Disrupting the epileptogenic network with stereoelectroencephalography-guided radiofrequency thermocoagulation.

Stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RF-TC) is a treatment option for focal drug-resistant epilepsy. In previous studies, this technique has shown seizure reduction by ≥50% in 50% of patients at 1 year. However, the relationship between the location of the ablation within the epileptogenic network and clinical outcomes remains poorly understood. Seizure outcomes were analyzed for patients who underwent SEEG-guided RF-TC and across subgroups depending on the location of the ablation within the epileptogenic network, defined as SEEG sites involved in seizure generation and spread. Eighteen patients who had SEEG-guided RF-TC were included. SEEG-guided seizure-onset zone ablation (SEEG-guided SOZA) was performed in 12 patients, and SEEG-guided partial seizure-onset zone ablation (SEEG-guided P-SOZA) in 6 patients. The early spread was ablated in three SEEG-guided SOZA patients. Five patients had ablation of a lesion. The seizure freedom rate in the cohort ranged between 22% and 50%, and the responder rate between 67% and 85%. SEEG-guided SOZA demonstrated superior results for both outcomes compared to SEEG-guided P-SOZA at 6 months (seizure freedom p = .294, responder rate p = .014). Adding the early spread ablation to SEEG-guided SOZA did not increase seizure freedom rates but exhibited comparable effectiveness regarding responder rates, indicating a potential network disruption.

Optimal hippocampal targeting in responsive neurostimulation for mesial temporal lobe epilepsy.

OBJECTIVE: The aim of this study was to identify features of responsive neurostimulation (RNS) lead configuration and contact placement associated with greater seizure reduction in mesial temporal lobe epilepsy (MTLE). METHODS: A single-center series of patients with MTLE treated with RNS were retrospectively analyzed to assess the relationship between anatomical targeting and seizure reduction. Targeting was determined according to both the preoperatively conceived lead configuration and the actual placement of RNS contacts. Three lead configurations were used: 1) single bilateral, with 1 depth lead in each hippocampus; 2) single unilateral, with 1 hippocampal depth lead and another implant outside the mesial temporal lobe; and 3) dual unilateral, with 2 leads in 1 hippocampus. Contact placement on postoperative imaging was measured according to the number of hippocampal contacts per targeted hippocampus (contact density) and per patient (contact count), distribution throughout the hippocampus, and proximity to the anteromedial hippocampus. RESULTS: Dual unilateral lead placement resulted in significantly higher hippocampal contact density compared with the single hippocampal approaches, but only showed a nonsignificant trend toward a higher rate of response. However, those patients with more than 4 contacts in a single hippocampus, achievable only with dual unilateral leads, had a significantly higher rate of response. The higher likelihood of response was poorly explained by more widespread hippocampal coverage, but well correlated with proximity to the anteromedial hippocampus. CONCLUSIONS: Dual unilateral hippocampal implantation increased RNS contact density in patients with unilateral MTLE, which contributed to improved outcomes, not by stimulating more of the hippocampus, but instead by being more likely to stimulate a latent subtarget in the anterior hippocampus. It remains to be explored whether a single electrode targeted selectively to this region would also result in improved outcomes.

Teaching NeuroImage: Unilateral Primary Angiitis of the CNS.

A 48-year-old woman was referred with an 18-year history of focal-onset seizures. She also reported years-long slowly progressive right-sided weakness that was corroborated on examination. Repeated brain MRIs over 15 years showed multifocal left hemispheric T2 fluid-attenuated inversion recovery-hyperintense lesions with patchy enhancement and microhemorrhages, no diffusion restriction, and a left cerebellar infarct (Figure 1, A-F). Only 2 nonspecific white matter lesions were seen contralaterally, indicating largely unihemispheric disease. Differential diagnosis included unilateral primary angiitis of the CNS (PACNS), Rasmussen encephalitis, and myelin oligodendrocyte glycoprotein antibody-associated disease.1 Serum and CSF testing for autoimmune, infectious, and malignant etiologies and whole-body fluorodeoxyglucose-PET, whole-exome genetic sequencing, and MR vessel-wall imaging were nondiagnostic. Brain biopsy revealed vasculitis (Figure 2, A-F), and the patient was diagnosed with unilateral PACNS. Treatment with mycophenolate mofetil has been initiated. Unilateral PACNS is a rare unihemispheric disease characterized by an indolent course and seizures, recognition of which is critical to accurate diagnosis.1,2.

Spinal Nerve Root Stimulation for Chronic Pain: A Systematic Review.

