Treatment effects in epilepsy: a mathematical framework for understanding response over time.

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting over 65 million people worldwide. Treatment typically commences with the use of anti-seizure medications, including both mono- and poly-therapy. Should these fail, more invasive therapies such as surgery, electrical stimulation and focal drug delivery are often considered in an attempt to render the person seizure free. Although a significant portion ultimately benefit from these treatment options, treatment responses often fluctuate over time. The physiological mechanisms underlying these temporal variations are poorly understood, making prognosis a significant challenge when treating epilepsy. Here we use a dynamic network model of seizure transition to understand how seizure propensity may vary over time as a consequence of changes in excitability. Through computer simulations, we explore the relationship between the impact of treatment on dynamic network properties and their vulnerability over time that permit a return to states of high seizure propensity. For small networks we show vulnerability can be fully characterised by the size of the first transitive component (FTC). For larger networks, we find measures of network efficiency, incoherence and heterogeneity (degree variance) correlate with robustness of networks to increasing excitability. These results provide a set of potential prognostic markers for therapeutic interventions in epilepsy. Such markers could be used to support the development of personalized treatment strategies, ultimately contributing to understanding of long-term seizure freedom.

Number needed to treat with intravenous tenecteplase to reduce the need for mechanical thrombectomy in large vessel occlusion acute ischemic stroke patients: A retrospective look at real-world experience data.

OBJECTIVE: We sought to describe short term outcomes in patients with large vessel occlusion acute ischemic stroke (LVOAIS) who were treated with intravenous tenecteplase (TNK) as compared to alteplase (tPA), focusing on reduction in the need for mechanical thrombectomy (MT). BACKGROUND: In LVOAIS, TNK has shown improved reperfusion and outcomes with a similar safety profile to tPA. Ultra-early reperfusion has been described with TNK which would prevent the need for MT. We analyze the magnitude of this effect in a "real-world" setting. DESIGN/METHODS: In this retrospective study, demographic, clinical, and imaging information from patients with LVOAIS treated with intravenous thrombolysis was collected. Data was compared between the group treated with TNK and tPA. RESULTS: One hundred eighty-six patients met the criteria for the study. Of these,144patients received tPA and 42 received TNK. Nine had clinical improvement prior to groin puncture and did not require angiography. When combining the number of patients who had recanalization on angiography before MT and those who had clinical improvement prior to angiography, there were a total of 23 patients. This was noted in 9.7 % of patients who received tPA and 21.4 % of those who received TNK (p = 0.043). For patients treated with TNK we observed a rapid clinical improvement, improved NIHSS, improved functional outcomes and decreased length of stay compared to patients treated with tPA. For patients with spontaneous recanalization either angiographically or with clinical improvement from intravenous thrombolysis, MT may not be required. CONCLUSIONS: Intravenous TNK in patients with LVOAIS decreases the need for MT, and is associated with improved outcomes and reduced length of stay.

Estimating the likelihood of epilepsy from clinically noncontributory electroencephalograms using computational analysis: A retrospective, multisite case-control study.

OBJECTIVE: This study was undertaken to validate a set of candidate biomarkers of seizure susceptibility in a retrospective, multisite case-control study, and to determine the robustness of these biomarkers derived from routinely collected electroencephalography (EEG) within a large cohort (both epilepsy and common alternative conditions such as nonepileptic attack disorder). METHODS: The database consisted of 814 EEG recordings from 648 subjects, collected from eight National Health Service sites across the UK. Clinically noncontributory EEG recordings were identified by an experienced clinical scientist (N = 281; 152 alternative conditions, 129 epilepsy). Eight computational markers (spectral [n = 2], network-based [n = 4], and model-based [n = 2]) were calculated within each recording. Ensemble-based classifiers were developed using a two-tier cross-validation approach. We used standard regression methods to assess whether potential confounding variables (e.g., age, gender, treatment status, comorbidity) impacted model performance. RESULTS: We found levels of balanced accuracy of 68% across the cohort with clinically noncontributory normal EEGs (sensitivity =61%, specificity =75%, positive predictive value =55%, negative predictive value =79%, diagnostic odds ratio =4.64, area under receiver operated characteristics curve =.72). Group level analysis found no evidence suggesting any of the potential confounding variables significantly impacted the overall performance. SIGNIFICANCE: These results provide evidence that the set of biomarkers could provide additional value to clinical decision-making, providing the foundation for a decision support tool that could reduce diagnostic delay and misdiagnosis rates. Future work should therefore assess the change in diagnostic yield and time to diagnosis when utilizing these biomarkers in carefully designed prospective studies.

