The Burden of Invasive Fungal Disease Following Chimeric Antigen Receptor T-Cell Therapy and Strategies for Prevention.

Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy approved for the treatment of hematologic malignancies. This therapy leads to a variety of immunologic deficits that could place patients at risk for invasive fungal disease (IFD). Studies assessing IFD in this setting are limited by inconsistent definitions and heterogeneity in prophylaxis use, although the incidence of IFD after CAR T-cell therapy, particularly for lymphoma and myeloma, appears to be low. This review evaluates the incidence of IFD after CAR T-cell therapy, and discusses optimal approaches to prevention, highlighting areas that require further study as well as future applications of cellular therapy that may impact IFD risk. As the use of CAR T-cell therapy continues to expand for hematologic malignancies, solid tumors, and most recently to include non-oncologic diseases, understanding the risk for IFD in this uniquely immunosuppressed population is imperative to prevent morbidity and mortality.

Serial Bronchoalveolar Lavage Fluid Aspergillus Galactomannan and Treatment Response in Invasive Pulmonary Aspergillosis.

We studied patients diagnosed with aspergillosis based on positive bronchoalveolar lavage (BAL) Aspergillus galactomannan (GM) who had follow-up BAL sampling within 180 days. GM trend and clinical outcome were concordant in only 60% (30/50). While useful for the initial diagnosis, BAL GM trending does not always correlate with treatment response.

Racial disparities in the utilization of invasive neuromodulation devices for the treatment of drug-resistant focal epilepsy.

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

Severe mental illness: cardiovascular risk assessment and management.

Patients with severe mental illness (SMI) including schizophrenia and bipolar disorder die on average 15-20 years earlier than the general population often due to sudden death that, in most cases, is caused by cardiovascular disease. This state-of-the-art review aims to address the complex association between SMI and cardiovascular risk, explore disparities in cardiovascular care pathways, describe how to adequately predict cardiovascular outcomes, and propose targeted interventions to improve cardiovascular health in patients with SMI. These patients have an adverse cardiovascular risk factor profile due to an interplay between biological factors such as chronic inflammation, patient factors such as excessive smoking, and healthcare system factors such as stigma and discrimination. Several disparities in cardiovascular care pathways have been demonstrated in patients with SMI, resulting in a 47% lower likelihood of undergoing invasive coronary procedures and substantially lower rates of prescribed standard secondary prevention medications compared with the general population. Although early cardiovascular risk prediction is important, conventional risk prediction models do not accurately predict long-term cardiovascular outcomes as cardiovascular disease and mortality are only partly driven by traditional risk factors in this patient group. As such, SMI-specific risk prediction models and clinical tools such as the electrocardiogram and echocardiogram are necessary when assessing and managing cardiovascular risk associated with SMI. In conclusion, there is a necessity for differentiated cardiovascular care in patients with SMI. By addressing factors involved in the excess cardiovascular risk, reconsidering risk stratification approaches, and implementing multidisciplinary care models, clinicians can take steps towards improving cardiovascular health and long-term outcomes in patients with SMI.

Responsive Neurostimulation for People With Drug-Resistant Epilepsy and Autism Spectrum Disorder.

PURPOSE: Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System. METHODS: This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis. RESULTS: Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a >50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction >90%). For the super responders, two of the four patients had the device implanted for >2 years. The response rate was 70% for those in whom the device was implanted for >2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported. CONCLUSIONS: Based on the authors' experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE.

Growth kinetics of venous tumor thrombus in patients with renal cell carcinoma.

INTRODUCTION: Some patients with renal cell carcinoma (RCC) present with venous tumor thrombus (VTT). The extent of the VTT is related to survival, so prompt surgical care is recommended. However, studies evaluating the natural history of VTT in patients with RCC are rare. We sought to evaluate the growth kinetics of VTT in patients with RCC using preoperative cross-sectional images. MATERIALS AND METHODS: We identified patients who underwent radical nephrectomy and venous tumor thrombectomy at our institution from 01/2009 to 02/2022. We included those with a minimum of 2 adequate preoperative imaging studies (contrast-enhanced Computerized Tomography (CT), noncontrast Magnetic resonance imaging (MRI), or contrast-enhanced MRI), at least 14 days apart. We measured VTT in each study to calculate growth rate, and evaluated predictors of faster growth (demographics, histology, laterality, tumor diameter, and staging). To assess the relation between clinical variables and VTT growth, we used the Wilcoxon Rank-Sum, Kruskal-Wallis, and Spearman correlation tests. RESULTS: A total of 30 patients were included in the analysis. The median time interval between studies was 33 days. Patients were mostly Caucasian and Males (90% and 70%, respectively). Most patients underwent a CT scan as their initial imaging study (66%), followed with an MRI as second study (73%). The mean venous tumor thrombus growth rate was 0.3 mm/d (standard deviation of 0.5mm), and only rhabdoid/sarcomatoid differentiation showed an association with tumor thrombus growth rate (0.3 vs. 0.63 mm/d, P = 0.038). CONCLUSIONS: To the best of our knowledge, this is the first study evaluating the natural growth rate of venous tumor thrombus in patients with renal cell carcinoma. We found that tumor thrombi grew an average of 0.3 mm/d (1.0 cm/month) and that those with sarcomatoid and/or rhabdoid differentiation grew faster (0.63 mm/d). Further studies are needed to validate these results and provide a better understanding of tumor thrombus kinetics.

