A Multi-Institutional Study of Older Hearing Aids Beginners-A Prospective Single-Arm Observation on Executive Function and Social Interaction.

OBJECTIVES: To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment. DESIGN: Multi-institutional prospective single-arm observational study. SETTING AND PARTICIPANTS: Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan. METHODS: The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA). RESULTS: Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement. CONCLUSIONS AND IMPLICATIONS: HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family.

Pertussis Epidemic in Lower-Grade Schoolchildren Without Preschool Vaccination Boosters.

We investigated the characteristics of patients with pertussis who did not receive preschool vaccination boosters. Fifteen patients with laboratory-confirmed pertussis and 29 pertussis-negative patients were compared. All pertussis-positive patients, but only 17% of pertussis-negative patients, were elementary school age and older. There is a need to study the utility of routine preschool pertussis vaccine booster in Japan.

Effectiveness of four doses of pertussis vaccine during infancy diminished in elementary school age: A test-negative case-control study in Japan.

OBJECTIVE: The Japanese national immunization program recommends that children receive 4 doses of acellular pertussis vaccine between 3 months and 2 years of age. Nevertheless, the number of pertussis cases is increasing in elementary school children aged 6-12 years. Therefore, a test-negative case-control study was conducted to assess the effectiveness of the pertussis vaccine program. METHODS: Subjects included children aged ≥3 months who visited a collaborating hospital due to pertussis-specific cough between October 2017 and November 2019. All subjects underwent diagnostic tests for pertussis, and those diagnosed as positive were regarded as cases. Subjects diagnosed as pertussis-negative were classified as controls. Vaccination history was collected using a questionnaire administered to parents with reference to immunization records. Logistic regression models were employed to calculate the odds ratio (OR) and 95% confidence interval for laboratory-confirmed pertussis. RESULTS: Of 187 recruited subjects (120 cases and 67 controls), questionnaire responses were obtained for 145 subjects (95 cases and 50 controls). Compared with unvaccinated subjects, the vaccine effectiveness (VE) of 4 doses was 70% among all subjects and reached to 90% with marginal significance among subjects under 6 years of age. However, among school-aged subjects, the VE was not suggestive of protection against pertussis (VE: 8%). For vaccinees given 4 doses, the OR for developing pertussis increased significantly with longer duration since the fourth dose (compared with <4.5 years, OR of 6.0-8.2 years = 5.74; OR of ≥8.3 years = 3.88; P for trend by duration < 0.01). CONCLUSION: Effectiveness of administering 4 doses of pertussis vaccine during infancy decreases with time passed since the fourth dose. This regimen does not protect school-aged children against pertussis.

Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency.

BACKGROUND: Infants are vulnerable to zinc deficiency. Thus, abnormally low breast milk zinc levels cause transient neonatal zinc deficiency (TNZD) in breast-fed infants. TNZD has been considered to be rare because of a paucity of citations in the published literature. However, recent studies of affected mothers identified four missense mutations in the solute carrier family 30 member 2 gene (SLC30A2), which encodes the zinc transporter, ZnT2. METHODS: Genetic analyses of SLC30A2/ZnT2 in three Japanese mothers secreting low-zinc milk (whose infants developed TNZD) were performed. The effects of identified mutations were examined in a cell-based assay. Furthermore, 31 single-nucleotide polymorphisms (SNPs) in SLC30A2/ZnT2 were evaluated for their potential involvement in low-zinc levels in milk. RESULTS: Each mother had a different novel heterozygous mutation in SLC30A2/ZnT2. One mutation reduced splicing efficiency of the SLC30A2/ZnT2 transcript, and all ZnT2 mutants were defective in zinc transport and were unstable in cells. Moreover, four SNPs caused a significant loss of zinc-transport activity, similar to that in disease-causing ZnT2 mutants. CONCLUSION: Our results indicate that many SLC30A2/ZnT2 mutations cause or potentially cause TNZD. Genetic information concerning TNZD pathogenesis is limited, and our results suggest that the TNZD frequency may be higher than previously thought.

Detection of antibodies against fimbria type 3 (Fim3) is useful diagnostic assay for pertussis.