Circadian distribution of epileptiform discharges in epilepsy: Candidate mechanisms of variability.

Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy-so-called interictal epileptiform activity-with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.

Clinical, microbiological characteristics and predictors of mortality in patients with carbapenemase-producing Enterobacterales bloodstream infections: a multicentre study.

Objectives: To investigate the clinical, microbiological characteristics and outcomes of patients with bloodstream infections (BSI) due to carbapenemase-producing Enterobacterales (CPE). Methods: A multicentre retrospective observational study of patients with BSIs due to CPE admitted to six UK hospitals was conducted between 2011 and 2021. Multivariate analysis was used to identify factors predicting 30-day case fatality rate (CFR). Results: There were 84 episodes of CPE-BSIs, 37 (44%) due to OXA-48, 35 (42%) to metallo-betalactamases (MBL) and 12 (14%) to KPC. 63% of patients were male with a median age of 64 years. Common organisms included Klebsiella spp. (61%), Escherichia coli (20%) and Enterobacter spp. (13%). Urinary devices were more often involved in OXA-48 BSIs (12/37; 32%) compared to infections caused by MBL and KPC (4/35; 11% and 1/12; 8%; P = 0.046). In contrast, central venous catheters were more frequently present in KPC-BSIs (10/12; 92%) compared with OXA-48 and MBL (11/37; 30% and 20/35; 57%; P = 0.002). Effective definitive antimicrobials were received by 72/84 (86%) patients, comprising monotherapy (32/72; 44%) or combination therapy (40/72; 56%). 30-day case fatality rate (CFR) was 38%. Sepsis or septic shock was associated with death [OR 3.81 (CI 1.19-12.14), P = 0.024]. Conclusion: Strategies targeting high-risk patients and adherence to infection prevention bundles for urinary devices and central venous catheters can reduce OXA-48 and KPC-BSIs. Early recognition and management of severe sepsis, prompt initiation of appropriate antimicrobial therapy and development of novel antimicrobials are crucial to mitigate the high CFR associated with CPE-BSIs.

Classification of human chronotype based on fMRI network-based statistics.

Chronotype-the relationship between the internal circadian physiology of an individual and the external 24-h light-dark cycle-is increasingly implicated in mental health and cognition. Individuals presenting with a late chronotype have an increased likelihood of developing depression, and can display reduced cognitive performance during the societal 9-5 day. However, the interplay between physiological rhythms and the brain networks that underpin cognition and mental health is not well-understood. To address this issue, we use rs-fMRI collected from 16 people with an early chronotype and 22 people with a late chronotype over three scanning sessions. We develop a classification framework utilizing the Network Based-Statistic methodology, to understand if differentiable information about chronotype is embedded in functional brain networks and how this changes throughout the day. We find evidence of subnetworks throughout the day that differ between extreme chronotypes such that high accuracy can occur, describe rigorous threshold criteria for achieving 97.3% accuracy in the Evening and investigate how the same conditions hinder accuracy for other scanning sessions. Revealing differences in functional brain networks based on extreme chronotype suggests future avenues of research that may ultimately better characterize the relationship between internal physiology, external perturbations, brain networks, and disease.

Variation in Carotid Artery Stenosis Measurements Among Facilities Seeking Carotid Stenting Facility Accreditation.