Watchman device migration and embolization: A report from the NCDR LAAO Registry.

INTRODUCTION: Incomplete anchoring of the Watchman left atrial appendage closure (LAAO) device can result in substantial device migration or device embolization (DME) requiring percutaneous or surgical retrieval. METHODS: We performed a retrospective analysis of Watchman procedures (January 2016 through March 2021) reported to the National Cardiovascular Data Registry LAAO Registry. We excluded patients with prior LAAO interventions, no device released, and missing device information. In-hospital events were assessed among all patients and postdischarge events were assessed among patients with 45-day follow-up. RESULTS: Of 120 278 Watchman procedures, the in-hospital DME rate was 0.07% (n = 84) and surgery was commonly performed (n = 39). In-hospital mortality rate was 14% among patients with DME and 20.5% among patients who underwent surgery. In-hospital DME was more common: at hospitals with a lower median annual procedure volume (24 vs. 41 procedures, p < .0001), with Watchman 2.5 versus Watchman FLX devices (0.08% vs. 0.04%, p = .0048), with larger LAA ostia (median 23 vs. 21 mm, p = .004), and with a smaller difference between device and LAA ostial size (median difference 4 vs. 5 mm, p = .04). Of 98 147 patients with 45-day follow-up, postdischarge DME occurred in 0.06% (n = 54) patients and cardiac surgery was performed in 7.4% (n = 4) of cases. The 45-day mortality rate was 3.7% (n = 2) among patients with postdischarge DME. Postdischarge DME was more common among men (79.7% of events but 58.9% of all procedures, p = .0019), taller patients (177.9 vs. 172 cm, p = .0005), and those with greater body mass (99.9 vs. 85.5 kg, p = .0055). The rhythm at implant was less frequently AF among patients with DME compared to those without (38.9% vs. 46.9%, p = .0098). CONCLUSION: While Watchman DME is rare, it is associated with high mortality and frequently requires surgical retrieval, and a substantial proportion of events occur after discharge. Due to the severity of DME events, risk mitigation strategies and on-site cardiac surgical back-up are of paramount importance.

Focal epilepsies: Update on diagnosis and classification.

Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions-developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.

N-Tools-Browser: Web-Based Visualization of Electrocorticography Data for Epilepsy Surgery.

Epilepsy affects more than three million people in the United States. In approximately one-third of this population, anti-seizure medications do not control seizures. Many patients pursue surgical treatment that can include a procedure involving the implantation of electrodes for intracranial monitoring of seizure activity. For these cases, accurate mapping of the implanted electrodes on a patient's brain is crucial in planning the ultimate surgical treatment. Traditionally, electrode mapping results are presented in static figures that do not allow for dynamic interactions and visualizations. In collaboration with a clinical research team at a Level 4 Epilepsy Center, we developed N-Tools-Browser, a web-based software using WebGL and the X-Toolkit (XTK), to help clinicians interactively visualize the location and functional properties of implanted intracranial electrodes in 3D. Our software allows the user to visualize the seizure focus location accurately and simultaneously display functional characteristics (e.g., results from electrical stimulation mapping). Different visualization modes enable the analysis of multiple electrode groups or individual anatomical locations. We deployed a prototype of N-Tools-Browser for our collaborators at the New York University Grossman School of Medicine Comprehensive Epilepsy Center. Then, we evaluated its usefulness with domain experts on clinical cases.

Intraoperative microseizure detection using a high-density micro-electrocorticography electrode array.

