A spatial perturbation framework to validate implantation of the epileptogenic zone.

Stereo-electroencephalography (SEEG) is the gold standard to delineate surgical targets in focal drug-resistant epilepsy. SEEG uses electrodes placed directly into the brain to identify the seizure-onset zone (SOZ). However, its major constraint is limited brain coverage, potentially leading to misidentification of the 'true' SOZ. Here, we propose a framework to assess adequate SEEG sampling by coupling epileptic biomarkers with their spatial distribution and measuring the system's response to a perturbation of this coupling. We demonstrate that the system's response is strongest in well-sampled patients when virtually removing the measured SOZ. We then introduce the spatial perturbation map, a tool that enables qualitative assessment of the implantation coverage. Probability modelling reveals a higher likelihood of well-implanted SOZs in seizure-free patients or non-seizure free patients with incomplete SOZ resections, compared to non-seizure-free patients with complete resections. This highlights the framework's value in sparing patients from unsuccessful surgeries resulting from poor SEEG coverage.

Timing matters for accurate identification of the epileptogenic zone.

OBJECTIVE: Interictal biomarkers of the epileptogenic zone (EZ) and their use in machine learning models open promising avenues for improvement of epilepsy surgery evaluation. Currently, most studies restrict their analysis to short segments of intracranial EEG (iEEG). METHODS: We used 2381 hours of iEEG data from 25 patients to systematically select 5-minute segments across various interictal conditions. Then, we tested machine learning models for EZ localization using iEEG features calculated within these individual segments or across them and evaluated the performance by the area under the precision-recall curve (PRAUC). RESULTS: On average, models achieved a score of 0.421 (the result of the chance classifier was 0.062). However, the PRAUC varied significantly across the segments (0.323-0.493). Overall, NREM sleep achieved the highest scores, with the best results of 0.493 in N2. When using data from all segments, the model performed significantly better than single segments, except NREM sleep segments. CONCLUSIONS: The model based on a short segment of iEEG recording can achieve similar results as a model based on prolonged recordings. The analyzed segment should, however, be carefully and systematically selected, preferably from NREM sleep. SIGNIFICANCE: Random selection of short iEEG segments may give rise to inaccurate localization of the EZ.

A Subpopulation of Spikes Predicts Successful Epilepsy Surgery Outcome.

OBJECTIVE: Epileptic spikes are the traditional interictal electroencephalographic (EEG) biomarker for epilepsy. Given their low specificity for identifying the epileptogenic zone (EZ), they are given only moderate attention in presurgical evaluation. This study aims to demonstrate that it is possible to identify specific spike features in intracranial EEG that optimally define the EZ and predict surgical outcome. METHODS: We analyzed spike features on stereo-EEG segments from 83 operated patients from 2 epilepsy centers (37 Engel IA) in wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep. After automated spike detection, we investigated 135 spike features based on rate, morphology, propagation, and energy to determine the best feature or feature combination to discriminate the EZ in seizure-free and non-seizure-free patients by applying 4-fold cross-validation. RESULTS: The rate of spikes with preceding gamma activity in wakefulness performed better for surgical outcome classification (4-fold area under receiver operating characteristics curve [AUC] = 0.755 ± 0.07) than the seizure onset zone, the current gold standard (AUC = 0.563 ± 0.05, p = 0.015) and the ripple rate, an emerging seizure-independent biomarker (AUC = 0.537 ± 0.07, p = 0.006). Channels with a spike-gamma rate exceeding 1.9/min had an 80% probability of being in the EZ. Combining features did not improve the results. INTERPRETATION: Resection of brain regions with high spike-gamma rates in wakefulness is associated with a high probability of achieving seizure freedom. This rate could be applied to determine the minimal number of spiking channels requiring resection. In addition to quantitative analysis, this feature is easily accessible to visual analysis, which could aid clinicians during presurgical evaluation. ANN NEUROL 2023;93:522-535.

Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis.

