End-stage ADPKD with a low-frequency PKD1 mosaic variant accelerated by chemoradiotherapy.

Autosomal dominant polycystic kidney disease (ADPKD) is commonly caused by PKD1, and mosaic PKD1 variants result in milder phenotypes. We present the case of a 32 year-old male with chronic active Epstein-Barr virus who underwent bone marrow transplantation with chemoradiotherapy at age 9. Despite a low-frequency mosaic splicing PKD1 variant, he developed severe renal cysts and end-stage renal disease in his 30 s. This case highlights how environmental factors may contribute to the genetic predisposition to ADPKD.

Association of perinatal factors with neurodevelopmental referrals in a population-based cohort study in Japan.

Although the causes of neurodevelopmental disorders remain unknown, several environmental risk factors have attracted considerable attention. We conducted a retrospective, longitudinal, population-based cohort study using data from infant health examinations of children born to mothers with pregnancies between April 1, 2014 and March 31, 2016 in Kobe City to identify the perinatal factors associated with neurodevelopmental referrals in 3-year-old children. There were 15,223 and 1283 children in the normal and referral groups, respectively. Neurodevelopmental referrals at the health checkup for 3-year-old children were significantly associated with the lack of social support during pregnancy (adjusted odds ratio [aOR] 1.99, 99% CI 1.14-3.45, p = 0.001), history of psychiatric consultation (aOR 1.56, 99% CI 1.10-2.22, p = 0.001), no social assistance post-delivery (aOR 1.49, 99% CI 1.03-2.16, p = 0.006), Edinburgh Post-natal Depression Scale (EPDS) score ≥ 9 (aOR 1.36, 99% CI 1.01-1.84, p = 0.008), infant gender (male) (aOR 2.51, 99% CI 2.05-3.06, p < 0.001), and cesarean delivery (aOR 1.39, 99% CI 1.11-1.75, p < 0.001). In conclusion, this exploratory study in the general Japanese population identified six perinatal factors associated with neurodevelopmental referrals in 3-year-old children: infant gender (male), cesarean section, maternal history of psychiatric consultation, EPDS score ≥ 9, lack of social support during pregnancy, and no social assistance post-delivery.

Clinical characteristics of SARS-CoV-2-associated encephalopathy in children: Nationwide epidemiological study.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sometimes triggers acute encephalopathy as a serious neurological complication in children. We previously reported the clinico-radiological findings of SARS-CoV-2-associated encephalopathy. The advent of the SARS-CoV-2 omicron variant led to a marked increase in pediatric patients with coronavirus disease 2019 (COVID-19); however, epidemiological changes with acute encephalopathy according to the emergence of SARS-CoV-2 have not yet been documented. Therefore, the present study investigated epidemiological differences in SARS-CoV-2-associated encephalopathy during the BA.1/BA.2 and BA.5 predominant periods and also between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. METHODS: We conducted a nationwide survey of SARS-CoV-2-associated encephalopathy in Japanese children between June and November 2022. We compared the present results during the BA.5 predominant period and previous findings during the BA.1/BA.2 predominant period. We also compared the clinico-radiological syndromes of encephalopathy between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. RESULTS: Although many patients with SARS-CoV-2-associated encephalopathy in the BA.5 predominant period had seizures as their initial symptoms, no significant differences were observed in the clinical features. Patients with SARS-CoV-2-associated encephalopathy had worse outcomes than those with non-SARS-CoV-2-associated encephalopathy (p-value = 0.003). Among 103 patients with SARS-CoV-2-associated encephalopathy, 14 (13.6%) had severe types of acute encephalopathy, namely, encephalopathy with acute fulminant cerebral edema (AFCE) and hemorrhagic shock and encephalopathy syndrome (HSES). Also, 28 (27.2%) patients with SARS-CoV-2-associated encephalopathy had poor outcome: severe neurological sequelae or death. Ninety-five patients (92.2%) were not vaccinated against SARS-CoV-2. CONCLUSIONS: In SARS-CoV-2-associated encephalopathy, high percentages of AFCE and HSES can result in poor outcomes.

