A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Investigating the role of county-level colorectal cancer screening rates on stage at diagnosis of colorectal cancer in rural Georgia.

BACKGROUND: To examine the impact of county-level colorectal cancer (CRC) screening rates on stage at diagnosis of CRC and identify factors associated with stage at diagnosis across different levels of screening rates in rural Georgia. METHODS: We performed a retrospective analysis utilizing data from 2004 to 2010 Surveillance, Epidemiology, and End Results Program. The 2013 United States Department of Agriculture rural-urban continuum codes were used to identify rural Georgia counties. The 2004-2010 National Cancer Institute small area estimates for screening behaviors were applied to link county-level CRC screening rates. Descriptive statistics and multinominal logistic regressions were performed. RESULTS: Among 4,839 CRC patients, most patients diagnosed with localized CRC lived in low screening areas; however, many diagnosed with regionalized and distant CRC lived in high screening areas (p-value = 0.009). In multivariable analysis, rural patients living in high screening areas were 1.2-fold more likely to be diagnosed at a regionalized and distant stage of CRC (both p-value < 0.05). When examining the factors associated with stage at presentation, Black patients who lived in low screening areas were 36% more likely to be diagnosed with distant diseases compared to White patients (95% CI, 1.08-1.71). Among those living in high screening areas, patients with right-sided CRC were 38% more likely to have regionalized disease (95% CI, 1.09-1.74). CONCLUSION: Patients living in high screening areas were more likely to have a later stage of CRC in rural Georgia. IMPACT: Allocating CRC screening/treatment resources and improving CRC risk awareness should be prioritized for rural patients in Georgia.

The relationship of cancer history and chronic disease status to colorectal cancer screening: A cross-sectional analysis of 2020-2021 Behavioral Risk Factor Surveillance System.

PURPOSE: We examined whether having a history of cancer and chronic diseases was associated with guideline-concordant colorectal cancer (CRC) screening utilization. METHODS: Self-reported data from the 2020 and 2021 Behavioral Risk Factor Surveillance System in Oregon and West Virginia were used. Guideline-concordant CRC screening was the outcome of interest. The exposure was having a personal history of cancer, chronic diseases, or both. Multivariable logistic regressions were applied to assess the abovementioned association. RESULTS: Among 10,373 respondents aged 45-75 years, 75.5% of those with a history of cancer and chronic diseases had guideline-concordant CRC screening use versus 52.8% of those without any history (p-value < 0.05). In multivariable analysis, having a history of cancer (OR 1.74; 95% CI 1.11-2.71), chronic diseases (OR 1.35; 95% CI 1.14-1.59), and both cancer and chronic diseases (OR 2.14; 95% CI 1.62-2.82) were positively associated with screening uptake compared to respondents without any history. Regardless of disease history, older age was associated with greater CRC screening uptake (p-value < 0.05). Among respondents with chronic diseases only or without any condition, those with a health care provider had 1.7-fold and 2.7-fold increased odds of receiving CRC screening, respectively. However, current smokers were 28% and 34% less likely to be screened for CRC among those with chronic diseases only and without any conditions, respectively. CONCLUSION: Having a personal history of cancer and chronic diseases appears to be positively associated with guideline-concordant CRC screening use. Effective implementation of patient-centered communication through primary care initiatives may increase adherence to CRC screening recommendations.

Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations.

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.

Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Rural-Urban Disparities in Telemedicine Use Among U.S. Adults with Cancer.