Early multiple sclerosis lesions feature relative preservation of oligodendrocyte cell bodies with dying back retraction of their myelinating processes. Cell loss occurs with disease progression. Putative injury mediators include metabolic stress (low glucose/nutrient), pro-inflammatory mediators (interferon γ and tumour necrosis factor α), and excitotoxins (glutamate). Our objective was to compare the impact of these disease relevant mediators on the injury responses of human mature oligodendrocytes. In the current study, we determined the effects of these mediators on process extension and survival of human brain derived mature oligodendrocytes in vitro and used bulk RNA sequencing to identify distinct effector mechanisms that underlie the responses. All mediators induced significant process retraction of the oligodendrocytes in dissociated cell culture. Only metabolic stress (low glucose/nutrient) conditions resulted in delayed (4-6 days) non-apoptotic cell death. Metabolic effects were associated with induction of the integrated stress response, which can be protective or contribute to cell injury dependent on its level and duration of activation. Addition of Sephin1, an agonist of the integrated stress response induced process retraction under control conditions and further enhanced retraction under metabolic stress conditions. The antagonist ISRIB restored process outgrowth under stress conditions, and if added to already stressed cells, reduced delayed cell death and prolonged the period in which recovery could occur. Inflammatory cytokine functional effects were associated with activation of multiple signalling pathways (including Jak/Stat-1) that regulate process outgrowth, without integrated stress response induction. Glutamate application produced limited transcriptional changes suggesting a contribution of effects directly on cell processes. Our comparative studies indicate the need to consider both the specific injury mediators and the distinct cellular mechanisms of responses to them by human oligodendrocytes to identify effective neuroprotective therapies for multiple sclerosis.

Spatio-temporal spike dynamics predict surgical outcome in adult focal epilepsy.

OBJECTIVE: We hypothesized that spatio-temporal dynamics of interictal spikes reflect the extent and stability of epileptic sources and determine surgical outcome. METHODS: We studied 30 consecutive patients (14 good outcome). Spikes were detected in prolonged stereo-electroencephalography recordings. We quantified the spatio-temporal dynamics of spikes using the variance of the spike rate, line length and skewness of the spike distribution, and related these features to outcome. We built a logistic regression model, and compared its performance to traditional markers. RESULTS: Good outcome patients had more dominant and stable sources than poor outcome patients as expressed by a higher variance of spike rates, a lower variance of line length, and a lower variance of positive skewness (ps < 0.05). The outcome was correctly predicted in 80% of patients. This was better or non-inferior to predictions based on a focal lesion (p = 0.016), focal seizure-onset zone, or complete resection (ps > 0.05). In the five patients where traditional markers failed, spike distribution predicted the outcome correctly. The best results were achieved by 18-h periods or longer. CONCLUSIONS: Analysis of spike dynamics shows that surgery outcome depends on strong, single and stable sources. SIGNIFICANCE: Our quantitative method has the potential to be a reliable predictor of surgical outcome.

New interinstitutional, multimodal presurgical evaluation protocol associated with improved seizure freedom for poorly defined cases of focal epilepsy in children.

OBJECTIVE: In an attempt to improve postsurgical seizure outcomes for poorly defined cases (PDCs) of pediatric focal epilepsy (i.e., those that are not visible or well defined on 3T MRI), the authors modified their presurgical evaluation strategy. Instead of relying on concordance between video-electroencephalography and 3T MRI and using functional imaging and intracranial recording in select cases, the authors systematically used a multimodal, 3-tiered investigation protocol that also involved new collaborations between their hospital, the Montreal Children's Hospital, and the Montreal Neurological Institute. In this study, the authors examined how their new strategy has impacted postsurgical outcomes. They hypothesized that it would improve postsurgical seizure outcomes, with the added benefit of identifying a subset of tests contributing the most. METHODS: Chart review was performed for children with PDCs who underwent resection following the new strategy (i.e., new protocol [NP]), and for the same number who underwent treatment previously (i.e., preprotocol [PP]); ≥ 1-year follow-up was required for inclusion. Well-defined, multifocal, and diffuse hemispheric cases were excluded. Preoperative demographics and clinical characteristics, resection volumes, and pathology, as well as seizure outcomes (Engel class Ia vs > Ia) at 1 year postsurgery and last follow-up were reviewed. RESULTS: Twenty-two consecutive NP patients were compared with 22 PP patients. There was no difference between the two groups for resection volumes, pathology, or preoperative characteristics, except that the NP group underwent more presurgical evaluation tests (p < 0.001). At 1 year postsurgery, 20 of 22 NP patients and 10 of 22 PP patients were seizure free (OR 11.81, 95% CI 2.00-69.68; p = 0.006). Magnetoencephalography and PET/MRI were associated with improved postsurgical seizure outcomes, but both were highly correlated with the protocol group (i.e., independent test effects could not be demonstrated). CONCLUSIONS: A new presurgical evaluation strategy for children with PDCs of focal epilepsy led to improved postsurgical seizure freedom. No individual presurgical evaluation test was independently associated with improved outcome, suggesting that it may be the combined systematic protocol and new interinstitutional collaborations that makes the difference rather than any individual test.

Characterization of concurrent target suppression by JNJ-61178104, a bispecific antibody against human tumor necrosis factor and interleukin-17A.

