Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

Genotypic and phenotypic analysis of Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder caused by mutations in the TSC1 or TSC2 gene. The aim of this study was to analyze the genotypes and phenotypes of Korean patients diagnosed with TSC and expand our understanding of this disorder. This retrospective observational study included 331 patients clinically diagnosed with TSC between November 1990 and April 2023 at Severance Children's Hospital, Seoul, South Korea. The demographic and clinical characteristics of the patients were investigated. Thirty novel variants were identified. Of the 331 patients, 188 underwent genetic testing, and genotype-phenotype variation was analyzed according to the type of gene mutation and functional domain. Fourty-nine patients (49/188, 26%) were had TSC1 mutations, 103 (55%) had TSC2 mutations, and 36 (19%) had no mutation identified (NMI). Hotspots were identified in exons 8 of TSC1 and exons 35 and 41 of TSC2. Patients with TSC2 mutations exhibited a significantly younger age at the time of seizure onset and had refractory epilepsy. Infantile epileptic spasms syndrome (IESS) was more common in the middle mutation domain of TSC2 than in the hamartin domain. Additionally, retinal hamartoma, cardiac rhabdomyoma, and renal abnormalities were significantly associated with TSC2 compared with other gene types. This study contributes to our understanding of TSC by expanding the genotypic spectrum with novel variants and providing insights into the clinical spectrum of patients with TSC in Korea.

Management of Uncomplicated Appendicitis in Adults: A Nationwide Analysis From 2018 to 2019.

INTRODUCTION: Nonoperative management (NOM) of uncomplicated appendicitis (UA) has been increasingly utilized in recent years. The aim of this study was to describe nationwide trends of sociodemographic characteristics, outcomes, and costs of patients undergoing medical versus surgical management for UA. METHODS: The 2018-2019 National (Nationwide) Inpatient Sample was queried for adults (age ≥18 y) with UA; diagnosis, as well as laparoscopic and open appendectomy, were defined by the International Classification of Diseases, 10th Revision, Clinical Modification codes. We examined several characteristics, including cost of care and length of hospital stay. RESULTS: Among the 167,125 patients with UA, 137,644 (82.4%) underwent operative management and 29,481 (17.6%) underwent NOM. In bivariate analysis, we found that patients who had NOM were older (53 versus 43 y, P < 0.001) and more likely to have Medicare (33.6% versus 16.1%, P < 0.001), with higher prevalence of comorbidities such as diabetes (7.8% versus 5.5%, P < 0.001). The majority of NOM patients were treated at urban teaching hospitals (74.5% versus 66.3%, P < 0.001). They had longer LOS's (5.4 versus 2.3 d, P < 0.001) with higher inpatient costs ($15,584 versus $11,559, P < 0.001) than those who had an appendectomy. Through logistic regression we found that older patients had up to 4.03-times greater odds of undergoing NOM (95% CI: 3.22-5.05, P < 0.001). CONCLUSIONS: NOM of UA is more commonly utilized in patients with comorbidities, older age, and those treated in teaching hospitals. This may, however, come at the price of longer length of stay and higher costs. Further guidelines need to be developed to clearly delineate which patients could benefit from NOM.

Firearm-Related Injuries and the US Opioid and Other Substance Use Epidemic: A Nationwide Evaluation of Emergency Department Encounters.

INTRODUCTION: There has been a sharp climb in the Unites States' death rate among opioid and other substance abuse patients, as well as an increased prevalence in gun violence. We aimed to investigate the association between substance abuse and gun violence in a national sample of patients presenting to US emergency departments (EDs). METHODS: We queried the 2018-2019 Nationwide Emergency Department Sample for patients ≥18 years with substance abuse disorders (opioid and other) using International Classification of Diseases, 10th Revision, Clinical Modification codes. Within this sample, we analyzed characteristics and outcomes of patients with firearm-related injuries. The primary outcome was mortality; secondary outcomes were ED charges and length of stay. RESULTS: Among the 25.2 million substance use disorder (SUD) patients in our analysis, 35,306 (0.14%) had a firearm-related diagnosis. Compared to other SUD patients, firearm-SUD patients were younger (33.3 versus 44.7 years, P < 0.001), primarily male (88.6% versus 54.2%, P < 0.001), of lower-income status (0-25th percentile income: 56.4% versus 40.5%, P < 0.001), and more likely to be insured by Medicaid or self-pay (71.6% versus 53.2%, P < 0.001). Firearm-SUD patients had higher mortality (1.4% versus 0.4%, P < 0.001), longer lengths of stay (6.5 versus 4.9 days, P < 0.001), and higher ED charges ($9269 versus $5,164, P < 0.001). Firearm-SUD patients had a 60.3% rate of psychiatric diagnoses. Firearm-SUD patients had 5.5 times greater odds of mortality in adjusted analyses (adjusted odds ratio: 5.5, P < 0.001). CONCLUSIONS: Opioid-substance abuse patients with firearm injuries have higher mortality rates and costs among these groups, with limited discharge to postacute care resources. All these factors together point to the urgent need for improved screening and treatment for this vulnerable group of patients.