Isolation of Bordetella pertussis and detection of the pertussis genome are not always successful because of low bacterial loads in adult patients with pertussis. Antibodies against pertussis toxin (PT) are measured but have low sensitivity in vaccinated subjects. There is no reliable diagnostic method at present. In this study, a fluorescent-EIA against several pertussis antigens and genome detection were investigated to establish clinical laboratory diagnostic methods for pertussis. The study was conducted in an outpatient clinic between September 2007 and 2013. Subjects consisted of 209 patients including adults suspected of pertussis and 35 staff members of the clinic. Loop-mediated isothermal amplification (LAMP) was performed to detect the pertussis genome in 5' UTR of the pertussis toxin (PT) gene. The catalytic region of the adenylate cyclase toxin (catACT), C-terminal of filamentous hemagglutinin (cFHA), and type 3 fimbria (Fim3) were selected, which are not pertussis vaccine component. Conventional PT and FHA antibodies were examined together with type 2 fimbria (Fim2) antibodies, and these are vaccine antigens. Pertussis DNA was detected in 23 (11%) out of 209. Detection sensitivity was high in young infants. Antibodies against Fim3 showed a higher positive rate in all age groups. Staff members at the pediatric outpatient clinic showed serological booster responses in Fim2 and Fim3 antibodies more sensitively than those in PT antibodies during outbreaks. LAMP was useful for detecting the pertussis genome in young infants, whereas a serological assay for fluorescent-EIA against Fim2 and Fim3 was preferable for adolescents and adults.

Seasonal split influenza vaccine induced IgE sensitization against influenza vaccine.

Although anaphylaxis is an extremely rare vaccine-associated adverse event, it occurred in young children following administration of the 2011/12 seasonal split influenza vaccine, which contained 2-phenoxyethanol as the preservative. These children had high levels of IgE antibodies against influenza vaccine components. We herein investigated why these children were sensitized. One hundred and seventeen series of serum samples were obtained immediately before, and one month after the first and second immunizations with the HA split vaccine of 2011/12. Forty-two sequential serum samples were collected in the acute and convalescent phases (2 and 4 weeks) after natural infection with H1N1 Pdm in 2009. IgE antibodies developed following the vaccination of young children with seasonal split vaccines, whereas no significant IgE response was observed following natural infection with H1N1 Pdm 2009. The prevalence of IgE antibodies was not influenced by outbreaks of H1N1 Pdm. Repeated immunization with the HA split vaccine induced IgE sensitization against the influenza vaccine irrespective of the H1N1, H3N2, or B influenza subtypes. The reasons why anaphylaxis only occurred in recipients of the influenza vaccine containing 2-phenoxyethanol are still being investigated, and the size distribution of antigen particles may have shifted to a slightly larger size. Since the fundamental reason was IgE sensitization, current split formulation for the seasonal influenza vaccine needs to be reconsidered to prevent the induction of IgE sensitization.

Humoral immune response to influenza A(H1N1)pdm2009 in patients with natural infection and in vaccine recipients in the 2009 pandemic.

The 2009 pandemic H1N1 mainly affected adolescents and children, and most of the elderly in Japan escaped clinical illness. To clarify the role of humoral immunity in the infection, the time kinetics of hemagglutination inhibition (HI), neutralization (NT), and IgG subclass antibody response directed against influenza A(H1N1)pdm2009 were analyzed in three consecutive specimens obtained from 51 young adults and children (group 1) who contracted pandemic influenza and from 74 pediatric clinic employees (group 2) inoculated with pandemic monovalent vaccine. In group 1 patients, 6 and 30 patients had lower HI and NT antibody in the acute phase respectively. Thereafter, HI and NT antibody titers increased fourfold or more in 50 patients with peak response in the third specimens obtained four weeks after the onset. IgG1 in 45 patients, IgG3 in 18 patients, and IgG4 in 29 patients showed elevated responses. Forty (54%) and 70 (95%) subjects in group 2 had positive HI and NT antibodies in the prevaccination samples, with increased antibody responses in the follow-up peaking in the second specimens. Forty of those vaccinated had increased IgG1 responses peaking in the third specimens, whereas elevated IgG3 was observed in 22 recipients with the highest level in the second samples. IgG4 did not show any increase in subjects in group 2. A few participants showed an IgG2 response in both groups. An immunologically naive population contracted influenza with apparent clinical symptoms. However, already primed subjects through subclinical infection elicited the unique pattern of IgG subclass responses by vaccination, which differed from those of naive populations.

Production of inflammatory cytokines in response to diphtheria-pertussis-tetanus (DPT), haemophilus influenzae type b (Hib), and 7-valent pneumococcal (PCV7) vaccines.

