Epidemiological impact of universal varicella vaccination on consecutive emergency department visits for varicella and its economic impact among children in Kobe City, Japan.

INTRODUCTION: Previous studies reported a dramatic decline in the incidence of varicella and varicella-related deaths after implementing universal varicella vaccination (VarV). Although previous studies reported the effectiveness and economic impact of VarV, they were unknown in the emergency department (ED) setting. METHODS: To determine the effectiveness and economic impact of VarV in the ED, Kobe, Japan, we retrospectively reviewed the clinical database of consecutive patients younger than 16 years presenting to our primary ED from 2011 to 2019. RESULTS: Of the 265,191 children presenting to our ED, 3,092 patients were clinically diagnosed with varicella. The number of patients with varicella was approximately 500 annually, before introducing the universal two-dose VarV for children aged 1 to <3 years in October 2014, in the Japanese national immunization program, and decreased to approximately 200 in 2019. The number of patients with varicella younger than 1 year (ineligible for the vaccination) also decreased. Regarding the economic impact, the medical cost in our ED reduced after the introduction of VarV was JPY 4.1 million (US$ 40,049) annually. From the central data, approximately 95% of children were vaccinated after October 2014; however, a relatively large percentage of infected unvaccinated children (59.0%) presented to ED in this study. After the implementation of the universal VarV, infection was mainly observed in older children (i.e., the unvaccinated generation). CONCLUSIONS: Our data showed the effectiveness and economic impact of VarV in the ED setting. Additionally, our data suggested that the public vaccination program should include older unvaccinated children and other unvaccinated individuals.

Multivariate analysis of the impact of weather and air pollution on emergency department visits for unprovoked seizure among children: A retrospective clinical observational study.

BACKGROUND: An unprovoked seizure is a seizure or a cluster of seizures occurring within 24 h in a patient older than 1 month of age without precipitating factors. Recent studies have reported that extrinsic factors, such as meteorological conditions and air pollutants, may be important in seizure occurrence. Thus, this study aimed to examine the association between the number of visits to the emergency department (ED) by children for nighttime unprovoked seizures and exposure to multi-faceted factors, such as meteorological conditions and air pollution. METHODS: We conducted a clinical observational analysis and reviewed consecutive patients younger than 16 years of age who visited the primary ED center in Kobe City, Japan, during nighttime (7:30 p.m.-7:00 a.m.) between January 1, 2011 and December 31, 2015. We investigated the effects of meteorological factors and air pollutants on the number of patients with unprovoked seizures using multivariate analysis of Poisson regression estimates. RESULTS: In total, 151,119 children visited the ED, out of which 97 patients presented with unprovoked seizures. The mean age of the patients was 4.7 years (range, 1 month to 15.3 years), and 54.6% of them were boys. The total number of patients with unprovoked seizures showed no significant changes with the seasons; however, there were dominant peaks during the fall and fewer visits during the summer. The multivariate analysis of Poisson regression estimates revealed a significant positive relationship between the number of patients presenting with unprovoked seizures and precipitation (+1 patient/87 mm; p = 0.03) and methane (+1 patient/0.14 ppm; p = 0.03) levels and a negative relationship between the number of patients presenting with unprovoked seizures and nitrogen dioxide level (-1 patient/0.02 ppm; p = 0.04). CONCLUSIONS: The present study is the first to evaluate the association between the number of children who presented to the ED with nighttime unprovoked seizures and environmental factors after controlling for confounding factors.

Current Situation of Treatment for Anaphylaxis in a Japanese Pediatric Emergency Center.