OBJECTIVE: Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being stimulation of the dorsal columns; however, certain neuropathic pain areas involve dermatomes that are suboptimally covered by SCS. Stimulation of the spinal nerve roots has the advantage of targeting one or several dermatomes at the same time. The aim of this systematic review is to investigate the efficacy of spinal nerve root stimulation (SNRS) for chronic pain disorders. MATERIALS AND METHODS: A detailed literature review was performed through the Ovid Embase and MEDLINE data bases in addition to reference searching. Gray literature was included by searching through common search engines using a simplified search strategy. Studies included were focused on adult patients (aged >18 years), diagnosis of chronic pain syndrome (including but not limited to complex regional pain syndrome, persistent spinal pain syndrome, neuropathic pain secondary to trauma or infection, postherpetic pain, and cancer pain). Patients must have undergone SNRS insertion, with ≥six months of documented pain intensity scores on follow-up. RESULTS: A total of 40 studies underwent full text review, and 13 articles were included in final analysis. Mean preoperative pain intensity was 8.14 ± 0.74 on the visual analog scale, whereas mean postoperative pain intensity at one year was 3.18 ± 1.44. Of 119 patients, 83 (70%) achieved ≥50% reduction in pain intensity after SNRS, whereas 36 (30%) achieved <50% reduction in pain intensity. Only three studies assessed changes in analgesia medication dose and reported morphine equivalent doses varied by case series. Overall, there was a trend toward a reduction in analgesia medications in the postoperative period. CONCLUSIONS: SNRS led to a mean 44% reduction in pain intensity, with a low level of certainty. In addition, there is some evidence to suggest that using SNRS is associated with reduced use of analgesics, including morphine and gabapentin.

Serological assays for differentiating natural COVID-19 infection from vaccine induced immunity.

BACKGROUND: Natural SARS-CoV-2 infection may elicit antibodies to a range of viral proteins including non-structural protein ORF8. RNA, adenovirus vectored and sub-unit vaccines expressing SARS-CoV-2 spike would be only expected to elicit S-antibodies and antibodies to distinct domains of nucleocapsid (N) protein may reliably differentiate infection from vaccine-elicited antibody. However, inactivated whole virus vaccines may potentially elicit antibody to wider range of viral proteins, including N protein. We hypothesized that antibody to ORF8 protein will discriminate natural infection from vaccination irrespective of vaccine type. METHODS: We optimized and validated the anti-ORF8 and anti-N C-terminal domain (NCTD) ELISA assays using sera from pre-pandemic, RT-PCR confirmed natural infection sera and BNT162b2 (BNT) or CoronaVac vaccinees. We then applied these optimized assays to a cohort of blood donor sera collected in April-July 2022 with known vaccination and self-reported infection status. RESULTS: We optimized cut-off values for the anti-ORF8 and anti-N-CTD IgG ELISA assays using receiver-operating-characteristic (ROC) curves. The sensitivity of the anti-ORF8 and anti-N-CTD ELISA for detecting past infection was 83.2% and 99.3%, respectively. Specificity of anti-ORF8 ELISA was 96.8 % vs. the pre-pandemic cohort or 93% considering the pre-pandemic and vaccine cohorts together. The anti-N-CTD ELISA specificity of 98.9% in the pre-pandemic cohort, 93% in BNT vaccinated and only 4 % in CoronaVac vaccinated cohorts. Anti-N-CTD antibody was longer-lived than anti-ORF8 antibody after natural infection. CONCLUSIONS: Anti-N-CTD antibody assays provide good discrimination between natural infection and vaccination in BNT162b2 vaccinated individuals. Anti-ORF8 antibody can help discriminate infection from vaccination in either type of vaccine and help estimate infection attack rates (IAR) in communities.

Optimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation.

Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]: 1.50% (95% confidence interval 1.17-1.80%); relative risk [RR]: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: -1.08% (-1.55%, -0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality.

Lack of spontaneous typical seizures during intracranial monitoring with stereo-electroencephalography.