Tumor necrosis factor (TNF) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). JNJ-61178104 is a novel human anti-TNF and anti-IL-17A monovalent, bispecific antibody that binds to both human TNF and human IL-17A with high affinities and blocks the binding of TNF and IL-17A to their receptors in vitro. JNJ-61178104 also potently neutralizes TNF and IL-17A-mediated downstream effects in multiple cell-based assays. In vivo, treatment with JNJ-61178104 resulted in dose-dependent inhibition of cellular influx in a human IL-17A/TNF-induced murine lung neutrophilia model and the inhibitory effects of JNJ-61178104 were more potent than the treatment with bivalent parental anti-TNF or anti-IL-17A antibodies. JNJ-61178104 was shown to engage its targets, TNF and IL-17A, in systemic circulation measured as drug/target complex formation in normal cynomolgus monkeys (cyno). Surprisingly, quantitative target engagement assessment suggested lower apparent in vivo target-binding affinities for JNJ-61178104 compared to its bivalent parental antibodies, despite their similar in vitro target-binding affinities. The target engagement profiles of JNJ-61178104 in humans were in general agreement with the predicted profiles based on cyno data, suggesting similar differences in the apparent in vivo target-binding affinities. These findings show that in vivo target engagement of monovalent bispecific antibody does not necessarily recapitulate that of the molar-equivalent dose of its bivalent parental antibody. Our results also offer valuable insights into the understanding of the pharmacokinetics/pharmacodynamics and target engagement of other bispecific biologics against dimeric and/or trimeric soluble targets in vivo.

Characteristics of Patients with Hypertension at a Nicaraguan Clinic.

OBJECTIVE: Describe the characteristics and pharmacological management of hypertensive patients in a Nicaraguan ambulatory care clinic. METHODS: The study analyzed a random sample of 349 charts of patients aged older than 18 years from an ambulatory care clinic in Nicaragua and analyzed those who were diagnosed or had a known history of hypertension. RESULTS: Out of 349 patients, 19.77% (n=69) had a history of hypertension. Hypertensive patients were 66.2% female (n=45) with mean age of 56.1 years (SD=13.7). The most common comorbid condition was type 2 diabetes mellitus, which was present in 18.8% (n=13) of hypertensive patients. Other comorbid conditions included 10% (n=7) with chronic kidney disease and 75.8% (n=50) who were either overweight or obese. The most commonly prescribed antihypertensive medications were losartan, captopril, and enalapril. CONCLUSIONS: Hypertension is common in this clinic population and most commonly treated with angiotension-receptor blockers or angiotensin converting enzyme inhibitors.

Evaluation of Antimicrobial Utilization and Concordance with National Guidelines at a Tertiary Hospital in the Southern Highlands Zone of Tanzania.

Antimicrobial resistance is a growing concern in sub-Saharan Africa, and antimicrobial stewardship (AMS) programs have not been widely implemented in this region. We evaluated antibiotic prescribing patterns and concordance with national guidelines at Mbeya Zonal Referral Hospital (MZRH) in Tanzania. Adult inpatient medical records were chronologically reviewed from January 1, 2018 until 100 records documenting antibiotic therapy were evaluated. The primary endpoint was concordance with national guidelines for indication-based antibiotic selection and duration. Data were summarized using descriptive statistics. Overall, 155 records with sufficient data were reviewed. The 100 records which involved antibiotic therapy represented 171 unique antibiotic courses. The most common indication for antibiotics was bacterial pneumonia. Ceftriaxone and metronidazole, the most commonly used antibiotics, were administered in 40% and 24% of courses, respectively. Indication-based antibiotic selection was concordant with national guidelines in 63% of courses, but this fell to 15% when course duration was taken into account. Antibiotic courses were completed as prescribed 28% of the time among evaluable courses. A microbiologic culture of any kind was obtained in 17% of patients. In conclusion, antibiotic therapy was often incomplete, was generally guideline discordant, exhibited limited diversity of selection, and frequently lacked diagnostic confirmation. These data, combined with local susceptibility patterns, may be used to foster AMS efforts for improved compliance with guidelines at MZRH in the future.

North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies.

Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-κB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors.

Distinct transcriptomic and exomic abnormalities within myelodysplastic syndrome marrow cells.

To provide biologic insights into mechanisms underlying myelodysplastic syndromes (MDS) we evaluated the CD34+ marrow cells transcriptome using high-throughput RNA sequencing (RNA-Seq). We demonstrated significant differential gene expression profiles (GEPs) between MDS and normal and identified 41 disease classifier genes. Additionally, two main clusters of GEPs distinguished patients based on their major clinical features, particularly between those whose disease remained stable versus patients who transformed into acute myeloid leukemia within 12 months. The genes whose expression was associated with disease outcome were involved in functional pathways and biologic processes highly relevant for MDS. Combined with exomic analysis we identified differential isoform usage of genes in MDS mutational subgroups, with consequent dysregulation of distinct biologic functions. This combination of clinical, transcriptomic and exomic findings provides valuable understanding of mechanisms underlying MDS and its progression to a more aggressive stage and also facilitates prognostic characterization of MDS patients.