OBJECTIVE: Anaphylaxis is a systemic allergic reaction that sometimes requires prompt treatment with intramuscular adrenaline. The aim of the study was to investigate the current situation regarding anaphylaxis treatment in a representative pediatric primary emergency facility in Japan. METHODS: We retrospectively examined the medical records dating from April 2011 through March 2014 from Kobe Children's Primary Emergency Medical Center, where general pediatricians work on a part-time basis. Clinical characteristics and current treatments for patients with anaphylaxis who presented to the facility were investigated. Furthermore, we compared the clinical characteristics between anaphylaxis patients given intramuscular adrenaline and those not given it. RESULTS: During the study period, 217 patients were diagnosed with anaphylaxis. The median Sampson grade at the time of visit was 2, and 90 patients (41%) were grade 4 or higher. No patients received self-intramuscular injected adrenaline before arrival at our emergency medical center because none of the patients had been prescribed it. Further treatment during the visit was provided to 128 patients (59%), with only 17 (8%) receiving intramuscular adrenaline. Patients given intramuscular adrenaline had significantly lower peripheral saturation of oxygen at the visit (P = 0.025) and more frequent transfer to a referral hospital (P < 0.001) than those not given intramuscular adrenaline. CONCLUSIONS: Education for Japanese pediatric practitioners and patients is warranted, because no patients used self-intramuscular injected adrenaline as a prehospital treatment for anaphylaxis, and only severely affected patients who needed oxygen therapy or hospitalization received intramuscular adrenaline in a pediatric primary emergency setting.

Clinical factors associated with prehospital exacerbation of anaphylaxis in children.

BACKGROUND: The severity of anaphylaxis often varies with time. Because prehospital intervention and initial treatment at hospital are affected by changing symptoms, the aim of this study was to determine the clinical factors associated with prehospital remission and exacerbation in the course of anaphylaxis in children. METHODS: Data from medical records on anaphylactic children who were treated for 3 years at Kobe Children's Primary Emergency Medical Center were retrospectively analyzed. Severity of symptoms was evaluated using Sampson's grade (S-G). Patients with increased S-G at the hospital visit from disease onset (worsened group) were compared with those with decreased S-G at the visit (improved group). Uni- and multivariate analyses were performed to identify clinical differences between the groups, with P<0.05 considered statistically significant. RESULTS: Among 115 anaphylactic children who showed S-G changes from onset to hospital visit, 43 were assigned to the worsened group and 72 to the improved group. Univariate analysis showed no significant differences in age, sex, history of asthma, prehospital treatment, type of antigen, or period from symptom onset to hospital visit between the groups. However, the time from antigen exposure to symptom onset was significantly longer, and S-G at onset was significantly lower in the worsened group than in the improved group. Multivariate analysis identified time from antigen exposure to symptom onset (odds ratio: 3.89, P<0.01) and S-G at onset (odds ratio: 0.06, P<0.001) as independent predictors of exacerbation. CONCLUSIONS: Anaphylactic children with slower and milder symptoms at onset are more likely to show deterioration.

Changes in the numbers of patients with acute gastroenteritis after voluntary introduction of the rotavirus vaccine in a Japanese children's primary emergency medical center.

BACKGROUND: Acute gastroenteritis (AGE) is a major reason for presentation to pediatric primary emergency medical centers. Because rotavirus vaccines were introduced in November 2011 for voluntary vaccination in Japan, we analyzed the changes in the numbers of AGE patients. METHODS: The number and proportion of patients visiting Kobe children's primary emergency medical center from January 2011 to February 2015 due to AGE, out of all visiting children, were investigated retrospectively. The rotavirus and norovirus epidemic periods were defined as the periods from March to June and from November to February, respectively, based on their disease prevalence. RESULTS: In patients ≤2 years of age, the numbers and proportions of patients with AGE were significantly decreased from 2464/14098 (17%) in 2011 to 1888/12321 (15%) in 2014 (p < 0.01). In patients ≤2 and 3-5 years of age, significant decreases in AGE patients between 2011 and 2014 were observed during the rotavirus season (from 20% [1090/5329] to 14% [642/4482] in patients aged ≤2 years and from 23% [704/3047] to 20% [572/2807] in patients aged 3-5 years, p < 0.01 and p < 0.05, respectively), but not during the norovirus season (from 19% [834/4436] to 19% [797/4160] in patients aged ≤2 years and from 20% [679/3334] to 25% [710/2852] in patients aged 3-5 years). CONCLUSIONS: The estimated rotavirus vaccine coverage in our area increased from 1% in 2011 to 49% in 2014; this coverage may have resulted in a reduction in AGE patients, both directly and indirectly, in our Japanese children's primary emergency medical center.