Surviving the cold: Assessing long-term outcomes among Korean CKD patients exposed to low perceived temperature during winter.

Perceived temperature (PT), which encompasses meteorological factors such as wind speed, cloud cover, and humidity, reflects the actual effect of temperature on the human body. However, limited data exist on the health implications of prolonged exposure to low temperatures during winter in individuals with chronic kidney disease (CKD). We investigated the association between winter PT and long-term outcomes among CKD patients. A total of 32,870 CKD patients from three tertiary hospitals in Seoul were enrolled in this retrospective study (2001-2018). PT was calculated using Staiger's equation, integrating temperature data from 29 automated weather stations across Seoul, along with dew point temperature, wind velocity, and cloud cover data. Kriging interpolation was utilized to estimate PT values at the patients' locations. Overall mortality and major adverse cardiovascular events (MACEs) were assessed using a time-varying Cox proportional hazards model. Additionally, the Cox regression model evaluated PT corresponding to temperature thresholds for cold surge watches or warnings. Over a median follow-up of 6.14 ± 3.96 years, 6147 deaths (18.7%) were recorded. We found that as the average or minimum PT and Ta decreased by 1 °C, the risk of overall mortality significantly increased. In multivariable analyses, the hazard ratio (HR) for the average PT was 1.049 (95% confidence interval [CI] 1.028-1.071), and that for the minimum PT was 1.038 (CI 1.027-1.052). Furthermore, a cold surge warning at a PT of -25.63 °C indicated an HR of 1.837 (CI 1.764-1.914) and a C-index of 0.792. The increased risk of mortality was more pronounced in patients with low or middle socioeconomic statuses. For MACEs, lower average and minimum PT and Ta were associated with an increased risk, following a similar trend to overall mortality, although not all results reached statistical significance. These findings emphasize the importance of targeted public health policies to mitigate risks among vulnerable CKD patients.

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy.

BACKGROUND AND PURPOSE: There is extensive literature on monogenic epilepsies caused by mutations in familiar channelopathy genes such as SCN1A. However, information on other less-common channelopathy genes is scarce. This study aimed to explore the genetic and clinical characteristics of patients diagnosed with unusual voltage-gated sodium and potassium channelopathies related to epilepsy. METHODS: This observational, retrospective study analyzed pediatric patients with epilepsy who carried pathogenic variants of unusual voltage-gated sodium and potassium channelopathy genes responsible for seizure-associated phenotypes. Targeted next-generation sequencing (NGS) panel tests were performed between November 2016 and June 2022 at Severance Children's Hospital, Seoul, South Korea. Clinical characteristics and the treatment responses to different types of antiseizure medications were further analyzed according to different types of gene mutation. RESULTS: This study included 15 patients with the following unusual voltage-gated sodium and potassium channelopathy genes: SCN3A (n=1), SCN4A (n=1), KCNA1 (n=1), KCNA2 (n=4), KCNB1 (n=6), KCNC1 (n=1), and KCNMA1 (n=1). NGS-based genetic testing identified 13 missense mutations (87%), 1 splice-site variant (7%), and 1 copy-number variant (7%). Developmental and epileptic encephalopathy was diagnosed in nine (60%) patients. Seizure freedom was eventually achieved in eight (53%) patients, whereas seizures persisted in seven (47%) patients. CONCLUSIONS: Our findings broaden the genotypic and phenotypic spectra of less-common voltage-gated sodium and potassium channelopathies associated with epilepsy.

Identification of etiologies according to baseline clinical features of pediatric new-onset refractory status epilepticus in single center retrospective study.