Haemophilus influenzae type b (Hib) and 7-valent pneumococcal (PCV7) vaccines both became recommended in Japan in 2010. In this study, cytokine production was investigated in peripheral blood mononuclear cells (PBMCs) cultures stimulated with diphtheria and tetanus toxoids combined with acellular pertussis vaccine (DPT), Hib, and PCV7 separately or concurrent different combinations, all as final off-the-shelf vaccines without the individual vaccine components as controls. Higher IL-1ß levels were produced when cultures were stimulated with PCV than with DPT or Hib, and the concurrent stimulation including PCV7 enhanced the production of IL-1ß. Although Hib induced higher levels of IL-6, no significant difference was observed in IL-6 production with the concurrent stimulation. The concurrent stimulation with Hib/PCV7 and DPT/Hib/PCV7 produced higher levels of TNF-α and human G-CSF. Cytokine profiles were examined in serum samples obtained from 61 vaccine recipients with febrile reactions and 18 recipients without febrile illness within 24 h of vaccination. No significant difference was observed in cytokine levels of IL-1ß, IL-4, IL-6, IL-10, IL-12, IFN-γ, MIP-1, TNF-α, and prostaglandin E2 (PGE2) in sera between the two groups. However, significantly higher levels of human G-CSF were observed in recipients with febrile illness than in those without febrile reactions. Further investigations of the significance of elevated serum G-CSF levels are required in vaccine recipients with febrile illness.

Effects of clonazepam on self-induced photoparoxysmal responses.

A 5-year-old girl exhibited daily episodes of repetitive blinking lasting 5-10 s. Electroencephalography (EEG) revealed marked photoparoxysmal responses (PPR) at 3-20 Hz of photic stimulation and diffuse spike-wave bursts during sleep. A 24-h video EEG identified 11 episodes of repetitive blinking, 3 of which resulted in widespread spike-wave discharges. These suggested that the behavior of the patient represented self-induction of PPR. Valproate sodium was ineffective in decreasing PPR, as revealed by EEG, and the frequency of blinking episodes, but clonazepam attenuated PPR and significantly decreased the blinking behavior.

Modified adult measles in outbreaks in Japan, 2007-2008.

Different genotypes of C1, D3, D5, and H1 were isolated in outbreaks of 1984, 1987-1988, 1991-1993, and 2001, respectively, when the previous circulating genotype was replaced successively by a new genotype, through molecular studies of measles since 1984 in Japan. In March 2007, several patients with measles were observed in outpatient clinics, who were all young adolescents in high school and university students. The outbreak expanded subsequently throughout Japanese districts in May and is still ongoing in 2008. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) was used to detect the measles genome from 18 clinical samples obtained from patients suspected of modified measles infection with a very mild febrile illness. The measles genome was detected in nine patients by reverse transcription polymerase chain reaction (RT-PCR) and in 12 patients by RT-LAMP. Six measles strains were isolated in the 2007-2008 outbreak and identified as the D5 genotype (MVi/Bangkok.THA/93 type) different from the D5 sub-cluster (MVi/Palau.BLA/93 type) isolated in 1990-2005. Similar Bangkok type D5 strains were isolated in Phnom Penh in 2002 and in Taiwan in 2003, suggesting that the D5 strains might have been introduced via South East Asia, rather than resulting from the accumulation of mutations in the D5 strains of 1990-2005. One D9 strain was isolated from a sporadic case in Aichi in 2006. There was no difference in the antigenicity of the D9 and D5 strains in comparison with the vaccine strain. Infrastructure of systematic laboratory-based surveillance system should be established in order to confirm measles virus infection in Japan.

Staphylococcal enterotoxin B enhances a flare-up reaction of murine contact hypersensitivity through up-regulation of interferon-gamma.

BACKGROUND: We often see aggravation of eczematous skin lesions associated with bacterial infection, but the mechanism of this phenomenon is unclear. Staphylococcus aureus is known to colonize on the eczematous lesion and produce some exotoxins, which act as bacterial superantigens. OBJECTIVES: To investigate the potential role of superantigens in chronic dermatitis, we investigated the effect of staphylococcal enterotoxin B (SEB) on the skin reaction, the proliferative response and the cytokine production of local lymph node cells in the mouse model of contact hypersensitivity reaction. METHODS: Sensitized BALB/c mice were repeatedly challenged with dinitrofluorobenzene (DNFB), and intravenously injected with SEB and dinitrobenzne sulfonic acid sodium salt (DNBS). The ear swelling response was measured after DNBS injection. Cervical lymph node cells of those mice were cultured with DNBS in vitro. Their proliferative responses and the production of cytokines were assessed. RESULTS: SEB markedly enhanced the flare-up reaction of ear swelling induced by DNBS, the proliferative response of lymph node cells and the production of IFN-gamma. In contrast, the production of IL-5 was decreased. CONCLUSIONS: The present study may provide some clues for elucidating the mechanism involved in the exacerbation of dermatitis associated with staphylococcal infection.