Impact of the State of Emergency during the COVID-19 Pandemic in 2020 on Asthma Exacerbations among Children in Kobe City, Japan.

The coronavirus disease (COVID-19) pandemic altered environmental factors. We studied the impact of these changes on asthma exacerbation (AE) by comparing the AE-related environmental factors between COVID-19 (2020) and pre-COVID-19 (2011-2019) eras. Between 2011 and 2020, 278,465 children (<16 years old) visited our emergency department, and 7476 were diagnosed with AE. The number of patients showed spring and fall peaks in 2011-2019. Multivariate analyses showed significant positive relationships of the number of AE patients with the average temperature among all patients and 0-5-year-olds and with sulfur dioxide (SO2) levels in 2011-2019 among 0-5-year-olds. Although the spring peak in the number of patients was not observed in 2020 after declaration of a state of emergency, the fall peak was again observed after the state of emergency was lifted. No changes in average temperature were detected, but SO2 was significantly reduced following declaration of the state of emergency in 2020. Therefore, SO2 reduction might have contributed to the disappearance of the peak of AE. However, a fall peak was observed again in 2020, although SO2 levels continued to be low. These data suggest that person to person interaction seems to be associated with AE, presumably due to unknown viral infections.

Multivariate analysis of the impact of weather and air pollution on emergency department visits for night-time headaches among children: retrospective, clinical observational study.

OBJECTIVES: To examine the association between the number of visits to the emergency department (ED) by children for night-time headaches and exposure to multifaceted factors, such as meteorological conditions and air pollution. DESIGN: We conducted a clinical observational time-series analysis study. SETTING: We reviewed consecutive patients younger than 16 years of age at the primary ED centre in Kobe city, Japan, during the night shift (19:30-7:00 hours) between 1 January 2011 and 31 December 2019. PARTICIPANTS: In total, 265 191 children visited the ED; 822 presented with headache during the study period. PRIMARY OUTCOME MEASURES: We investigated the effects of meteorological factors and air pollutants by multivariate analysis of Poisson regression estimates. A subanalysis included the relationship between the number of patients with night-time headaches and the above factors by sex. Furthermore, the effect of typhoon landing on patient visits for headache was also analysed. Headache was not classified because examinations were performed by general paediatricians (non-specialists). RESULTS: The number of patients with night-time headaches displayed distinct seasonal changes, with peaks during the summer. Multivariate analysis of Poisson regression estimates revealed a significant positive relationship between the number of patients for headache and mean temperature. Subanalysis by sex indicated a positive relationship between the number of patients with headache and mean temperature in both sexes; however, it was significant only for females. No relationship was found between the number of patients with headache and air pollution. There was no change in the number of patients for night-time headaches 3 days before and after typhoon landing. CONCLUSIONS: High temperature is the main factor for visiting ED for night-time headaches among children in Kobe city. Our results suggest that preventive measures against night-time headaches may be possible by reducing time spent outside during summer.

Clinical features predicting group A streptococcal pharyngitis in a Japanese paediatric primary emergency medical centre.

Objectives To identify clinical features that predict Group A streptococcal (GAS) pharyngitis in a Japanese paediatric primary emergency medical centre. Methods The prevalence of GAS pharyngitis according to age and body temperature (BT) was calculated among 3098 paediatric patients with pharyngitis. The numbers of GAS-positive and -negative patients for each clinical parameter, and each point increase in the McIsaac score were compared and likelihood ratios (LRs) were calculated. Results The prevalence of GAS pharyngitis was extremely low in patients aged < 1 (1.2%) and 1 year (3.9%). The GAS-positive rate was significantly higher in patients with a BT < 38.0°C compared with ≥ 38.0°C (30.0% vs. 19.8%). A BT ≥ 38.0°C was not a predictive finding for GAS pharyngitis (positive LR: 0.82). Rash was the most useful individual predictor, and a McIsaac score of 4 or 5 increased the probability; however, the positive LRs were 1.74 and 1.30, respectively. Conclusions The prevalence of GAS pharyngitis is extremely low in patients aged < 1 and 1 year, and a BT ≥ 38.0°C is not a predictive symptom. Although a rash and McIsaac score of 4 or 5 are associated with an increased probability, they cannot be used to confirm GAS infection.