Introduction: The COVID-19 pandemic has resulted in significant changes in health care delivery worldwide, including the widespread adoption of telemedicine. This study examines the prevalence of telemedicine use among cancer survivors in the United States based on rurality and investigates its association with telemedicine use. Methods: The 2021 National Health Interview Survey was used to analyze telemedicine use among cancer survivors during the pandemic. Telemedicine use was the primary outcome, and rurality was the main exposure. Descriptive statistics and multiple logistic regression models were used to examine the association. Results: Out of 27,500 eligible cancer survivors, 51.6% reported using telemedicine in 2021. Telemedicine usage varied across rural areas, with 41.4% of rural cancer survivors using telemedicine compared with 57.5% of cancer survivors in large metropolitan areas (p < 0.001). Rural cancer survivors had significantly lower odds of using telemedicine during the pandemic compared with large metropolitan cancer survivors. Cancer survivors residing in rural areas were 0.56 times less likely (odds ratio [OR] = 0.56; 95% confidence interval [CI] = 0.41-0.75), and those residing in medium and small metropolitan areas were 0.69 times less likely (OR = 0.69; 95% CI = 0.56-0.86) to report telemedicine use compared with cancer survivors in large metropolitan areas. Conclusions: Substantial disparities in telemedicine use were observed between rural and urban areas among cancer survivors. Rural cancer survivors were less likely to utilize telemedicine during the COVID-19 pandemic. Ensuring equitable access to telemedicine requires continued reimbursement for telemedicine services, along with additional efforts to improve access to and utilization of health care for rural cancer survivors.

The relationship of chronic disease conditions to mental and physical health among cancer survivors.

PURPOSE: This study examined the relationship between the presence of chronic disease conditions and mental and physical health among cancer survivors in the United States. METHODS: We conducted a cross-sectional analysis utilizing survey data from the 2016-2017 Behavioral Risk Factor Surveillance System (BRFSS) on 65,673 eligible cancer survivors. The primary outcomes of interest were self-rated metal/physical health in the past 30 days. Descriptive statistics and multivariate logistic regression were used to examine the mentioned association. RESULTS: 15.3% and 24.8% of survivors reported having several days of poor mental and physical health (14-30 days compared to 0-13 days), and 42.4% of survivors reported having one to two chronic diseases. In multivariate analysis, survivors with one to two chronic diseases were more likely to report several days of poor mental (OR, 2.74; 95% CI, 2.22-3.38) and physical (OR, 1.95; 95% CI, 1.72-2.22) health. Survivors with 3+ chronic diseases had markedly higher odds of having several days of poor mental (OR, 6.41; 95% CI, 5.19-7.91) and physical health (OR, 4.71; 95% CI, 4.16-5.34). Among survivors with at least one chronic disease, older age, insured, and more perceived social/emotional support were negatively associated with mental health (p value <0.05). Similarly, older age was related to fewer days of poor physical health (p value <0.05) regardless of chronic disease conditions. CONCLUSION: Having chronic diseases was associated with more days of poor mental and physical health among cancer survivors. Integrated, extensive care should include mental/physical health components and chronic disease management in cancer survivorship care.

The Genetics of Primary Familial Brain Calcification: A Literature Review.

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics.

OBJECTIVE: Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated. METHODS: DCX variants were identified using whole exome and Sanger sequencing from six families with lissencephaly/SBH. We examined how these variants affect DCX functions using microtubule binding, regrowth, and colocalization assays. RESULTS: We found novel DCX variants p.Val177AlafsTer31 and p.Gly188Trp, as well as reported variants p.Arg196His, p.Lys202Met, and p.Thr203Ala. Incidentally, all of the missense variants were clustered on the C-terminal DCX domain. The microtubule binding ability was significantly decreased in p.Val177AlafsTer31, p.Gly188Trp, p.Lys202Met, and previously reported p.Asp262Gly variants. Furthermore, expression of p.Val177AlafsTer31, p.Gly188Trp, p.Arg196His, p.Lys202Met, and p.Asp262Gly variants hindered microtubule growth in cells. There were also decreases in the colocalization of p.Val177AlafsTer31, p.Thr203Ala, and p.Asp262Gly variants to microtubules. SIGNIFICANCE: Our results indicate that these variants in the C-terminal DCX domain altered microtubule binding and dynamics, which may underlie neuronal migration defects during brain development.

Response to Sodium Channel blocking Antiseizure medications and coding polymorphisms of Sodium Channel genes in Taiwanese epilepsy patients.