BACKGROUND: Based on the inclusion criteria of clinical trials, the degree of cervical carotid artery stenosis is often used as an indication for stent placement in the setting of extracranial carotid atherosclerotic disease. However, the rigor and consistency with which stenosis is measured outside of clinical trials are unclear. In an agreement study using a cross-sectional sample, we compared the percent stenosis as measured by real-world physician operators to that measured by independent expert reviewers. METHODS: As part of the carotid stenting facility accreditation review, images were obtained from 68 cases of patients who underwent carotid stent placement. Data collected included demographics, stroke severity measures, and the documented degree of stenosis, termed operator-reported stenosis (ORS), by 34 operators from 14 clinical sites. The ORS was compared with reviewer-measured stenosis (RMS) as assessed by 5 clinicians experienced in treating carotid artery disease. RESULTS: The median ORS was 90.0% (interquartile range, 80.0%-90.0%) versus a median RMS of 61.1% (interquartile range, 49.8%-73.6%), with a median difference of 21.8% (interquartile range, 13.7%-34.4%), P<0.001. The median difference in ORS and RMS for asymptomatic versus symptomatic patients was not statistically different (24.6% versus 19.6%; P=0.406). The median difference between ORS and RMS for facilities granted initial accreditation was smaller compared with facilities whose accreditation was delayed (17.9% versus 25.5%, P=0.035). The intraclass correlation between ORS and RMS was 0.16, indicating poor agreement. If RMS measurements were used, 72% of symptomatic patients and 10% of asymptomatic patients in the population examined would meet the Centers for Medicare and Medicaid Services criteria for stent placement. CONCLUSIONS: Real-world operators tend to overestimate carotid artery stenosis compared with external expert reviewers. Measurements from facilities granted initial accreditation were closer to expert measurements than those from facilities whose accreditation was delayed. Since decisions regarding carotid revascularization are often based on percent stenosis, such measuring discrepancies likely lead to increased procedural utilization.

Case Report: A case of disseminated cutaneous listeriosis following appendicitis from Lao PDR.

Background: Listeria monocytogenes is a food-borne pathogen that is a rare cause of bacteraemia and meningitis in immunosuppressed patients, and carries a high mortality rate. Cutaneous manifestations of listeriosis are rare, and are usually associated with direct inoculation of the skin. Case: A 41-year-old woman who initially presented to a hospital in Laos with appendicitis was diagnosed with disseminated listeriosis with cutaneous involvement. Intra-abdominal pathology probably contributed to bacterial bloodstream invasion. Initial treatment with meropenem was switched to ampicillin based on best practice, however our patient died 5 days after diagnosis. Conclusions: This case highlights listeriosis as an important cause of mortality in low- and middle-income countries, exacerbated by poor availability of laboratory diagnostics and ineffective empiric antibiotic regimens. Improvements in food hygiene, surveillance, and increased laboratory capacity are important strategies to reduce rates of infection and clinical outcomes.

Nuclear Modification of Transverse Momentum Dependent Parton Distribution Functions by a Global QCD Analysis.

We perform the first simultaneous global QCD extraction of the transverse momentum dependent (TMD) parton distribution functions and the TMD fragmentation functions in nuclei. We have considered the world set of data from semi-inclusive electron-nucleus deep inelastic scattering and Drell-Yan dilepton production. In total, this data set consists of 90 data points from HERMES, Fermilab, RHIC, and LHC. Working at next-to-leading order and next-to-next-to-leading logarithmic accuracy, we achieve a χ^{2}/d.o.f.=1.196. In this analysis, we perform the first extraction of nuclear modified TMDs and compare these to those in free nucleons. We also make predictions for the ongoing JLab 12 GeV program and future electron-ion collider measurements.

Retrospective review of the epidemiology, microbiology, management and outcomes of intra-cranial abscesses at a neurosurgical tertiary referral centre, 2018-2020.

BACKGROUND: Intracranial abscesses are rare but serious, and are associated with significant morbidity and mortality. Due to both the rarity and severity of these infections, well-controlled trials have not been reported in the literature, and optimal management is a matter for expert opinion. Advances in surgical management have improved outcomes and increased rates of microbiological diagnosis. However, the approach to antimicrobial chemotherapy varies considerably, including the choice of antibiotic, the duration of treatment, and the timing of oral switch. METHODS: We conducted a retrospective review of 43 cases of intracranial abscesses from a large, tertiary neurosurgical centre in London, UK, between 2018 and 2020, including 29 primary intra-parenchymal abscesses, 11 subdural abscesses and 3 extradural abscesses. RESULTS: The majority of cases had surgical intervention; 6/43 (14%) required repeat intervention (all intra-parenchymal abscesses). A microbiological diagnosis was made in 83% of cases. Intravenous antibiotics were given for a median of 33 days (IQR 23-44 days), with a variable duration of oral follow-on antibiotics. Total duration of antibiotic treatment ranged from 0 to 467 days. Only three patients from our cohort are known to have died. CONCLUSION: Shorter courses of intravenous antibiotics for brain abscesses were not associated with increased mortality. In the absence of well-controlled trials, a national registry of intracranial abscesses would provide invaluable data to inform optimal treatment.

