Epilepsy is defined by the seemingly random occurrence of spontaneous seizures. The ability to anticipate seizures would enable preventative treatment strategies. A central but unresolved question ...concerns the relationship of seizure timing to fluctuating rates of interictal epileptiform discharges (here termed interictal epileptiform activity, IEA), a marker of brain irritability observed between seizures by electroencephalography (EEG). Here, in 37 subjects with an implanted brain stimulation device that detects IEA and seizures over years, we find that IEA oscillates with circadian and subject-specific multidien (multi-day) periods. Multidien periodicities, most commonly 20-30 days in duration, are robust and relatively stable for up to 10 years in men and women. We show that seizures occur preferentially during the rising phase of multidien IEA rhythms. Combining phase information from circadian and multidien IEA rhythms provides a novel biomarker for determining relative seizure risk with a large effect size in most subjects.
Co-published with What are the institutional politics associated with fostering trans* inclusive policies? When formalizing a policy, what unanticipated challenges may emerge? How are students, ...particularly trans* students, influenced by the implementation of gender-inclusive housing practices and policies? Also, what are campus administrators and practitioners learning from their involvement with the development of trans* work on campus? Housing and Residence Life (HRL) plays an important role in the safety, well-being, and sense of belonging for college students, but gender-inclusive policies and practices in HRL are largely under-explored in student affairs and higher education publications. There are five key objectives that guide this book: 1. To promote and challenge student affairs and higher education staff knowledge about trans* students' identities and experiences; 2. To support and celebrate the accomplishments of educators and professionals in their strides to promote trans* inclusive policies and practices; 3. To highlight the unique role that housing and residence life plays in creating institutional change and serving trans* student populations; 4. To demonstrate the value and use of scholarly personal narratives, particularly for narrating experiences related to implementing trans* inclusive policies in housing and residence life; and 5. To create a strong partnership between scholarship and student affairs practice by developing an avenue for practitioner-scholars to publish their experiences related to gender-inclusive policies in housing and residence life and for others to use these stories to improve their practice. Administrators, educators, and student affairs staff will find this book useful at any stage in the process of creating gender-inclusive housing policies on their campuses.
Rapid correction of severe hyponatremia can result in serious neurologic complications, including osmotic demyelination. Few data exist on incidence and risk factors of rapid correction or osmotic ...demyelination.
In a retrospective cohort of 1490 patients admitted with serum sodium <120 mEq/L to seven hospitals in the Geisinger Health System from 2001 to 2017, we examined the incidence and risk factors of rapid correction and osmotic demyelination. Rapid correction was defined as serum sodium increase of >8 mEq/L at 24 hours. Osmotic demyelination was determined by manual chart review of all available brain magnetic resonance imaging reports.
Mean age was 66 years old (SD=15), 55% were women, and 67% had prior hyponatremia (last outpatient sodium <135 mEq/L). Median change in serum sodium at 24 hours was 6.8 mEq/L (interquartile range, 3.4-10.2), and 606 patients (41%) had rapid correction at 24 hours. Younger age, being a woman, schizophrenia, lower Charlson comorbidity index, lower presentation serum sodium, and urine sodium <30 mEq/L were associated with greater risk of rapid correction. Prior hyponatremia, outpatient aldosterone antagonist use, and treatment at an academic center were associated with lower risk of rapid correction. A total of 295 (20%) patients underwent brain magnetic resonance imaging on or after admission, with nine (0.6%) patients showing radiologic evidence of osmotic demyelination. Eight (0.5%) patients had incident osmotic demyelination, of whom five (63%) had beer potomania, five (63%) had hypokalemia, and seven (88%) had sodium increase >8 mEq/L over a 24-hour period before magnetic resonance imaging. Five patients with osmotic demyelination had apparent neurologic recovery.
Among patients presenting with severe hyponatremia, rapid correction occurred in 41%; nearly all patients with incident osmotic demyelination had a documented episode of rapid correction.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_06_05_CJASNPodcast_18_7_G.mp3.
Reopening colleges and universities during the coronavirus disease 2019 (COVID-19) pandemic poses a special challenge worldwide. Taiwan is one of the few countries where schools are functioning ...normally. To secure the safety of students and staff, the Ministry of Education in Taiwan established general guidelines for college campuses. The guidelines delineated creation of a task force at each university; school-based risk screening based on travel history, occupation, contacts, and clusters; measures on self-management of health and quarantine; general hygiene measures (including wearing masks indoors); principles on ventilation and sanitization; regulations on school assemblies; a process for reporting suspected cases; and policies on school closing and make-up classes. It also announced that a class should be suspended if 1 student or staff member in it tested positive and that a school should be closed for 14 days if it had 2 or more confirmed cases. As of 18 June 2020, there have been 7 confirmed cases in 6 Taiwanese universities since the start of the pandemic. One university was temporarily closed, adopted virtual classes, and quickly reopened after 14 days of contact tracing and quarantine of possible contacts. Taiwan's experience suggests that, under certain circumstances, safely reopening colleges and universities this fall may be feasible with a combination of strategies that include containment (access control with contact tracing and quarantine) and mitigation (hygiene, sanitation, ventilation, and social distancing) practices.