Range of protein induced by vitamin K absence or antagonist-II levels in neonates at birth.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000-4999 mAU/mL), and 10.7% latent VK deficiency (200-999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p < 0.001). Gestational age correlated with PIVKA-II levels (r2 = 0.117, p < 0.0001). Median serum PIVKA-II levels and incidence of PIVKA-II-positive cases (≥ 50 mAU/mL, 16.4%) were lower at 5 days after birth than at birth, possibly reflecting the postnatal VK prophylaxis impact. Only one infant was diagnosed with VK deficiency bleeding (PIVKA-II levels, at birth: 10,567 mAU/mL; at day 5: 2418 mAU/mL). Thus, serum PIVKA-II levels after birth weakly correlated with gestational age. VK deficiency was more common in term infants than in preterm infants.

Association of early bedtime at 3 years of age with higher academic performance and better non-cognitive skills in elementary school.

This study investigated the relationship between sleep habits in early childhood and academic performance and non-cognitive skills in the first grade. We retrospectively analyzed a longitudinal population-based cohort from birth through early childhood, up to elementary school, in Amagasaki City, Japan. The primary outcome was academic performance in the first grade. Other outcomes were self-reported non-cognitive skills. Overall, 4395 children were enrolled. Mean national language scores for children with bedtimes at 18:00-20:00, 21:00, 22:00, and ≥ 23:00 were 71.2 ± 19.7, 69.3 ± 19.4, 68.3 ± 20.1, and 62.5 ± 21.3, respectively. Multiple regression analysis identified bedtime at 3 years as a significant factor associated with academic performance. However, sleep duration was not significantly associated with academic performance. Bedtime at 3 years also affected non-cognitive skills in the first grade. Diligence decreased with a later bedtime (21:00 vs. 18:00-20:00; odds ratio [OR]: 1.98, 95% confidence interval [CI] 1.27-3.09; 22:00 vs. 18:00-20:00; OR: 2.15, 95% CI 1.37-3.38; ≥ 23:00 vs. 18:00-20:00; OR: 2.33, 95% CI 1.29-4.20). Thus, early bedtime at 3 years may be associated with a higher academic performance and better non-cognitive skills in the first grade. Optimum early-childhood sleep habits may positively impact academic future.

Comparison of neurological manifestation in children with and without coronavirus 2019 experiencing seizures with fever.

Whether neurologic symptoms due to SARS-CoV-2 differ from those of non-SARS-CoV-2 viral infection is unclear. We aimed to describe these neurological manifestations and compare the clinical characteristics and treatments in children with seizures and fever with or without COVID-19. We retrospectively analyzed data from 105 hospitalized children (<18 years) with clinical seizures and fever between September 2021 and August 2022. We compared the clinical characteristics and treatments between the COVID-19 (n = 20) and non-COVID-19 (n = 85) groups. Patients with COVID-19 were older than those without (32.5 [20-86] months vs. 20 [16-32] months, p = 0.029). Seizure type and duration and impaired consciousness duration did not differ between groups. Six and 32 patients experienced status epilepticus lasting 30 min in the COVID-19 and non-COVID-19 groups, respectively. Most treatments did not differ between groups; however, electroencephalography was used less frequently for COVID-19. Neurological sequelae occurred in one and four patients in the COVID-19 and non-COVID-19 groups, respectively. In conclusion, seizures with fever due to SARS-CoV-2 were more common in older children. Seizure characteristics and neurologic sequelae did not differ in children with and those without COVID-19. In general, electroencephalography was used less during COVID-19 for infection control measures.

Timing of therapeutic interventions against infection-triggered encephalopathy syndrome: a scoping review of the pediatric literature.