OBJECTIVE: In the presurgical evaluation of patients with drug-resistant epilepsy (DRE), occasionally, patients do not experience spontaneous typical seizures (STS) during a stereo-electroencephalography (SEEG) study, which limits its effectiveness. We sought to identify risk factors for patients who did not have STS during SEEG and to analyze the clinical outcomes for this particular set of patients. METHODS: We conducted a retrospective analysis of all patients with DRE who underwent depth electrode implantation and SEEG recordings between January 2013 and December 2018. RESULTS: SEEG was performed in 155 cases during this period. 11 (7.2%) did not experience any clinical seizures (non-STS group), while 143 experienced at least one patient-typical seizure during admission (STS group). No significant differences were found between STS and non-STS groups in terms of patient demographics, lesional/non-lesional epilepsy ratio, pre-SEEG seizure frequency, number of ASMs used, electrographic seizures or postoperative seizure outcome in those who underwent resective surgery. Statistically significant differences were found in the average number of electrodes implanted (7.0 in the non-STS group vs. 10.2 in STS), days in Epilepsy Monitoring Unit (21.8 vs. 12.8 days) and the number of cases that underwent resective surgery following SEEG (27.3% vs. 60.8%), respectively. The three non-STS patients (30%) who underwent surgery, all had their typical seizures triggered during ECS studies. Three cases were found to have psychogenic non-epileptic seizures. None of the patients in the non-STS group were offered neurostimulation devices. Five of the non-STS patients experienced transient seizure improvement following SEEG. SIGNIFICANCE: We were unable to identify any factors that predicted lack of seizures during SEEG recordings. Resective surgery was only offered in cases where ECS studies replicated patient-typical seizures. Larger datasets are required to be able to identify factors that predict which patients will fail to develop seizures during SEEG.

Involvement of the posterior cingulate gyrus in temporal lobe epilepsy: A study using stereo-EEG.

OBJECTIVE: To analyze the involvement of the posterior cingulate gyrus (PCG) during mesial temporal lobe seizures (MTLS). METHODS: We retrospectively reviewed the stereo-EEG (SEEG) recordings of patients with MTLS performed in our institution from February 2013 to December 2020. Only patients who had electrode implantation in the PCG were included. Patients with lesions that could potentially alter the seizure spread pathways were excluded. We assessed the propagation patterns of MTLS with respect to the different structures sampled. RESULTS: Nine of 97 patients who had at least one seizure originating in the mesial temporal region met the inclusion criteria. A total of 174 seizures were analyzed. The PCG was the first site of propagation in most of the cases (8/9 patients and 77.5% of seizures, and 7/8 patients and 65.6% of seizures after excluding an outlier patient). The fastest propagation times were towards the contralateral mesial temporal region and ipsilateral PCG. Seven patients underwent standard anterior temporal lobectomy and, of these, all but one were Engel 1 at last follow up. CONCLUSION: We found the PCG to be the first propagation site of MTLS in this group of patients. These results outline the relevance of the PCG in SEEG planning strategies. Further investigations are needed to corroborate whether fast propagation to the PCG predicts a good surgical outcome.

Antibacterial efficacy of an ultra-short palmitoylated random peptide mixture in mouse models of infection by carbapenem-resistant Klebsiella pneumoniae.

Indiscriminate use of antibiotics has imposed a selective pressure for the rapid rise in bacterial resistance, creating an urgent need for novel therapeutics for managing bacterial infectious diseases while counteracting bacterial resistance. Carbapenem-resistant Klebsiella pneumoniae strains have become a major challenge in modern medicine due to their ability to cause an array of severe infections. Recently, we have shown that the 20-mer random peptide mixtures are effective therapeutics against three ESKAPEE pathogens. Here, we evaluated the toxicity, biodistribution, bioavailability, and efficacy of the ultra-short palmitoylated 5-mer phenylalanine:lysine (FK5P) random peptide mixtures against multiple clinical isolates of carbapenem-resistant K. pneumoniae and K. oxytoca. We demonstrate the FK5P rapidly and effectively killed various strains of K. pneumoniae, inhibited the formation of biofilms, and disrupted mature biofilms. FK5P displayed strong toxicity profiles both in vitro and in mice, with prolonged favorable biodistribution and a long half-life. Significantly, FK5P reduced the bacterial burden in mouse models of acute pneumonia and bacteremia and increased the survival rate in a mouse model of bacteremia. Our results demonstrate that FK5P is a safe and promising therapy against Klebsiella species as well as other ESKAPEE pathogens.

A population-averaged structural connectomic brain atlas dataset from 422 HCP-aging subjects.