BACKGROUND: Many antiseizure medications (ASMs) control seizures by blocking voltage-dependent sodium channels. Polymorphisms of sodium channel genes may affect the response to ASMs due to altering the effect of ASMs on blocking sodium channels. METHODS: We conducted a retrospective study of epilepsy patients followed up at the Neurological Department of Kaohsiung Chang Gung Memorial Hospital, Taiwan between January 2010 and December 2018. We categorized the patients into response, partial response, and failure to sodium channel blocking ASM groups. Sodium channel blocking ASMs included phenytoin, carbamazepine, lamotrigine, oxcarbazepine, lacosamide, zonisamide, topiramate, and valproic acid. A subgroup of predominant sodium channel blocking ASMs included phenytoin, carbamazepine, lamotrigine, oxcarbazepine, and lacosamide. Associations between the response of ASMs and single-nucleotide polymorphisms of SCN1A, SCN1B, SCN2A, and SCN9A were analyzed. RESULTS: Two hundred Taiwanese patients and 21 single-nucleotide polymorphisms among SCN1A, SCN1B, SCN2A, and SCN9A were evaluated. We found allele C of rs55742440 in SCN1B was statistically significantly associated with not achieving seizure-free with sodium channel blocking ASMs. For the predominant sodium channel blocking ASMs group, no SNPs were associated with the response of ASMs. CONCLUSION: Single-nucleotide polymorphism in SCN1B was associated with the response to sodium channel blocking ASMs. This highlights the possibility that beta subunits may affect the function of sodium channels and resulted in different responsiveness to ASMs.

Conversation-Based Information Delivery Method for Facility Management.

Facility management platforms are widely used in the facility maintenance phase of the building life cycle. However, a large amount of complex building information affects facility managers' efficiency and user experience in retrieving specific information on the facility management platform. Therefore, this research aims to develop a conversation-based method to improve the efficiency and user experience of facility management information delivery. The proposed method contains four major modules: decision mechanism, equipment dataset, intent analysis, and knowledge base. A chatbot prototype was developed based on the proposed method. The prototype was then validated through a feasibility test and field test at the Shulin Arts Comprehensive Administration Building in Taiwan. The results showed that the proposed method changes the traditional information delivery between users and the facility management platform. By integrating natural language processing (NLP), building information modelling (BIM), and ontological techniques, the proposed method can increase the efficiency of FM information retrieval.

Does Emergency Medical Services Transportation Mitigate Post-stroke Discharge Disability? A Prospective Observational Study.

BACKGROUND: Whether emergency medical services (EMS) transport improves disability outcomes compared with other transport among acute ischemic stroke (AIS) patients is unknown. OBJECTIVE: To study severity-adjusted associations of hospital arrival mode (EMS vs. other transport) with in-hospital and discharge disability outcomes. DESIGN: Prospective observational study. PARTICIPANTS: AIS patients discharged April 2016 to October 2017 from a safety-net hospital in South Carolina. MAIN MEASURES: National Institutes of Health Stroke Scale (NIHSS) change at discharge (admission NIHSS score minus discharge NIHSS, continuous variable), 24-h NIHSS change (attaining high improvement, admission NIHSS minus 24-h NIHSS being 75th percentile or higher), door to neuroimaging (DTI) time, and IV alteplase receipt. NIHSS change was assessed within stroke severity groups, mild, moderate, and severe (admission NIHSS 0-5, 6-14, and ≥ 15, respectively). KEY RESULTS: Of 1168 patients, 838 were study-eligible (52% male, 52.4% Black, 72.2% EMS arrivals, 56.6% mild strokes). Severe and moderate stroke patients were more likely than mild stroke patients to use EMS (adjusted odds ratios, AOR [95% CI] 11.7 [5.0, 27.4] and 4.0 [2.6, 6.3], respectively). EMS arrival was associated with shorter DTI time (adjusted difference - 88.4 min) and higher likelihood of alteplase administration (AOR 5.3 [2.5, 11.4]), both key mediating variables in disability outcomes. High 24-h NIHSS improvement was more likely for EMS arrivals vs. other arrivals among moderate strokes (AOR 3.4 [1.1, 10.9]) and severe strokes (AOR > 999). EMS arrivals had substantially higher NIHSS improvement at discharge within the severe stroke group (adjusted NIHSS change at discharge, 5.9 points higher, p = 0.01). Alteplase recipients showed higher discharge NIHSS improvement than non-recipients (by 2.8 and 1.9 points among severe and moderate strokes, respectively; p = 0.01, 0.02). CONCLUSIONS: The findings offer evidence for including stroke education as a standard of care in the primary care management of patients with stroke-risk comorbidities/lifestyle in order to minimize post-stroke disability.