Our goal was to conduct a scoping review of the literature on the treatment of infection-triggered encephalopathy syndrome/acute encephalopathy in children, focusing on treatment targets and treatment initiation timing. We performed literature searches using PubMed for articles reporting treatments of infection-triggered encephalopathy syndrome/acute encephalopathy. We included articles describing specific treatments for acute encephalopathy with control groups. For the purpose of searching new therapies only experimentally tried in the case series, we also included case series studies without control groups in this review, if the studies contained at least two cases with clear treatment goals. Therapies were classified based on their mechanisms of action into brain protection therapy, immunotherapy, and other therapies. We operationally categorized the timing of treatment initiation as T1 (6-12 h), T2 (12-24 h), T3 (24-48 h), and T4 (>48 h) after the onset of seizures and/or impaired consciousness. Thirty articles were included in this review; no randomized control study was found. Eleven retrospective/historical cohort studies and five case-control studies included control groups with or without specific therapies or outcomes. The targeted conditions and treatment timing varied widely across studies. However, the following three points were suggested to be effective in multiple studies: (1) Careful seizure management and targeted temperature management within 12 h (T1) of onset of febrile seizure/prolonged impaired consciousness without multiple organ failure may reduce the development of acute encephalopathy with biphasic seizures and late reduced diffusion; (2) immunotherapy using corticosteroids, tocilizumab, or plasma exchange within 24 h (T1-T2) of onset of acute necrotizing encephalopathy may reduce sequelae; and (3) anakinra therapy and ketogenic diet demonstrate little evidence of neurologic sequelae reduction, but may reduce seizure frequency and allow for weaning from barbiturates, even when administered weeks (T4) after onset in children with febrile infection-related epilepsy syndrome. Although available studies have no solid evidence in the treatment of infection-triggered encephalopathy syndrome/acute encephalopathy, this scoping review lays the groundwork for future prospective clinical trials.

Severe pediatric acute encephalopathy syndromes related to SARS-CoV-2.

Background and objectives: To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. Methods: A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Results: Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group (P < 0.01). Discussion: Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

Dravet syndrome and hemorrhagic shock and encephalopathy syndrome associated with an intronic deletion of SCN1A.

OBJECTIVE: Hemorrhagic shock and encephalopathy syndrome (HSES) is a serious condition that requires intensive care and is associated with a high mortality rate. However, its pathogenesis remains unclear. In the present study, a genetic analysis was performed to determine the genetic background of patients with clinically suspected Dravet syndrome (DS) who developed HSES. METHODS: Whole exome sequencing was performed, followed by minigene analysis of the intron variant detected by whole exome sequencing to confirm its effect on splicing. RESULTS: Whole exome sequencing revealed a novel 21-bp deletion in intron 3 of SCN1A NM_001165963.4 (NC_000002.11:g.166073675_166073695del). This deletion was not found in the patient's parents and was proven to be de novo. Minigene analysis revealed an aberrant mRNA lacking 40 and 106 bp from the 5' end of exon 4 of SCN1A. Therefore, we diagnosed this case as DS due to the deletion in intron 3 of SCN1A. CONCLUSIONS: We report a case of DS with HSES caused by a 21-bp deletion in the intron of SCN1A that was confirmed by minigene analysis. The present case met Levin's criteria for HSES and the splicing analysis of SCN1A is an important finding. This study has important implications for understanding HSES pathogenesis.

Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures.

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.

Clinical and laboratory characteristics of complex febrile seizures in the acute phase: a case-series study in Japan.

BACKGROUND: Patients with complex febrile seizures (CFS) often display abnormal laboratory results, unexpectedly prolonged seizures, and/or altered consciousness after admission. However, no standardized values have been established for the clinical and laboratory characteristics of CFS in the acute phase, making the management of CFS challenging. This study aimed to determine the clinical and laboratory characteristics of children with CFS during the acute phase. In particular, the duration of impaired consciousness and the detailed distribution of blood test values were focused. METHODS: We retrospectively reviewed medical records of a consecutive pediatric cohort aged 6-60 months who were diagnosed with CFS and admitted to Kobe Children's Hospital between October 2002 and March 2017. During the study period, 486 seizure episodes with confirmed CFS were initially reviewed, with 317 seizure episodes included in the analysis. Detailed clinical and laboratory characteristics were summarized. RESULTS: Among 317 seizure episodes (296 children with CFS), 302 required two or fewer anticonvulsants to be terminated. In 296 episodes showing convulsive seizures, median seizure duration was 30.5 min. The median time from onset to consciousness recovery was 175 min. Impaired consciousness lasting > 6, 8, and 12 h was observed in 13.9%, 7.6%, and 1.9% patients with CFS, respectively. Additionally, the distribution of aspartate aminotransferase, lactate dehydrogenase, creatinine, and glucose were clarified with 3, 10, 50, 90, and 97 percentile values. CONCLUSION: This study detailed the clinical and laboratory findings of acute-phase CFS using the data of the largest 15-year consecutive cohort of children with CFS. These results provide important information for appropriate acute management of CFS.

Impact after the Change from Voluntary to Universal Oral Rotavirus Vaccination on Consecutive Emergency Department Visits for Acute Gastroenteritis among Children in Kobe City, Japan (2016-2022).