The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes.

The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.

Geographic and temporal patterns of variation in total mercury concentrations in blood of harlequin ducks and blue mussels from Alaska.

We compared total mercury (Hg) concentrations in whole blood of harlequin ducks (Histrionicus histrionicus) sampled within and among two geographically distinct locations and across three years in southwest Alaska. Blue mussels were collected to assess correlation between Hg concentrations in locally available forage and birds. Mercury concentrations in harlequin duck blood were significantly higher at Unalaska Island (0.31±0.19 mean±SD, µg/g blood) than Kodiak Island (0.04±0.02 mean±SD, µg/g blood). We found no evidence for annual variation in blood Hg concentration between years at Unalaska Island. However, blood Hg concentration did vary among specific sampling locations (i.e., bays) at Unalaska Island. Findings from this study demonstrate harlequin ducks are exposed to environmental sources of Hg, and whole blood Hg concentrations are associated with their local food source.

The spectrum of structural and functional imaging abnormalities in temporal lobe epilepsy.

OBJECTIVE: Although most temporal lobe epilepsy (TLE) patients show marked hippocampal sclerosis (HS) upon pathological examination, 40% present with no significant cell loss but gliotic changes only. To evaluate effects of hippocampal pathology on brain structure and functional networks, we aimed at dissociating multimodal magnetic resonance imaging (MRI) characteristics in patients with HS (TLE-HS) and those with gliosis only (TLE-G). METHODS: In 20 TLE-HS, 19 TLE-G, and 25 healthy controls, we carried out a novel MRI-based hippocampal subfield surface analysis that integrated volume, T2 signal intensity, and diffusion markers with seed-based hippocampal functional connectivity. RESULTS: Compared to controls, TLE-HS presented with marked ipsilateral atrophy, T2 hyperintensity, and mean diffusivity increases across all subfields, whereas TLE-G presented with dentate gyrus hypertrophy, focal increases in T2 intensity and mean diffusivity. Multivariate assessment confirmed a more marked ipsilateral load of anomalies across all subfields in TLE-HS, whereas anomalies in TLE-G were restricted to the subiculum. A between-cohort dissociation was independently suggested by resting-state functional connectivity analysis, revealing marked hippocampal decoupling from anterior and posterior default mode hubs in TLE-HS, whereas TLE-G did not differ from controls. Back-projection connectivity analysis from cortical targets revealed consistently decreased network embedding across all subfields in TLE-HS, while changes in TLE-G were limited to the subiculum. Hippocampal disconnectivity strongly correlated to T2 hyperintensity and marginally to atrophy. INTERPRETATION: Multimodal MRI reveals diverging structural and functional connectivity profiles across the TLE spectrum. Pathology-specific modulations of large-scale functional brain networks lend novel evidence for a close interplay of structural and functional disruptions in focal epilepsy. Ann Neurol 2016;80:142-153.

Tuberculosis testing: Which patients, which test?

The most appropriate test to identify latent TB depends on the patient's risk for developing active TB and other factors. This review provides practical guidance on who to test, how, and when.

MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.

Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood.

Tuberculosis: which drug regimen and when.

Early treatment can prevent mortality, but there are differences in treating latent vs active TB. This resource--with drug reference charts--can guide your care.

PF4/heparin antibody testing and treatment of heparin-induced thrombocytopenia in the intensive care unit.

BACKGROUND: The diagnosis of heparin-induced thrombocytopenia (HIT) may be challenging in critically ill patients, as heparin exposures are ubiquitous, and thrombocytopenia is common. Unwarranted ordering and incorrect interpretation of heparin antibody tests can expose a patient to adverse drug events and imposes a significant economic burden on our health care system. METHODS: A prospective, observational study was performed over 4 months on all adult patients located in 5 intensive care units, with a heparin antibody test ordered. RESULTS: A platelet factor 4/heparin enzyme-linked immunosorbent assay (ELISA) test was ordered in 131 patients. In total, 110 patients had a low 4Ts score (0-3), and of these 103 had a negative ELISA result. In patients with a low 4Ts score, 0 (0%) of 110 had an optical density value >1.0. One hundred twenty-nine patients (98%) had another possible cause of thrombocytopenia identified. CONCLUSION: In critically ill patients, low 4Ts scores indicate a low probability of HIT, and heparin antibody testing in these patients is not useful.