Mumps virus reinfection is not a rare event confirmed by reverse transcription loop-mediated isothermal amplification.

Clinically apparent mumps reinfection is considered extremely rare, but several cases have been suspected of reinfection in an out-patient clinic. In this study, virological examination, virus isolation, the reverse transcription loop-mediated isothermal amplification (RT-LAMP), and IgG and IgM EIA antibodies, were examined in order to identify mumps reinfection. Patients were divided into three categories; the reinfection group comprised 29 patients with a history of natural infection, the vaccine-failure group consisted of 37 patients with an immunization history, and two patients had histories of both immunization and mumps infection. Another 25 patients were enrolled as a primary infection group. Mumps virus was isolated in 5 (17%) and the genome was detected in 12 (41%) of 29 in the reinfection group. Reinfection was confirmed in 21/28, demonstrating high avidity of IgG EIA. Mumps virus was isolated in 15 (41%) and there was a higher positivity of genome amplification in 25 (68%) of 37 patients in the vaccine-failure group. Among these, 23 were confirmed as secondary vaccine failure by high avidity IgG EIA serology. In the primary infection group, the isolation rate and genome detection rate was higher in 16 (64%) and in 18 (72%) of 25 patients, respectively. There was no significant difference in virus load among the three groups but high mumps virus load was suspected in the IgM EIA-positive group based on the shorter amplification time on RT-LAMP. Mumps virus reinfection was confirmed by RT-LAMP and an IgG avidity test and was not a rare event.

A comparative study of the incidence of aseptic meningitis in symptomatic natural mumps patients and monovalent mumps vaccine recipients in Japan.

To compare the incidence of aseptic meningitis associated with symptomatic natural mumps infection and in mumps vaccine recipients, we conducted a prospective comparative study. Consecutive samples of 1051 children with mumps were enrolled by 10 pediatricians and 21,465 vaccine recipients by 143 pediatric primary care practitioners, from January 1, 2000 to January 1, 2003. Parents used a daily diary to record symptoms during the period of illness (15 days) or 30-day period following immunization. Mumps infection was confirmed by virus isolation and/or detection of mumps virus genome in salivary and CSF samples. The incidence of aseptic meningitis was 13/1051 (1.24%) in patients with symptomatic natural mumps infection and was estimated to be 0.7-1.1% of overall infection in considering asymptomatic infection, and 10/21,465 (0.05%) in vaccine recipients. Although aseptic meningitis is a clear side effect of the mumps vaccine, the incidence is considerably lower than among those with symptomatic natural infection. Our results provide an informative data for consideration to resume mumps vaccine as a part of routine immunization schedule for Japanese children.

Efficacy of inactivated trivalent influenza vaccine in alleviating the febrile illness of culture-confirmed influenza in children in the 2000-2001 influenza season.

During the 2000/2001 influenza season in Japan, children ranging in age from 6 months to 13 years with fever exceeding 37.5 degrees C were recruited. Vaccine efficacy was evaluated by comparing the rates of pre-seasonal vaccination between groups stratified by fever severity. Seven hundred and sixty one patients (33.1%), culture positive for influenza were enrolled for analysis. The numbers of patients for A/H1N1 and A/H3N2 were insufficient for statistical analysis. For influenza B the odds ratio for vaccinated children to have a maximum fever exceeding 39.5 degrees C was 0.52 (95% CI, 0.30-0.92) Our findings suggest modest impact of influenza vaccination on limiting severity of disease symptoms.

Molecular epidemiology of mumps virus in Japan and proposal of two new genotypes.

We isolated 872 strains of mumps virus from naso-pharyngeal secretions in seven different districts of Japan from January 2000 to July 2001. Among them, 57 strains were geno-typed by nucleotide sequencing in part of the hemagglutinin-neuraminidase (HN) and small hydrophobic (SH) protein regions. Four different genotypes (B, G, K, and L) of mumps virus were co-circulating in Japan and the distribution of genotypes varied in geographically different districts. Two new clusters designated as genotypes K and L had more than 7% nucleotide variation in the SH gene. Among the 57 strains, 11 were classified as B, 35 as G, three as K, and eight as L, which was mainly isolated in Tokyo. We also examined 104 stains isolated in a clinic in Mie prefecture from 1993 to 2003. Genotype B was the indigenous strain and genotype K was introduced in 1994. Genotypes B and K co-circulated in the 1990s and were replaced by genotype G in 2000. There was no significant change in neutralizing test antibody titers against genotypes B, G, K, and L using seven post-vaccination sera with Hoshino strain (genotype B) and these four genotypes had a different antigenicity from genotype A. We should continue to watch on mumps virus molecular epidemiology.