Colorectal cancer prevention by a CLEAR principles-based colonoscopy protocol: an observational study.

BACKGROUND AND AIMS: Colorectal cancer (CRC) prevention by colonoscopy has been lower than expected. We studied CRC prevention outcomes of a colonoscopy protocol based on Clean the colon, Look Everywhere, and complete Abnormality Removal (CLEAR) principles. METHODS: This observational follow-up study studied patients provided screening colonoscopy at a free-standing private ambulatory surgery center in South Carolina by 80 endoscopists from October 2001 to December 2014, followed through December 2015. The colonoscopy protocol, optimized for polyp clearance, featured in-person bowel preparation instructions reinforced by phone, polyp search and removal throughout insertion and gradual withdrawal with circumferential tip movements, and a team approach using all personnel present to maximize polyp detection, patient safety, and clear-margin polypectomy including requesting repeat inspection or additional tissue removal. Outcome measures were postscreening lifetime CRC risk relative to Surveillance Epidemiology and End Results (SEER)-18 and interval cancer rate (postcolonoscopy CRCs among cancer-free patients at screening). RESULTS: Of 25,862 patients (mean age, 58.1 years; 52% black; 205,522 person-years of observation), 159 had CRC at screening and 67 patients developed interval CRC. The interval CRC rate was 3.34 per 10,000 person-years of observation, 5.79 and 2.24 among patients with and without adenomas, respectively. The rate was similar among older patients (mean age 68.5 years at screening) and with prolonged follow-up. Postscreening lifetime CRC risk was 1.6% (bootstrap 95% confidence interval, 1.3%-1.8%) versus 4.7% in SEER-18, 67% lower. Subgroups with mean screening ages of 50 and 68.5 years showed risk reductions of 80% and 72%, respectively. The adverse event rate was less than usually reported rates: perforation 2.6 per 10,000, bleeding with hospitalization 2.4 per 10,000, and no deaths. CONCLUSIONS: A colonoscopy protocol optimized for polyp clearance prevented 67% of CRC compared with a SEER-18 population given ongoing population screening.

The role of targeted gene panel in pediatric drug-resistant epilepsy.

About 10-30% of pediatric patients with epilepsy have drug-resistant epilepsy. Genetic panels may be useful in identifying etiology and guiding treatment in pediatric patients with drug-resistant epilepsy. In our tertiary center, we used two epilepsy panels, an initial 24-genes panel followed by a more comprehensive 122-genes panel to screen for genetic cause over recent 2 years. A total of 96 patients with drug-resistant epilepsy were evaluated using the 24-genes panel, which revealed 10 (10.4%) of the patients with pathogenic variants. Another 22 patients without causative genetic variants using first-gene panel were evaluated using the 122-genes panel. Out of the 22 patients, 4 had pathogenic variants, and 6 had variants of unknown significance. The total yield rate for the second panel was 18.2% (4/22). In conclusion, although whole exome sequencing has entered clinical practice, epilepsy gene panels may still play some roles because of lower cost and faster time, especially in those with fever-associated epilepsy.

A prospective, multicenter, noninterventional study in Taiwan to evaluate the safety and tolerability of lacosamide as adjunctive therapy for epilepsy in clinical practice.

