift for clinicians in the Middle East and North Africa. The decision to prescribe a DOAC for a patient with cancer is not always straightforward, particularly in challenging subgroups of patients with an increased risk of bleeding. In patients with gastrointestinal malignancies who are at high risk of major gastrointestinal bleeds, apixaban may be the preferred DOAC; however, caution should be exercised if patients have upper or unresected lower gastrointestinal tumors. In patients with gastrointestinal malignancies and upper or unresected lower gastrointestinal tumors, LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable. In this review, we discuss the overall evidence for DOACs in the treatment of cancer-associated VTE and provide treatment suggestions for challenging subgroups of patients with cancer associated VTE.

Patients with cancer are at risk of blood clots forming in their veins, which can cause illness and death. To prevent such blood clots, most patients with cancer need anticoagulant therapy. There are three types of anticoagulants available for the treatment of cancer-associated blood clots in a vein, namely, vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Drug trials have shown that DOACs are more effective than LMWH; however, DOACs can have a greater risk of causing major gastrointestinal bleeding. Among DOACs, edoxaban and rivaroxaban are drugs associated with higher rates of gastrointestinal bleeding. Recently updated guidelines for doctors recommend that DOACs be used as the first treatment for patients with cancer at risk of blood clot formation in a vein. For doctors in the Middle East and North Africa, this new approach differs from existing practices. Notably, choosing a treatment also depends on the type of cancer, because gastrointestinal cancers and cancers of the genitals and urinary system have an especially high risk of gastrointestinal bleeding. The choice also depends on the presence of kidney problems, drug­drug interactions, and access to the drugs. Apixaban may be the preferred DOAC in patients with gastrointestinal cancer, but this drug should be used with care in patients with upper or unresected lower gastrointestinal tumors. For patients with upper or unresected lower gastrointestinal tumors, treatment with LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable.

Designed mosaic nanoparticles enhance cross-reactive immune responses in mice.

1Using computational methods, we designed 60-mer nanoparticles displaying SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) by (i) creating RBD sequences with 6 mutations in the SARS-COV-2 WA1 RBD that were predicted to retain proper folding and abrogate antibody responses to variable epitopes (mosaic-2COMs; mosaic-5COM), and (ii) selecting 7 natural sarbecovirus RBDs (mosaic-7COM). These antigens were compared with mosaic-8b, which elicits cross-reactive antibodies and protects from sarbecovirus challenges in animals. Immunizations in naïve and COVID-19 pre-vaccinated mice revealed that mosaic-7COM elicited higher binding and neutralization titers than mosaic-8b and related antigens. Deep mutational scanning showed that mosaic-7COM targeted conserved RBD epitopes. Mosaic-2COMs and mosaic-5COM elicited higher titers than homotypic SARS-CoV-2 Beta RBD-nanoparticles and increased potencies against some SARS-CoV-2 variants than mosaic-7COM. However, mosaic-7COM elicited more potent responses against zoonotic sarbecoviruses and highly mutated Omicrons. These results support using mosaic-7COM to protect against highly mutated SARS-CoV-2 variants and zoonotic sarbecoviruses with spillover potential.

Effectiveness and safety of anticoagulants among patients with venous thromboembolism and active cancer who also had prior bleed or prior renal disease.

OBJECTIVE: Patients with active cancer and venous thromboembolism (VTE) have elevated risk of recurrent VTE (rVTE) and major bleeding (MB). The risk is even higher within those with a prior bleeding event or renal disease. There is a need to understand the risk of rVTE and MB of commonly used anticoagulants among these high-risk patients. METHODS: VTE patients with active cancer and treated with apixaban, warfarin, or low molecular weight heparin (LMWH) within 30 days of VTE were identified from five claims databases in the United States. Inverse probability of treatment weighting (IPTW) was used to balance patient characteristics. The post-IPTW population was stratified by prior bleed or renal disease status. Cox proportional hazards models were used to evaluate interactions between treatment and prior bleed or renal disease on risk of rVTE and MB, with p value <.1 considered significant. RESULTS: Study criteria were met by 30,586 VTE cancer patients: 35.0% had prior bleed and 29.0% had renal disease. For apixaban, LMWH, and warfarin cohorts, the incidence (events per 100 person-years) of MB was higher in patients with prior bleed (17.48 vs 7.58, 25.61 vs 13.11, and 20.38 vs 8.97) or renal disease (15.79 vs 8.71, 22.11 vs 15.90, and 18.49 vs 10.39) vs those without the conditions. Generally, there were no significant interactions between anticoagulant use and prior bleed or renal disease on rVTE and MB (p for interaction >.1). CONCLUSION: The incidence of MB was higher among those with prior bleed or renal disease. Effects of apixaban, warfarin, or LMWH were generally consistent regardless of prior bleed or renal disease status.

Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: A tertiary health center's experience.

OBJECTIVE: Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored. METHODS: Retrospective chart review of new onset IESS patients (January 2019-May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider-, caregiver-, disease-related). RESULTS: Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p = .021), development delay (p = .007), developmental regression/stagnation (p = .021), ES intermixed with other seizures (p = .011), and nonclustered ES at onset (p = .005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p = .004) and nonclustered ES at onset (p = .003). Sources contributing to difficulties determining date of ES onset included disease-related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver-related factors (delayed diagnosis). SIGNIFICANCE: Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences.

Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals.

Immunization with mosaic-8b [60-mer nanoparticles presenting 8 SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs)] elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19 vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.