Population-averaged brain atlases, that are represented in a standard space with anatomical labels, are instrumental tools in neurosurgical planning and the study of neurodegenerative conditions. Traditional brain atlases are primarily derived from anatomical scans and contain limited information regarding the axonal organization of the white matter. With the advance of diffusion MRI that allows the modeling of fiber orientation distribution (FOD) in the brain tissue, there is an increasing interest for a population-averaged FOD template, especially based on a large healthy aging cohort, to offer structural connectivity information for connectomic surgery and analysis of neurodegeneration. The dataset described in this article contains a set of multi-contrast structural connectomic MRI atlases, including T1w, T2w, and FOD templates, along with the associated whole brain tractograms. The templates were made using multi-contrast group-wise registration based on 3T MRIs of 422 Human Connectome Project in Aging (HCP-A) subjects. To enhance the usability, probabilistic tissue maps and segmentation of 22 subcortical structures are provided. Finally, the subthalamic nucleus shown in the atlas is parcellated into sensorimotor, limbic, and associative sub-regions based on their structural connectivity to facilitate the analysis and planning of deep brain stimulation procedures. The dataset is available on the OSF Repository: https://osf.io/p7syt.

The Human Cytomegalovirus Latency-Associated Gene Product Latency Unique Natural Antigen Regulates Latent Gene Expression.

Human cytomegalovirus (HCMV) infection can lead to either lytic or latent infection, which is dependent on the regulation of the viral major immediate early promoter (MIEP). Suppression of the MIEP is a pre-requisite for latency and is driven by repressive epigenetic modifications at the MIEP during latent infection. However, other viral genes are expressed during latency and this is correlated with activatory epigenetic modifications at latent gene promoters. Yet the molecular basis of the differential regulation of latent and lytic gene expression by epigenetics is unclear. LUNA, a latent viral transcript, has been suggested to be important for HCMV latency and has also been shown to be important for efficient reactivation likely through its known deSUMOylase activity. Intriguingly, we and others have also observed that LUNA enhances latency-associated expression of the viral UL138 gene. Here, we show that in the absence of LUNA, the expression of multiple latency-associated transcripts is reduced during latent infection, which is correlated with a lack of activatory marks at their promoters. Interestingly, we also show that LUNA interacts with the hematopoietic transcription factor GATA-2, which has previously been shown to bind to a number of latency-associated gene promoters, and that this interaction is dependent on the deSUMOylase domain of LUNA. Finally, we show that the deSUMOylase activity of LUNA is required for the establishment and/or maintenance of an open chromatin configuration around latency-associated gene promoters. As such, LUNA plays a key role in efficient latency-associated viral gene expression and carriage of viral genome during latent carriage.

The quorum-sensing peptidic inhibitor rescues host immune system eradication: A novel infectivity mechanism.

Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogen Bacillus cereus (Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell-cell signaling peptide PapR7 regulate virulence gene expression in response to fluctuations in population density, i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to affect the host immune system. Here, we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins similarly to the profile that was observed for isogenic strains. Our findings provide evidence that Bc infectivity is regulated by QS circuit-mediated destruction of host immunity, thus reveal a interesting strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes a readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.

A method for chronic and semi-chronic microelectrode array implantation in deep brain structures using image guided neuronavigation.

BACKGROUND: Accurate targeting of brain structures for in-vivo electrophysiological recordings is essential for basic as well as clinical neuroscience research. Although methodologies for precise targeting and recording from the cortical surface are abundant, such protocols are scarce for deep brain structures. NEW METHOD: We have incorporated stable fiducial markers within a custom cranial cap for improved image-guided neuronavigation targeting of subcortical structures in macaque monkeys. Anchor bolt chambers allowed for a minimally invasive entrance into the brain for chronic recordings. A 3D-printed microdrive allowed for semi-chronic applications. RESULTS: We achieved an average Euclidean targeting error of 1.6 mm and a radial error of 1.2 mm over three implantations in two animals. Chronic and semi-chronic implantations allowed for recording of extracellular neuronal activity, with single-neuron activity examples shown from one macaque monkey. COMPARISON WITH EXISTING METHOD(S): Traditional stereotactic methods ignore individual anatomical variability. Our targeting approach allows for a flexible, subject-specific surgical plan with targeting errors lower than what is reported in humans, and equal to or lower than animal models using similar methods. Utilizing an anchor bolt as a chamber reduced the craniotomy size needed for electrode implantation, compared to conventional large access chambers which are prone to infection. Installation of an in-house, 3D-printed, screw-to-mount mechanical microdrive is in contrast to existing semi-chronic methods requiring fabrication, assembly, and installation of complex parts. CONCLUSIONS: Leveraging commercially available tools for implantation, our protocol decreases the risk of infection from open craniotomies, and improves the accuracy of chronic electrode implantations targeting deep brain structures in large animal models.

Magnetic resonance imaging datasets with anatomical fiducials for quality control and registration.