One-third of epilepsy patients suffer from medication-resistant seizures. While surgery to remove epileptogenic tissue helps some patients, 30-70% of patients continue to experience seizures following resection. Surgical outcomes may be improved with more accurate localization of epileptogenic tissue. We have previously developed novel thin-film, subdural electrode arrays with hundreds of microelectrodes over a 100-1000 mm2 area to enable high-resolution mapping of neural activity. Here, we used these high-density arrays to study microscale properties of human epileptiform activity. We performed intraoperative micro-electrocorticographic recordings in nine patients with epilepsy. In addition, we recorded from four patients with movement disorders undergoing deep brain stimulator implantation as non-epileptic controls. A board-certified epileptologist identified microseizures, which resembled electrographic seizures normally observed with clinical macroelectrodes. Recordings in epileptic patients had a significantly higher microseizure rate (2.01 events/min) than recordings in non-epileptic subjects (0.01 events/min; permutation test, P = 0.0068). Using spatial averaging to simulate recordings from larger electrode contacts, we found that the number of detected microseizures decreased rapidly with increasing contact diameter and decreasing contact density. In cases in which microseizures were spatially distributed across multiple channels, the approximate onset region was identified. Our results suggest that micro-electrocorticographic electrode arrays with a high density of contacts and large coverage are essential for capturing microseizures in epilepsy patients and may be beneficial for localizing epileptogenic tissue to plan surgery or target brain stimulation.

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia.

BACKGROUND: Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways. METHODS AND FINDINGS: We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4-26; n = 10, Control, mean age 13.1, range 3-45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences. CONCLUSIONS: Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT02451696.

Periprocedural Pericardial Effusion Complicating Transcatheter Left Atrial Appendage Occlusion: A Report From the NCDR LAAO Registry.

BACKGROUND: Pericardial effusion (PE) is a potential complication of transcatheter left atrial appendage occlusion. The objective of this study was to investigate the incidence, associated characteristics, and outcomes of PE following left atrial appendage occlusion. METHODS: Patients in the NCDR LAAO Registry who underwent a Watchman procedure between January 1, 2016 and December 31, 2019 were included. The primary outcome was in-hospital PE requiring intervention (percutaneous drainage or surgery). Odds ratios (ORs) were calculated for adverse event rates associated with PE. RESULTS: The study population consisted of 65 355 patients. The mean patient age was 76.2±8.1 years, and the mean CHA2DS2-VASc score was 4.6±1.5. PE occurred in 881 patients (1.35%). Clinical variables independently associated with PE included older age, female sex, left ventricular function, paroxysmal atrial fibrillation, prior bleeding, lower serum albumin, and preprocedural dual antiplatelet therapy; procedural variables included number of delivery sheaths used, sinus rhythm during the procedure, and moderate sedation rather than general anesthesia. PE was associated with increased risk of in-hospital stroke (OR, 6.58 [95% CI, 3.32-13.06]; P<0.0001), death (OR, 56.88 [95% CI, 39.79-81.32]; P<0.0001), and the composite of death, stroke, or systemic embolism (OR, 28.64 [95% CI, 21.24-38.61]; P<0.0001). PE during the index hospitalization was associated with increased risk of death (OR, 3.52 [95% CI, 2.23-5.54]; P<0.0001) and the composite of death, stroke, or systemic embolism (OR, 3.42 [95% CI, 2.31-5.07]; P<0.0001) between discharge and 45-day follow-up. CONCLUSIONS: In-hospital PE during transcatheter left atrial appendage occlusion is infrequent but associated with a substantially higher risk of adverse events, including in-hospital and early postdischarge mortality. Strategies to minimize PE are critical to improve the risk-benefit ratio for this therapy.

Dietary Transitions and Health Outcomes in Four Populations - Systematic Review.

IMPORTANCE: Non-communicable chronic diseases (NCDs) such as obesity, type 2 diabetes, heart disease, and cancer were rare among non-western populations with traditional diets and lifestyles. As populations transitioned toward industrialized diets and lifestyles, NCDs developed. OBJECTIVE: We performed a systematic literature review to examine the effects of diet and lifestyle transitions on NCDs. EVIDENCE REVIEW: We identified 22 populations that underwent a nutrition transition, eleven of which had sufficient data. Of these, we chose four populations with diverse geographies, diets and lifestyles who underwent a dietary and lifestyle transition and explored the relationship between dietary changes and health outcomes. We excluded populations with features overlapping with selected populations or with complicating factors such as inadequate data, subgroups, and different study methodologies over different periods. The selected populations were Yemenite Jews, Tokelauans, Tanushimaru Japanese, and Maasai. We also review transition data from seven excluded populations (Pima, Navajo, Aboriginal Australians, South African Natal Indians and Zulu speakers, Inuit, and Hadza) to assess for bias. FINDINGS: The three groups that replaced saturated fats (SFA) from animal (Yemenite Jews, Maasai) or plants (Tokelau) with refined carbohydrates had negative health outcomes (e.g., increased obesity, diabetes, heart disease). Yemenites reduced SFA consumption by >40% post-transition but men's BMI increased 19% and diabetes increased ~40-fold. Tokelauans reduced fat, dramatically reduced SFA, and increased sugar intake: obesity and diabetes rose. The Tanushimaruans transitioned to more fats and less carbohydrates and used more anti-hypertensive medications; stroke and breast cancer declined while heart disease was stable. The Maasai transitioned to lower fat, SFA and higher carbohydrates and had increased BMI and diabetes. Similar patterns were observed in the seven other populations. CONCLUSION: The nutrient category most strongly associated with negative health outcomes - especially obesity and diabetes - was sugar (increased 600-650% in Yemenite Jews and Tokelauans) and refined carbohydrates (among Maasai, total carbohydrates increased 39% in men and 362% in women), while increased calories was less strongly associated with these disorders. Across 11 populations, NCDs were associated with increased refined carbohydrates more than increased calories, reduced activity or other factors, but cannot be attributed to SFA or total fat consumption.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