Advancing School Behavioral Health at Multiple Levels of Scale.

There is a national movement to advance school behavioral health, involving the mental health system partnering with schools' multitiered systems of support. This article underscores the critical need for school behavioral health and presents strategies to advance effective programming at district, state, and regional levels. Themes include diverse stakeholder involvement, teaming, data-based decision-making, implementation of evidence-based practices, screening, coaching and implementation support, progress monitoring and outcome evaluation, and using findings to scale-up effective programming. Implications for research, practice, and policy are reviewed along with ideas for the future development of this field.

Treatment of Capnocytophaga sputigena meningitis in a neurosurgical patient.

A woman in her 50s developed meningitis following an endoscopic, endonasal resection of a clival meningioma which was complicated by a cerebrospinal fluid (CSF) leak through the nose. CSF analysis showed a raised white cell count, and Capnocytophaga sputigena was isolated. This organism is an oral commensal and is implicated in periodontal disease; the CSF leak explains the portal of entry. C. sputigena is rarely isolated, and this is the first report of a central nervous system (CNS) infection caused by this organism. A worsening of our patient's dermatological condition, urticaria pigmentosa, coincided with empiric treatment with vancomycin and meropenem, which were therefore discontinued. Treatment was continued with chloramphenicol for 3 weeks, and the patient made a full recovery. Systemic chloramphenicol is uncommonly used in contemporary UK practice, but remains an excellent antibiotic for CNS penetration and it has excellent bioavailability. We anticipate increased chloramphenicol use as the number of multiresistant Gram-negative infection increases.

Intravenous thrombolysis prior to mechanical thrombectomy does not affect clinical or procedural outcomes in patients with large vessel occlusion acute ischemic stroke.

Mechanical thrombectomy (MT) has revolutionized the care of large vessel occlusion acute ischemic strokes (LVOAIS). However, the benefit of intravenous thrombolysis prior to MT remains unproven. Two recent trials showed equivocal results regarding the benefits of pre-MT intravenous thrombolysis in predominantly Asian populations. We evaluated clinical outcomes and procedural metrics for patients with LVOAIS who were treated with MT alone compared to those who were treated with both intravenous tPA and MT. In a retrospective study, LVOAIS patients treated with MT, with or without preceding intravenous thrombolysis, between January of 2017 and December of 2019 were identified. Patients were treated according to contemporary guidelines. Baseline demographic and clinical characteristics, procedural metrics, and clinical outcomes were collected. Among LVOAIS patients, those treated with intravenous thrombolysis and MT did not differ from those with MT alone on clinical outcomes at three months. Further, the two groups did not differ on thrombectomy procedure times, recanalization rates, and symptomatic intracranial hemorrhage rates. In our patients with LVOAIS, intravenous thrombolysis combined with MT offered no advantage compared to MT alone in clinical outcomes or recanalization rates. Our results are consistent with earlier studies in other populations. In addition, our results suggest that IV tPA does not impact the ease of clot removal by MT. Further studies will evaluate how newly available thrombolytic agents may benefit patients eligible for MT.

Virtual intracranial EEG signals reconstructed from MEG with potential for epilepsy surgery.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose virtual intracranial electroencephalography (ViEEG), which combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. We show the non-invasive ViEEG approach may have some advantage over intracranial electroencephalography (iEEG). Future work may be designed to test the potential of the virtual iEEG approach for use in surgical management of epilepsy.

Analysis of wearable time series data in endocrine and metabolic research.