Tools available for reproducible, quantitative assessment of brain correspondence have been limited. We previously validated the anatomical fiducial (AFID) placement protocol for point-based assessment of image registration with millimetric (mm) accuracy. In this data descriptor, we release curated AFID placements for some of the most commonly used structural magnetic resonance imaging datasets and templates. The release of our accurate placements allows for rapid quality control of image registration, teaching neuroanatomy, and clinical applications such as disease diagnosis and surgical targeting. We release placements on individual subjects from four datasets (N = 132 subjects for a total of 15,232 fiducials) and 14 brain templates (4,288 fiducials), totalling more than 300 human rater hours of annotation. We also validate human rater accuracy of released placements to be within 1 - 2 mm (using more than 45,000 Euclidean distances), consistent with prior studies. Our data is compliant with the Brain Imaging Data Structure allowing for facile incorporation into neuroimaging analysis pipelines.

Convex Optimization for Nonequilibrium Steady States on a Hybrid Quantum Processor.

Finding the transient and steady state properties of open quantum systems is a central problem in various fields of quantum technologies. Here, we present a quantum-assisted algorithm to determine the steady states of open system dynamics. By reformulating the problem of finding the fixed point of Lindblad dynamics as a feasibility semidefinite program, we bypass several well-known issues with variational quantum approaches to solving for steady states. We demonstrate that our hybrid approach allows us to estimate the steady states of higher dimensional open quantum systems and discuss how our method can find multiple steady states for systems with symmetries.

Current and Emerging Imaging Techniques for Neurofibromatosis Type 1-Associated Cutaneous Neurofibromas.

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

PROTEUS Study: A Prospective Randomized Controlled Trial Evaluating the Use of Artificial Intelligence in Stress Echocardiography.

BACKGROUND: Stress echocardiography (SE) is one of the most commonly used diagnostic imaging tests for coronary artery disease (CAD) but requires clinicians to visually assess scans to identify patients who may benefit from invasive investigation and treatment. EchoGo Pro provides an automated interpretation of SE based on artificial intelligence (AI) image analysis. In reader studies, use of EchoGo Pro when making clinical decisions improves diagnostic accuracy and confidence. Prospective evaluation in real world practice is now important to understand the impact of EchoGo Pro on the patient pathway and outcome. METHODS: PROTEUS is a randomized, multicenter, 2-armed, noninferiority study aiming to recruit 2,500 participants from National Health Service (NHS) hospitals in the UK referred to SE clinics for investigation of suspected CAD. All participants will undergo a stress echocardiogram protocol as per local hospital policy. Participants will be randomized 1:1 to a control group, representing current practice, or an intervention group, in which clinicians will receive an AI image analysis report (EchoGo Pro, Ultromics Ltd, Oxford, UK) to use during image interpretation, indicating the likelihood of severe CAD. The primary outcome will be appropriateness of clinician decision to refer for coronary angiography. Secondary outcomes will assess other health impacts including appropriate use of other clinical management approaches, impact on variability in decision making, patient and clinician qualitative experience and a health economic analysis. DISCUSSION: This will be the first study to assess the impact of introducing an AI medical diagnostic aid into the standard care pathway of patients with suspected CAD being investigated with SE. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT05028179, registered on 31 August 2021; ISRCTN: ISRCTN15113915; IRAS ref: 293515; REC ref: 21/NW/0199.

Real-world COVID-19 vaccine effectiveness against the Omicron BA.2 variant in a SARS-CoV-2 infection-naive population.

The SARS-CoV-2 Omicron variant has demonstrated enhanced transmissibility and escape of vaccine-derived immunity. Although first-generation vaccines remain effective against severe disease and death, robust evidence on vaccine effectiveness (VE) against all Omicron infections, irrespective of symptoms, remains sparse. We used a community-wide serosurvey with 5,310 subjects to estimate how vaccination histories modulated risk of infection in infection-naive Hong Kong during a large wave of Omicron BA.2 epidemic in January-July 2022. We estimated that Omicron infected 45% (41-48%) of the local population. Three and four doses of BNT162b2 or CoronaVac were effective against Omicron infection 7 days after vaccination (VE of 48% (95% credible interval 34-64%) and 69% (46-98%) for three and four doses of BNT162b2, respectively; VE of 30% (1-66%) and 56% (6-97%) for three and four doses of CoronaVac, respectively). At 100 days after immunization, VE waned to 26% (7-41%) and 35% (10-71%) for three and four doses of BNT162b2, and to 6% (0-29%) and 11% (0-54%) for three and four doses of CoronaVac. The rapid waning of VE against infection conferred by first-generation vaccines and an increasingly complex viral evolutionary landscape highlight the necessity for rapidly deploying updated vaccines followed by vigilant monitoring of VE.