OBJECTIVE: Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. METHODS: Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n = 2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. RESULTS: Fifty-five incident epilepsy cases were identified during a mean of 19 years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p = .022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n = 2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p = .003). SIGNIFICANCE: Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

Omnipolar Versus Bipolar Electrode Mapping in Patients With Atrial Fibrillation Undergoing Catheter Ablation.

BACKGROUND: Peak-to-peak bipolar voltage varies with electrode orientation, fractionation, and collision events. Novel, omnipolar mapping is less dependent on electrode orientation but has limited data in humans. OBJECTIVES: This study sought to compare bipolar peak-to-peak voltage with omnipolar maximum voltage (Vmax) during sinus rhythm in the left atrium of patients with persistent (PerAF) or paroxysmal atrial fibrillation (PAF). METHODS: Baseline voltage maps were generated with bipolar and omnipolar mapping in 20 patients undergoing de novo catheter ablation for PerAF or PAF and 9 patients with known scar from prior cardiac surgery, to validate voltage-based scar approximations. Low voltage was defined as <0.5 mV and scar <0.1 mV. Mean voltage was compared with unpaired t testing. Percent low voltage and scar were compared with chi-square testing. A point-to-point comparison was performed with Bland-Altman analysis. RESULTS: The mean age was 62.2 ± 9.9 years, 34% were women, and 41% had heart failure. Omnipolar mapping identified significantly higher mean voltage than bipolar mapping and classified less points as low voltage (PerAF: 32.90% vs 43.40%; PAF: 19.20% vs 25.60%) and scar (PerAF: 7.72% vs 12.10%; PAF: 4.03% vs 6.07%) (all P < 0.0001). Omnipolar Vmax displayed significant disagreement with bipolar by Bland-Altman analysis. Scar and low-voltage approximations were validated in atria with known scar, in which bipolar mapping overestimated the extent of low voltage (P < 0.0001) and scar (P < 0.0001). CONCLUSIONS: Omnipolar mapping identifies higher voltage and has greater specificity for the detection of low voltage and scar than conventional bipolar mapping in patients with PerAF or PAF.

Neuropathology in the North American sudden unexpected death in epilepsy registry.

Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Electrical storm in patients with left ventricular assist devices: Risk factors, incidence, and impact on survival.

BACKGROUND: Ventricular arrhythmias (VAs) and electrical storm (ES) are recognized complications following left ventricular assist device (LVAD) implantation; however, their association with long term-outcomes remains poorly understood. OBJECTIVE: The purpose of this study was to describe the clinical impact of ES in a population of patients undergoing LVAD implantation at a quaternary care center in the United States. METHODS: This was an observational retrospective study of patients undergoing LVAD implantation from 2009 to 2020 at Duke University Hospital. The incidence of ES (≥3 sustained VA episodes over a 24-hour period without an identifiable reversible cause) was determined from patient records. Risk factors for ES were identified using multivariable Cox proportional hazards modeling. RESULTS: Among 730 patients undergoing LVAD implant, 78 (10.7%) developed ES at a median of 269 (interquartile range [IQR] 7-766) days following surgery. Twenty-seven patients (34.6%) developed ES within 30 days, while 51 (65.4%) presented with ES at a median 639 (IQR 281-1017) days after implant. Following ES, 41% of patients died within 1 year. Patients who developed ES were more likely to have a history of VAs, ventricular tachycardia ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support around the time of LVAD implant than patients without ES. CONCLUSION: ES occurs in 1 in 10 patients after LVAD and is associated with higher mortality. Risk factors for ES include a history of VAs, VT ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support. Optimal management of ES surrounding LVAD implant, including escalation of medical therapy, catheter ablation, or adjunctive sympatholytic therapies, remains uncertain.

Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface.

Natural killer (NK) cells can kill infected or transformed cells via a lytic immune synapse. Diseased cells may exhibit altered mechanical properties but how this impacts NK cell responsiveness is unknown. We report that human NK cells were stimulated more effectively to secrete granzymes A and B, FasL (also known as FasLG), granulysin and IFNγ, by stiff (142 kPa) compared to soft (1 kPa) planar substrates. To create surrogate spherical targets of defined stiffness, sodium alginate was used to synthesise soft (9 kPa), medium (34 kPa) or stiff (254 kPa) cell-sized beads, coated with antibodies against activating receptor NKp30 (also known as NCR3) and the integrin LFA-1 (also known as ITGAL). Against stiff beads, NK cells showed increased degranulation. Polarisation of the microtubule-organising centre and lytic granules were impaired against soft targets, which instead resulted in the formation of unstable kinapses. Thus, by varying target stiffness to characterise the mechanosensitivity of immune synapses, we identify soft targets as a blind spot in NK cell recognition. This article has an associated First Person interview with the co-first authors of the paper.

Feasibility of using real-world data in the evaluation of cardiac ablation catheters: a test-case of the National Evaluation System for Health Technology Coordinating Center.

OBJECTIVES: To determine the feasibility of using real-world data to assess the safety and effectiveness of two cardiac ablation catheters for the treatment of persistent atrial fibrillation and ischaemic ventricular tachycardia. DESIGN: Retrospective cohort. SETTING: Three health systems in the USA. PARTICIPANTS: Patients receiving ablation with the two ablation catheters of interest at any of the three health systems. MAIN OUTCOME MEASURES: Feasibility of identifying the medical devices and participant populations of interest as well as the duration of follow-up and positive predictive values (PPVs) for serious safety (ischaemic stroke, acute heart failure and cardiac tamponade) and effectiveness (arrhythmia-related hospitalisation) clinical outcomes of interest compared with manual chart validation by clinicians. RESULTS: Overall, the catheter of interest for treatment of persistent atrial fibrillation was used for 4280 ablations and the catheter of interest for ischaemic ventricular tachycardia was used 1516 times across the data available within the three health systems. The duration of patient follow-up in the three health systems ranged from 91% to 97% at ≥7 days, 89% to 96% at ≥30 days, 77% to 90% at ≥6 months and 66% to 84% at ≥1 year. PPVs were 63.4% for ischaemic stroke, 96.4% for acute heart failure, 100% at one health system for cardiac tamponade and 55.7% for arrhythmia-related hospitalisation. CONCLUSIONS: It is feasible to use real-world health system data to evaluate the safety and effectiveness of cardiac ablation catheters, though evaluations must consider the implications of variation in follow-up and endpoint ascertainment among health systems.

Enterococcus gallinarum endophthalmitis and meningitis in an allogeneic hematopoietic stem cell transplant patient: A case report and literature review.

Endogenous endophthalmitis caused by Enterococcus gallinarum, an organism with intrinsic resistance to vancomycin, has rarely been reported. We present a case of persistent E. gallinarum bacteremia in a female recipient of hematopoietic stem cell transplant (HSCT) complicated by endophthalmitis and meningoventriculitis, resulting in a fatal outcome despite treatment with intravenous ampicillin and daptomycin. Treatment of endophthalmitis often presents a challenge due to the lack of options for antimicrobials with reliable ocular penetration. Therapeutic decisions can become particularly complex with the involvement of drug-resistant pathogens and host characteristics that limit the choice of antimicrobials due to drug toxicity. This case illustrates a rare manifestation of an opportunistic pathogen.

L'endophtalmite endogène causée par l'Enterococcus gallinarum, un organisme ayant une résistance intrinsèque à la vancomycine, est rarement déclarée. Les auteurs présentent un cas de bactériémie à E. gallinarum persistante chez une femme après une greffe de cellules souches hématopoïétiques compliquée par une endophtalmite et une méningoventriculite dont l'issue a été fatale malgré un traitement à l'ampicilline et à la daptomycine par voie intraveineuse. Il est souvent difficile de traiter l'endophtalmite, à cause du manque d'antimicrobiens ayant une pénétration oculaire fiable. Les décisions thérapeutiques peuvent devenir particulièrement complexes en raison des agents pathogènes pharmacorésistants et des caractéristiques de l'hôte qui limitent le choix d'antimicrobiens, dont la toxicité est élevée. Ce cas illustre une manifestation rare d'agent pathogène opportuniste.