RATIONALE: Lacosamide (LCM) was initially approved in Taiwan in March 2014 for use as adjunctive therapy for focal impaired awareness seizures and secondarily generalized seizures (SGS) in patients with epilepsy ≥16 years of age. The efficacy and tolerability of adjunctive LCM for the treatment of patients with focal seizures have been demonstrated in randomized, placebo-controlled trials. However, the trials do not reflect a flexible dose setting. This study (EP0063) was conducted to assess the safety and tolerability of LCM in real-world clinical practice in Taiwan. Effectiveness of LCM was also assessed as an exploratory objective. METHODS: EP0063 was a multicenter, prospective, noninterventional study with an expected observation period of 12 months ±â€¯60 days. Eligible patients were ≥16 years of age, had focal impaired awareness seizures and/or SGS (in line with approved indication in Taiwan at the time of the study), were taking at least one concomitant antiseizure medication (ASM), and had at least one seizure in the 3 months before baseline. Patients were prescribed LCM by their treating physician in the course of routine clinical practice. The primary safety variable was treatment-emergent adverse events (TEAEs) spontaneously reported to, or observed by, the treating physician. Based on safety data from previous studies of LCM and known side effects of other ASMs, certain TEAEs (including but not limited to cardiac and electrocardiogram, suicidality, and rash related terms) were analyzed separately. Effectiveness variables included Clinical Global Impression of Change (CGIC) and change in 28-day seizure frequency from baseline to 12 months (or final visit), and freedom from focal seizures. RESULTS: A total of 171 patients were treated with LCM, of whom 139 (81.3%) completed the study. The Kaplan-Meier estimated 12-month retention was 82.9%. Patients had a mean (standard deviation [SD], range) age of 38.5 (14.0, 16-77) years, and 96 (56.1%) were male. Patients were taking a mean (SD, range) of 2.8 (1.1, 1-6) ASMs at baseline. Mean (SD, range) duration of LCM treatment was 288.7 (111.9, 2-414) days, and the mean (SD, range) daily dosage of LCM was 205.0 (82.7, 50.0-505.2) mg/day. Overall, 95 (55.6%) patients reported at least one TEAE, most commonly dizziness (33 [19.3%] patients). Drug-related TEAEs were reported in 74 (43.3%) patients, and drug-related TEAEs leading to discontinuation of LCM were reported in 14 (8.2%) patients. Two (1.2%) patients died during LCM treatment, which were considered not related to LCM. Two (1.2%) patients had suicidality-related TEAEs; these TEAEs were considered either not related to LCM or the relationship was not recorded. Rash-related TEAEs were reported in five (2.9%) patients (considered LCM-related in two patients). Based on the CGIC, at 12 months (or final visit), 109 (63.7%) patients were considered to have improved, 54 (31.6%) had no change, and the remaining eight (4.7%) were minimally worse. At 12 months (or final visit), the median percentage change in focal seizure frequency was -50.0. During the first 6 months of the study, 21 (12.3%) patients were free from focal seizures; 37 (21.6%) patients were free from focal seizures in the last 6 months of the study; and 14 (8.2%) were free from focal seizures for the full 12 months of the study. CONCLUSIONS: Results of this prospective, noninterventional study suggest that adjunctive LCM was generally safe and well tolerated in this patient group in real-world practice in Taiwan. Effectiveness was also favorable, with more than 60% of patients considered to be improved by their physician at 12 months (or final visit).

PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization.