Rotavirus (RV) is the leading cause of acute gastroenteritis (AGE), particularly in infants. In 2006, the high efficacy of oral RV vaccines (RVVs, RotarixTM and RotaTeqTM) was demonstrated. Voluntary RVV started in Japan in 2011, and in October 2020 were launched as universal oral RVVs in Japan. However, the impact of changes from voluntary to universal RVVs has not been studied in a primary emergency medical center in Japan. We investigated changes in the number of pediatric patients with AGE after introducing universal RVVs in our center. A clinical database of consecutive patients aged <16 who presented to Kobe Children's Primary Emergency Medical Center between 1 April 2016 and 30 June 2022 was reviewed. After implementing universal RVVs, fewer children presented with RV-associated AGE (the reduction of proportion of the patients in 2022 was −61.7% (all ages), −57.9% (<1 years), −67.8% (1−<3 years), and −61.4% (3−<5 years) compared to 2019). A similar decrease in those of age who were not covered by the universal RVV was observed. There was a significant decline in the number of patients with AGE during the RV season who presented to the emergency department after implementing universal RVVs.

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis.

Background: Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. Methods: This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. Results: The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). Conclusions: We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.

Detecting pathogenic deep intronic variants in Gitelman syndrome.

Gitelman syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by loss of function in the SLC12A3 gene (NM_000339.2), which encodes the natrium chloride cotransporter. The detection of homozygous or compound heterozygous SLC12A3 variants is expected in GS, but 18%-40% of patients with clinical GS carry only one mutant allele. Previous reports identified some pathogenic deep intronic variants in SLC12A3. Here, we report the screening of SLC12A3 deep intronic variants in 13 patients with suspected GS carrying one mutated SLC12A3 allele. Variant screening used the HaloPlex Target Enrichment System Kit capturing whole introns and the promotor region of SLC12A3, followed by SureCall variant analysis. Rare intronic variants (<1% frequency) were identified, and pathogenicity evaluated by the minigene system. Deep intronic variant screening detected seven rare SLC12A3 variants from six patients. Only one variant showed pathogenicity in the minigene system (c.602-16G>A, intron 4) through activation of a cryptic acceptor site. No variants were detected in the promotor region. Deep intronic screening identified only one pathogenic variant in patients with suspected GS carrying monoallelic SLC12A3 variants. Our results suggest that deep intronic variants partially explain the cause of monoallelic variants in patients with GS.

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants.

Background: Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in COL4A3 and COL4A4 have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified. Methods: We conducted in silico splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed in vitro splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome (COL4A3 [c.693G>A (p.Val231=)] and COL4A4 [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)]). Results: Both in vivo and in vitro splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in COL4A4). Prediction analysis of wild-type and mutated COL4A4 sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, e.g., in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing. Conclusions: This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome.

Behavioral Therapy for Children with Avoidant/Restrictive Food Intake Disorder Dependent on Tube or Oral Enteral Nutrient Formula: A Feasibility Study.

In children with eating disorders, nutritional status and growth may depend on enteral nutrient formula. Ultimately, its goal is to introduce or reintroduce oral feeding. Japanese research on the treatment of tube or oral formula-dependent children is scarce. This study determined the feasibility of behavioral therapy for children with avoidant/restrictive food intake disorder and dependency on the tube or oral enteral nutrient formula in Japan. Medical records of children diagnosed with this disorder, dependent on the tube or oral enteral nutrient formula and who had received behavioral therapy intervention to withdraw from the formula were retrospectively investigated. We collected their characteristics at first visit and the caloric percentage from oral food intake six months after starting the treatment. In total, four patients (age range: 2-5 years) participated in this study. The feeding routes employed before the intervention were a nasogastric tube for one patient, a gastrostomy bottom for the other patient, and oral formula for the remaining patients (i.e., two children). At the sixth month of the behavioral treatment, none of the patients needed the formula, and the caloric percentage of required nutrition from oral food intake was 100%. Our data demonstrate that this behavioral therapy is feasible for children with avoidant/restrictive food intake disorder dependent on the tube or oral formula in Japan.

The association between prehospital vital signs of children and their critical clinical outcomes at hospitals.