Novel cryptic exons identified in introns 2 and 3 of the human dystrophin gene with duplication of exons 8-11.

The dystrophin gene, which is mutated in Duchenne muscular dystrophy, is the largest known human gene and characterized by the huge size of its introns. Intron 2 has been shown to include cryptic exons termed exons 2a and 2b, while intron 3 has been shown to include a cryptic exon designated exon 3a. In the present study, we identified 2 and 1 additional cryptic exons in introns 2 and 3, respectively. A previously unknown 157-bp insertion was identified between exons 2 and 3 of a dystrophin mRNA isolated from the lymphocytes of a dystrophinopathy patient with duplication of exons 8-11. Since this sequence exhibited the typical characteristics of a genomic exon, we designated it "exon 2c-l". A more detailed examination revealed that a position 4 bp downstream from the 5' end of exon 2c-l was also used as a splice acceptor site, and this exon was designated "exon 2c-s". In the same patient, a 357-bp insertion was identified between exons 3 and 4. Since this sequence also showed the typical characteristics of an exon, and its 3' end was the same as the splice donor site of exon 3a, we designated the novel cryptic exon "exon 3a-l", and changed the name of the previously reported exon 3a to "exon 3a-s". Among these novel cryptic exons, exon 3a-l was also incorporated into the dystrophin mRNA from normal lymphocytes, whereas exons 2c-l and 2c-s were not. The physiological or pathophysiological roles of these novel cryptic exons remain to be clarified.

[Treatment of Duchenne muscular dystrophy with gentamicin].

This article reviews the clinical application of gentamicin treatment for nonsense mutations. Since gentamicin is applied only for Duchenne muscular dystrophy caused by a nonsense mutation, genetic diagnosis of DMD is reviewed. Of the two reports describing gentamicin treatment of DMD, one concluded it to be effective, and the other to be ineffective.

Intravenous infusion of an antisense oligonucleotide results in exon skipping in muscle dystrophin mRNA of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease that is characterized by muscle dystrophin deficiency. We report that intravenous (IV) infusion of an antisense oligonucleotide created an in-frame dystrophin mRNA from an out-of-frame DMD mutation (via exon skipping) which led to muscle dystrophin expression. A 10-year-old DMD patient possessing an out-of-frame, exon 20 deletion of the dystrophin gene received a 0.5 mg/kg IV infusion of an antisense 31-mer phosphorothioate oligonucleotide against the splicing enhancer sequence of exon 19. This antisense construct was administered at one-week intervals for 4 wk. No side effects attributable to infusion were observed. Exon 19 skipping appeared in a portion of the dystrophin mRNA in peripheral lymphocytes after the infusion. In a muscle biopsy one week after the final infusion, the novel in-frame mRNA lacking both exons 19 and 20 was identified and found to represent approximately 6% of the total reverse transcription PCR product. Dystrophin was identified histochemically in the sarcolemma of muscle cells after oligonucleotide treatment. These findings demonstrate that phosphorothioate oligonucleotides may be administered safely to children with DMD, and that a simple IV infusion is an effective delivery mechanism for oligonucleotides that lead to exon skipping in DMD skeletal muscles.

Design of 2'-O-Me RNA/ENA chimera oligonucleotides to induce exon skipping in dystrophin pre-mRNA.

2'-O-Me RNA/ENA chimera oligonucleotides complementary to exon 45 and 46 of the dystrophin gene induced exon 45 and 46 skipping of the dystrophin pre-mRNA, respectively. The induction of exon skipping by the most effective 2'-O-Me RNA/ENA chimeras led to the expression of dystrophin in dystrophin-deficient myocytes by correcting the translational reading frames. Also, in the process of 2'-O-Me RNA/ENA chimera optimization to induce exon skipping in several exons, it was found that the optimized target sequences of the chimeras included guanosine- or adenosine-rich sequences that might function as spiking enhancer sequences (SES).