PURPOSE: New-onset refractory status epilepticus (NORSE) is defined as a state of prolonged seizure activity that does not improve despite the appropriate administration of medications, with underlying causes unknown after the initial diagnosis of status epilepticus. Because episodes of NORSE are accompanied by severe complications and a high risk of mortality, the prompt identification of the underlying cause is crucial for effective treatment and outcome prediction. This study assessed the relationship of NORSE etiologies with baseline clinical features in pediatric population. METHODS: Seventy-one pediatric patients, under 18 years of age at the initial diagnosis (4.50 ± 4.04, mean ± standard deviation), who experienced at least one episode of NORSE and underwent a comprehensive diagnostic evaluation between January 2005 and June 2020 at our center, were retrospectively selected. We reviewed clinical features at disease onset and long-term follow-up data. Uniform manifold approximation and projection (UMAP) was used to distinguish etiological clusters according to baseline clinical characteristics, and further analysis was performed based on underlying etiologies. RESULTS: Two distinct etiological groups-genetic and non-genetic-were identified based on the UMAP of clinical characteristics. Dravet syndrome (12/15, 80%) was more predominant in patients with a genetic diagnosis, whereas cryptogenic NORSE and encephalitis were prevalent in patients without a genetic diagnosis. The analysis of etiological categories revealed that age at the onset of status epilepticus (P=0.021) and progression to super refractory status epilepticus (SRSE) (P=0.038) were independently associated with differences in etiologies. CONCLUSION: Several clinical features in patients with NORSE, including the age of onset and the development of SRSE, can help identify underlying causes, which necessitate prompt and adequate treatment.

Reconsidering Fresh Frozen Plasma Availability to Reduce Blood Product Waste During Massive Transfusion Events in Trauma.

BACKGROUND: Within component therapy of massive transfusion protocol (MTP) in trauma, thawed plasma is particularly susceptible to expiring without use given its short 5-day shelf life. Optimizing the number of thawed products without compromising safety is important for hospital resource management. The goal is to examine thawed plasma utilization rates in trauma MTP events and optimize the MTP cooler content at our Level I trauma center. METHODS: Trauma MTP activations from 01/2019 to 12/2022 were retrospectively reviewed. During the study period, blood products were distributed in a 12:12:1 ratio of packed red blood cells (pRBC): plasma: platelets per cooler, with up to 4 additional units of low-titer, group O whole blood (LTOWB) available. The primary measure was percent return of unused, thawed plasma. RESULTS: There were 367 trauma MTP activations with a median (IQR) activation call-to-first cooler delivery time of 8 (6-10) minutes. 73.0% of thawed plasma was returned to the blood bank unused. In one third of MTP activations, all dispensed plasma was returned. The majority (74.1%) of patients required 6 or fewer units of plasma. In 81.5% of activations, 10 or fewer units of plasma and 10 or fewer units of pRBC were used. DISCUSSION: The majority of trauma MTP requirements may be accommodated with a reduced cooler content of 6 units pRBC, 6 units plasma, and 1 pheresis platelets, buffered by up to 4 units LTOWB (approximates 4 units of pRBC/4 units plasma), in conjunction with a sub-10min cooler delivery time. Follow-up longitudinal studies are needed.

Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: Polygenic risk score analysis.

BACKGROUND: The effect of dyslipidemia on kidney disease outcomes has been inconclusive, and it requires further clarification. Therefore, we aimed to investigate the effects of genetic factors on the association between dyslipidemia and the risk of chronic kidney disease (CKD) using polygenic risk score (PRS). METHODS: We analyzed data from 373,523 participants from the UK Biobank aged 40-69 years with no history of CKD. Baseline data included plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride, as well as genome-wide genotype data for PRS. Our primary outcome, incident CKD, was defined as a composite of estimated glomerular filtration rate < 60 ml/min/1.73 m2 and CKD diagnosis according to International Classification of Disease-10 codes. The effects of the association between lipid levels and PRS on incident CKD were assessed using the Cox proportional hazards model. To investigate the effect of this association, we introduced multiplicative interaction terms into a multivariate analysis model and performed subgroup analysis stratified by PRS tertiles. RESULTS: In total, 4,424 participants developed CKD. In the multivariable analysis, PRS was significantly predictive of the risk of incident CKD as both a continuous variable and a categorized variable. In addition, lower total cholesterol, LDL-C, HDL-C, and higher triglyceride levels were significantly associated with the risk of incident CKD. There were interactions between triglycerides and intermediate and high PRS, and the interactions were inversely associated with the risk of incident CKD. CONCLUSIONS: This study showed that PRS presented significant predictive power for incident CKD and individuals in the low-PRS group had a higher risk of triglyceride-related incident CKD.

The estimated mediating roles of anemia-related variables in the association between kidney function and mortality: a National Health and Nutrition Examination Survey (NHANES) study.