OBJECTIVE: Variants in human PRRT2 cause paroxysmal kinesigenic dyskinesia (PKD) and other neurological disorders. Most reported variants resulting in truncating proteins failed to localize to cytoplasmic membrane. The present study identifies novel PRRT2 variants in PKD and epilepsy patients and evaluates the functional consequences of PRRT2 missense variations. METHODS: We investigated two families with PKD and epilepsies using Sanger sequencing and a multiple gene panel. Subcellular localization of mutant proteins was investigated using confocal microscopy and cell surface biotinylation assay in Prrt2-transfected cells. RESULTS: Two novel PRRT2 variants, p.His232Glnfs*10 and p.Leu298Pro, were identified, and functional study revealed impaired localization of both mutant proteins to the plasma membrane. Further investigation of other reported missense variants revealed decreased protein targeting to the plasma membrane in eight of the 13 missense variants examined (p.Trp281Arg, p.Ala287Thr, p.Ala291Val, p.Arg295Gln, p.Leu298Pro, p.Ala306Asp, p.Gly324Glu, and p.Gly324Arg). In contrast, all benign variants we tested exhibited predominant localization to the plasma membrane similar to wild-type Prrt2. Most likely pathogenic variants were located at conserved amino acid residues near the C-terminus, whereas truncating variants spread throughout the gene. SIGNIFICANCE: PRRT2 missense variants clustering at the C-terminus often lead to protein mislocalization. Failure in protein targeting to the plasma membrane by PRRT2 variants may be a key mechanism in causing PKD and related neurological disorders.

Why acute ischemic stroke patients in the United States use or do not use emergency medical services transport? Findings of an inpatient survey.

BACKGROUND: Patients with acute ischemic stroke (AIS) who use emergency medical services (EMS) receive quicker reperfusion treatment which, in turn, mitigates post-stroke disability. However, nationally only 59% use EMS. We examined why AIS patients use or do not use EMS. METHODS: During 2016-2018, a convenience sample of AIS patients admitted to a primary stroke center in South Carolina were surveyed during hospitalization if they were medically fit, available for survey when contacted, and consented to participate. The survey was programed into EpiInfo with skip patterns to minimize survey burden and self-administered on a touchscreen computer. Survey questions covered symptom characteristics, knowledge of stroke and EMS importance, subjective reactions, role of bystanders and financial factors. Descriptive and multiple regression analyses were performed. RESULTS: Of 108 inpatients surveyed (out of 1179 AIS admissions), 49% were male, 44% African American, mean age 63.5 years, 59% mild strokes, 75 (69%) arrived by EMS, 33% were unaware of any stroke symptom prior to stroke, and 75% were unaware of the importance of EMS use for good outcome. Significant factors that influenced EMS use decisions (identified by regression analysis adjusting for stroke severity) were: prior familiarity with stroke (self or family/friend with stroke) adjusted odds ratio, 5.0 (95% confidence interval, 1.6, 15.1), perceiving symptoms as relevant for self and indicating possible stroke, 26.3 (7.6, 91.1), and bystander discouragement to call 911, 0.1 (0.01,0.7). Further, all 27 patients who knew the importance of EMS had used EMS. All patients whose physician office advised actions other than calling EMS at symptom onset, did not use EMS. CONCLUSION: Systematic stroke education of patients with stroke-relevant comorbidities and life-style risk factors, and public health educational programs may increase EMS use and mitigate post-stroke disability.

Perampanel Treatment for Refractory Status Epilepticus in a Neurological Intensive Care Unit.

BACKGROUND/OBJECTIVE: Perampanel is a novel anti-epileptic drug (AED) which acts as a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist to reduce glutamate-mediated postsynaptic excitation. Previous animal studies and a few case reports/series have suggested that it may be effective to treat refractory status epilepticus (RSE). METHODS: We retrospectively reviewed 67 consecutive patients with RSE, of whom 22 received perampanel. The clinical features, epidemiology-based mortality score in status epilepticus, status epilepticus severity score, seizure control, functional outcome, RSE etiology, and electroencephalogram findings were collected. Responder to perampanel was defined as seizure resolution within 4 days of therapy with perampanel being the last AED used plus no recurrence during hospitalization. RESULTS: Eight of the 22 (36.4%) RSE patients fulfilled the definition of responder to perampanel. An additional 1 patient responded to perampanel after 4 days of treatment. In total, perampanel was the last AED in 9 (40.1%) patients. Among the 8 responders to perampanel, 5 had convulsive SE, 1 had non-convulsive SE, and 2 had focal motor SE. The responders accounted for both of the patients with focal motor SE (100%), 5 (33.3%) of the 15 patients with convulsive SE, and 1 (20%) of the 5 patients with non-convulsive SE. The ictal and inter-ictal activities also decreased after perampanel therapy, and three patients (13.6%) had preferable outcomes at last follow-up. CONCLUSIONS: Perampanel may be an effective add-on treatment for RSE even in patients who failed multiple AEDs. Our study suggests that perampanel may be more effective for focal motor SE and convulsive SE than non-convulsive SE. As most previous studies have focused on non-convulsive SE, further studies are warranted to clarify the effectiveness of perampanel for different subtypes of SE.