Non–small cell lung carcinomas (NSCLCs) commonly present as 2 or more separate tumors. Biologically, this encompasses 2 distinct processes: separate primary lung carcinomas (SPLCs), representing ...independently arising tumors, and intrapulmonary metastases (IPMs), representing intrapulmonary spread of a single tumor. The advent of computed tomography imaging has substantially increased the detection of multifocal NSCLCs. The strategies and approaches for distinguishing between SPLCs and IPMs have evolved significantly over the years. Recently, genomic sequencing of somatic mutations has been widely adopted to identify targetable alterations in NSCLC. These molecular techniques have enabled pathologists to reliably discern clonal relationships among multiple NSCLCs in clinical practice. However, a standardized approach to evaluating and staging multiple NSCLCs using molecular methods is still lacking. Here, we reviewed the historical context and provided an update on the growing applications of genomic testing as a clinically relevant benchmark for determining clonal relationships in multiple NSCLCs, a practice we have designated “comparative molecular profiling.” We examined the strengths and limitations of the morphology-based distinction of SPLCs vs IPMs and highlighted pivotal clinical and pathologic insights that have emerged from studying multiple NSCLCs using genomic approaches as a gold standard. Lastly, we suggest a practical approach for evaluating multiple NSCLCs in the clinical setting, considering the varying availability of molecular techniques.
Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays, which cannot detect histologic transformation and have differential ...sensitivity for copy number changes and chromosomal rearrangements.
To characterize mechanisms of resistance to osimertinib, patients with metastatic
-mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified.
Among 62 patients who met eligibility criteria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2
amplification, 1
mutation, 1
fusion, and 1
fusion) whereas 4% (1/27) had an acquired
mutation (
G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired
mutation, chromosome 3q amplification, and
amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial
sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation
S768 + V769L and the mutation
H1094Y were identified and validated as resistance mechanisms with potential treatment options.
Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.
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Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here, we assess the performance of a massively parallel droplet-based method for mapping ...transposase-accessible chromatin in single cells using sequencing (scATAC-seq). We apply scATAC-seq to obtain chromatin profiles of more than 200,000 single cells in human blood and basal cell carcinoma. In blood, application of scATAC-seq enables marker-free identification of cell type-specific cis- and trans-regulatory elements, mapping of disease-associated enhancer activity and reconstruction of trajectories of cellular differentiation. In basal cell carcinoma, application of scATAC-seq reveals regulatory networks in malignant, stromal and immune cells in the tumor microenvironment. Analysis of scATAC-seq profiles from serial tumor biopsies before and after programmed cell death protein 1 blockade identifies chromatin regulators of therapy-responsive T cell subsets and reveals a shared regulatory program that governs intratumoral CD8
T cell exhaustion and CD4
T follicular helper cell development. We anticipate that scATAC-seq will enable the unbiased discovery of gene regulatory factors across diverse biological systems.
To reduce the power consumption and improve the device performance in scaled CMOS integrated circuits, transistors with steep subthreshold swing (SS) is highly desirable. The tunnel field-effect ...transistor (TFET) based on the band-to-band tunneling has been suggested as a replacement to conventional MOSFETs. In order to improve the device performance of TFET, enhanced carrier transport across the tunneling junction is crucial. In this paper, source-pocket Si TFET is presented and successfully fabricated by laser annealing. This TFET has enhanced lateral electric field across the source tunneling junction, resulting in a reduction of tunneling distance. The experimental data of the proposed paper, for the first time, shows steep SS (46 mV/dec at 1 pA/μm), excellent I ON / I OFF ratio ( <; 10 7 ), and improved output characteristics at T = 300 K due to the dramatic reduction of the tunneling resistance. Compared with other TFET works, the proposed method is efficient to improve the device performance on TFET.
Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic ...sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC).
We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341–468 gene next-generation sequencing and other molecular platforms.
The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers.
SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.
Abstract Objectives The purpose of this study was to explore the diagnostic usefulness of hybrid cardiac magnetic resonance (CMR) and positron emission tomography (PET) using 18F-fluorodeoxyglucose ...(FDG) for active cardiac sarcoidosis. Background Active cardiac sarcoidosis (aCS) is underdiagnosed and has a high mortality. Methods Patients with clinical suspicion of aCS underwent hybrid CMR/PET with late gadolinium enhancement (LGE) and FDG to assess the pattern of injury and disease activity, respectively. Patients were categorized visually as magnetic resonance (MR)+PET+ (characteristic LGE aligning exactly with increased FDG uptake), MR+PET− (characteristic LGE but no increased FDG), MR−PET− (neither characteristic LGE nor increased FDG), and MR−PET+ (increased FDG uptake in absence of characteristic LGE) and further characterized as aCS+ (MR+PET+) or aCS− (MR+PET−, MR−PET−, MR−PET+). FDG uptake was quantified using maximum target-to-normal-myocardium ratio and the net uptake rate ( K i ) from dynamic Patlak analysis. Receiver operating characteristic methods were used to identify imaging biomarkers for aCS. FDG PET was assessed using computed tomography/PET in 19 control subjects with healthy myocardium. Results A total of 25 patients (12 males; 54.9 ± 9.8 years of age) were recruited prospectively; 8 were MR+PET+, suggestive of aCS; 1 was MR+PET−, consistent with inactive cardiac sarcoidosis; and 8 were MR−PET−, with no imaging evidence of cardiac sarcoidosis. Eight patients were MR−PET+ (6 with global myocardial FDG uptake, 2 with focal-on-diffuse uptake); they demonstrated distinct K i values and hyperintense maximum standardized uptake value compared with MR+PET+ patients. Similar hyperintense patterns of global (n = 9) and focal-on-diffuse (n = 2) FDG uptake were also observed in control patients, suggesting physiological myocardial uptake. Maximum target-to-normal-myocardium ratio values were higher in the aCS+ group (p < 0.001), demonstrating an area under the curve of 0.98 on receiver operating characteristic analysis for the detection of aCS, with an optimal maximum target-to-normal myocardium ratio threshold of 1.2 (Youden index: 0.94). Conclusions CMR/PET imaging holds major promise for the diagnosis of aCS, providing incremental information about both the pattern of injury and disease activity in a single scan. (In Vivo Molecular Imaging MRI of Atherothrombotic Lesions; NCT01418313 )
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