Anemia is a common complication of chronic kidney disease (CKD), impacting long-term outcomes such as mortality and morbidity. Analyzing NHANES data from 1999 through 2016 for adults aged ≥ 20 years, we assessed the mediating effects of anemia biomarkers (hemoglobin, hematocrit, red cell distribution width [RDW], and mean corpuscular hemoglobin concentration [MCHC]) on CKD-related outcomes by using hazard ratios from a biomarker-adjusted model. Of 44,099 participants, 7463 experienced all-cause death. Cox proportional hazard models revealed a higher all-cause mortality risk in the > 45 years and CKD groups than in the early CKD group. Hemoglobin, hematocrit and MCHC were inversely related to all-cause mortality; RDW was related to mortality. Single mediation analysis showed greater mediating effects of anemia indicators on CKD and mortality in the elderly (> 65 years) population than those in the general population. In the multimediation analysis, the combined mediating effect of anemia was higher in the CKD population than in the general population. This study showed a proportional increase in the mediating effect of anemia with CKD stage, suggesting potential therapeutic avenues. However, further exploration of other mediating factors on kidney outcomes is necessary.

Efficacy of enteral feeding by gastrostomy tube placement in patients with Lennox-Gastaut syndrome on body weight and days of hospitalization: A retrospective case series.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe form of drug-resistant epilepsy that begins during childhood and frequently leads to significant neurological impairments. Patients with LGS are likely to receive improper oral nutrition because of issues such as dysphagia and aspiration risk, potentially resulting in long-term tube feeding and eventual gastrostomy tube placement. Therefore, we investigated the effects of gastrostomy tube placement on nutrition outcomes and frequency of hospitalization in LGS. METHODS: We retrospectively examined 67 patients diagnosed with LGS who had undergone gastrostomy tube placement between January 2005 and August 2022. Comprehensive clinical data and complications arising from the procedure were collected. Patients' nutrition condition and frequency of hospitalizations were analyzed before and after gastrostomy tube placement. RESULTS: Gastrostomy tube placement was performed for the following reasons: high risk of aspiration (50 out of 67, 74.6%), dysphagia (13 out of 67, 25.4%), persistent nasogastric tube feeding (2 out of 67, 3.0%), and severe malnutrition (2 out of 67, 3.0%). After the procedure, z scores for weight-for-age improved significantly, shifting from -3.35 ± 3.57 to -2.54 ± 2.70 over a 2-year interval (P < 0.001). Additionally, the total days of hospitalization and days of hospitalization due to respiratory symptoms reduced significantly from 41.94 ± 51.76 to 15.27 ± 26.68 (P < 0.001) and from 23.75 ± 36.92 to 10.52 ± 22.98 (P = 0.009), respectively. Among the patients, 50 (74.6%) experienced complications resulting from gastrostomy, with a relatively small proportion of major complications (11 out of 67, 16.4%) and no mortality. CONCLUSION: Gastrostomy tube placement is a relatively safe procedure with favorable effects on nutrition status and hospitalization rates in patients with LGS.

Long-term exposure to high perceived temperature and risk of mortality among patients with chronic kidney disease.

Health risks due to climate change are emerging, particularly from high-temperature exposure. The perceived temperature is an equivalent temperature based on the complete heat budget model of the human body. Therefore, we aimed to analyze the effect of perceived temperature on overall mortality among patients with chronic kidney disease. In total, 32,870 patients with chronic kidney disease in Seoul participated in this retrospective study (2001-2018) at three medical centers. The perceived temperature during the summer season was calculated using meteorological factors, including the air temperature near the automated weather station, dew point temperature, wind velocity, and total cloud amount. We assessed the association between perceived temperature using Kriging spatial interpolation and mortality in patients with CKD in the time-varying Cox proportional hazards model that was adjusted for sex, age, body mass index, hypertension, diabetes mellitus, estimated glomerular filtration rate, smoking, alcohol consumption, and educational level. During the 6.14 ± 3.96 years of follow-up, 3863 deaths were recorded. In multivariable analysis, the average level of perceived temperature and maximum level of perceived temperature demonstrated an increased risk of overall mortality among patients with chronic kidney disease. The concordance index for mortality of perceived temperature was higher than temperature, discomfort index, and heat index. When stratified by age, diabetes mellitus, and estimated glomerular filtration rate, patients with chronic kidney disease with young age (age <65 years) showed higher hazard ratio for mortality (interaction P = 0.049). Moreover, the risk of death in the winter and spring seasons was more significant compared to that of the summer and autumn seasons. Therefore, long-term exposure to high perceived temperature during summer increases the risk of mortality among patients with chronic kidney disease.