Tract-specific atrophy in focal epilepsy: Disease, genetics, or seizures?

OBJECTIVE: To investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts. METHODS: Medically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS-TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel-based analysis of diffusion-weighted imaging. A genetic effect was assessed in first-degree relatives of HS-TLE subjects who did not have epilepsy themselves (HS-1°Rel; n = 26). The role of disease process was uncovered by comparing HS-TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI-neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS-TLE and MRI-neg TLE, in comparison to healthy controls (n = 76). RESULTS: HS-1 °Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS-TLE subjects had lateralized atrophy of most temporal lobe tracts, and hippocampal volumes in HS-TLE correlated with parahippocampal cingulum and anterior commissure atrophy, indicating an effect of the underlying pathology. Ipsilateral atrophy of the tapetum, uncinate, and inferior fronto-occipital fasciculus was found in both HS-TLE and MRI-neg TLE, suggesting a common lateralized effect of focal seizures. Both epilepsy groups had bilateral atrophy of the dorsal cingulum and corpus callosum fibers, which we interpret as a consequence of bilateral insults (potentially generalized seizures and/or medications). INTERPRETATION: Underlying pathology, repeated focal seizures, and global insults each contribute to atrophy in specific tracts. Genetic factors make less of a contribution in this cohort. A multifactorial model of white matter atrophy in focal epilepsy is proposed. Ann Neurol 2017;81:240-250.

Reducing High-Users' Visits to the Emergency Department by a Primary Care Intervention for the Uninsured: A Retrospective Study.

Reducing avoidable emergency department (ED) visits is an important health system goal. This is a retrospective cohort study of the impact of a primary care intervention including an in-hospital, free, adult clinic for poor uninsured patients on ED visit rates and emergency severity at a nonprofit hospital. We studied adult ED visits during August 16, 2009-August 15, 2011 (preintervention) and August 16, 2011-August 15, 2014 (postintervention). We compared pre- versus post-mean annual visit rates and discharge emergency severity index (ESI; triage and resource use-based, calculated Agency for Healthcare Research and Quality categories) among high-users (≥3 ED visits in 12 months) and occasional users. Annual adult ED visit volumes were 16 372 preintervention (47.5% by high-users), versus 18 496 postintervention. High-users' mean annual visit rates were 5.43 (top quartile) and 0.94 (bottom quartile) preintervention, versus 3.21 and 1.11, respectively, for returning high-users, postintervention (all P < .001). Postintervention, the visit rates of new high-users were lower (lowest and top quartile rates, 0.6 and 3.23) than preintervention high-users' rates in the preintervention period. Visit rates of the top quartile of occasional users also declined. Subgroup analysis of medically uninsured high-users showed similar results. Upon classifying preintervention high-users by emergency severity, postintervention mean ESI increased 24.5% among the lowest ESI quartile, and decreased 12.2% among the top quartile. Pre- and post-intervention sample demographics and comorbidities were similar. The observed reductions in overall ED visit rates, particularly low-severity visits; highest reductions observed among high-users and the top quartile of occasional users; and the pattern of changes in emergency severity support a positive impact of the primary care intervention.