Many hormones in the body oscillate with different frequencies and amplitudes, creating a dynamic environment that is essential to maintain health. In humans, disruptions to these rhythms are strongly associated with increased morbidity and mortality. While mathematical models can help us understand rhythm misalignment, translating this insight into personalised healthcare technologies requires solving additional challenges. Here, we discuss how combining minimally invasive, high-frequency biosampling technologies with wearable devices can assist the development of hormonal surrogates. We review bespoke algorithms that can help analyse multidimensional, noisy, time series data and identify wearable signals that could constitute clinical proxies of endocrine rhythms. These techniques can support the development of computational biomarkers to support the diagnosis and management of endocrine and metabolic conditions.

Evaluation of the Implementation of the 4C Mortality Score in United Kingdom hospitals during the second pandemic wave

The 4C Mortality Score (4C Score) was designed to risk stratify hospitalised patients with COVID-19. We assessed inclusion of 4C Score in COVID-19 management guidance and its documentation in patients case notes in January 2021 in UK hospitals. 4C Score was included within guidance by 50% of sites, though score documentation in case notes was highly variable. Higher documentation of 4C Score was associated with score integration within admissions proformas, inclusion of 4C Score variables or link to online calculator, and management decisions. Integration of 4C Score within clinical pathways may encourage more widespread use.

Antibiotic usage and stewardship in patients with COVID-19: too much antibiotic in uncharted waters?

BACKGROUND: Antimicrobial usage and stewardship programmes during COVID-19 have been poorly studied. Prescribing practice varies despite national guidelines, and there is concern that stewardship principles have suffered. AIM: To analyse antibiotic prescriptions during the COVID-19 pandemic at a teaching hospital and to propose improved approaches to stewardship. METHODS: We reviewed COVID-19 admissions to medical wards and intensive care units (ICUs) in a London teaching hospital to assess initial antibiotic usage and evidence of bacterial co-infection, and to determine if our current antibiotic guidelines were adhered to. FINDINGS: Data from 130 inpatients (76% medical and 24% ICU) were obtained. On admission, 90% were treated with antibiotics. No microbiological samples taken on admission provided definitive evidence of respiratory co-infection. In 13% of cases, antibiotics were escalated, usually without supporting clinical, radiological or laboratory evidence. In 16% of cases, antibiotics were stopped or de-escalated within 72 h. Blood results and chest radiographs were characteristic of COVID-19 in 20% of ward patients and 42% of ICU patients. Overall mortality was 25% at 14 days - similar to rates described for the UK as a whole. CONCLUSION: The majority of patients received antibiotics despite limited evidence of co-infection. Most patients received narrower spectrum antibiotics than recommended by NICE. As understanding of the natural history of COVID-19 infections progresses, stewardship programmes will need to evolve; however, at this point, we feel that a more restrictive antibiotic prescribing approach is warranted. We propose strategies for effective stewardship and estimate the effect this may have on antibiotic consumption.

Changing practice to using pre-filled syringes for flushing IV cannulas.

In the UK, the Medicines and Healthcare products Regulatory Agency classifies 'pre-filled syringes' for flushing Intravenous (IV) cannulas and IV access devices as 'borderline' devices and offers some advice on how control measures can help mitigate risks. The Medicines Act (1968) and Medical Device Regulations try to address the legal position of these devices and allow each employer to identify those groups of staff allowed to use them. In turn, this may help address anomalies around the need to prescribe and document their use. This article describes how one large university health board in Wales implemented a change in products and practice and explores the issues around adopting and using CE-marked pre-filled, sterile syringes of 0.9% sodium chloride in place of manually drawing up an IV flush (the CE mark indicates devices that conforms with European legal requirements). Whether the use of individual components or a single pre-filled device can lead to a streamlined and cost-effective way to manage the flushing of IV cannula and vascular access devices was explored. Additional risk factors were identified, and the legal status clarified in line with current guidelines and regulations. As 0.9% sodium chloride in ampoules and vials is classified as a prescription-only medicine, the administration needs control via formal prescription or a patient group direction. Adopting and using these pre-filled syringes as CE-marked medical devices requires careful consideration and sign-off from each employing authority, before implementing them for flushing IV cannulas and IV access devices.