Vital signs are important for patient assessment, but little is known about interpreting those of children in prehospital settings. We conducted an observational study to investigate the association between prehospital vital signs of children and their clinical outcomes in hospitals. We plotted the data of patients with critical outcomes on published reference ranges, such as those of healthy children to evaluate the clinical relevance. Of the 18,493 children screened, 4477 transported to tertiary hospitals were included in the analysis. The outcomes 12 h after being transported to a tertiary hospital were as follows: deceased, 41; hospitalization with critical deterioration events, 65; hospitalization without critical deterioration events, 1086; returned home, 3090; and unknown, 195. The reference ranges of the heart rates (sensitivity: 57.7%, specificity: 67.5%) and respiratory rates (sensitivity: 54.5%, specificity: 67.7%) of healthy children worked best to detect the critical outcomes. Therefore, the reference ranges of healthy children were concluded to be suitable in prehospital settings; however, excessive reliance on vital signs carried potential risks due to their limited sensitivities and specificities. Future studies are warranted to investigate indicators with higher sensitivities and specificities.

Prognostic effects of treatment protocols for febrile convulsive status epilepticus in children.

BACKGROUND: Febrile status epilepticus is the most common form of status epilepticus in children. No previous reports compare the effectiveness of treatment strategies using fosphenytoin (fPHT) or phenobarbital (PB) and those using anesthetics as second-line anti-seizure medication for benzodiazepine-resistant convulsive status epilepticus (CSE). We aimed to examine the outcomes of various treatment strategies for febrile convulsive status epilepticus (FCSE) in a real-world setting while comparing the effects of different treatment protocols and their presence or absence. METHODS: This was a single-center historical cohort study that was divided into three periods. Patients who presented with febrile convulsive status epilepticus for ≥60 min even after the administration of at least one anticonvulsant were included. During period I (October 2002-December 2006), treatment was performed at the discretion of the attending physician, without a protocol. During period II (January 2007-February 2013), barbiturate coma therapy (BCT) was indicated for FCSE resistant to benzodiazepines. During period III (March 2013-April 2016), BCT was indicated for FCSE resistant to fPHT or PB. RESULTS: The rate of electroencephalogram monitoring was lower in period I than period II+III (11.5% vs. 85.7%, p<0.01). Midazolam was administered by continuous infusion more often in period I than period II+III (84.6% vs. 25.0%, p<0.01), whereas fPHT was administered less often in period I than period II+III (0% vs. 27.4%, p<0.01). The rate of poor outcome, which was determined using the Pediatric Cerebral Performance Category scale, was higher in period I than period II+III (23.1% vs. 7.1%, p=0.03). The rate of poor outcome did not differ between periods II and III (4.2% vs. 11.1%, p=0.40). CONCLUSIONS: While the presence of a treatment protocol for FCSE in children may improve outcomes, a treatment protocol using fPHT or PB may not be associated with better outcomes.

Last Nucleotide Substitutions of COL4A5 Exons Cause Aberrant Splicing.

INTRODUCTION: COL4A5 is a causative gene of X-linked Alport syndrome (XLAS). Male patients with XLAS with nonsense variants have the most severe phenotypes of early onset end-stage kidney disease (ESKD); those with splicing variants have middle phenotypes and those with missense variants have the mildest phenotypes. Therefore, genotyping for male patients with XLAS can be used to predict kidney prognosis. Single-base substitutions at the last nucleotide position in each exon are known to affect splicing patterns and could be splicing variants. Nevertheless, in XLAS, these variants are generally considered to be missense variants, without conducting a transcript analysis, which underestimates some patients as having mild phenotypes. This study aimed to investigate whether single-base substitutions at the last nucleotide position of COL4A5 exons cause aberrant splicing. METHODS: In total, 20 variants were found in the Human Gene Mutation Database (n = 14) and our cohort (n = 6). We performed functional splicing assays using a hybrid minigene analysis and in vivo transcript analyses of patients' samples when available. Then, we investigated genotype-phenotype correlations for patients with splicing variants detected in this study by comparing data from our previous studies. RESULTS: Among the 20 variants, 17 (85%) caused aberrant splicing. Male patients with splicing variants had more severe phenotypes when compared with those with missense variants. Findings from the in vivo analyses for 3 variants were identical to those from the minigene assay. CONCLUSION: Our study revealed that most single-base substitutions at the last nucleotide position of COL4A5 exons result in splicing variants, rather than missense variants, thereby leading to more severe phenotypes.