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Objectives: To examine the association of prehospital physician presence with neurologic outcomes of pediatric patients with out-of-hospital cardiac arrest (OHCA)., Design: Retrospective cohort study., Setting: Data from the Japanese Association for Acute Medicine-OHCA Registry., Interventions: None., Patients: Pediatric patients (age 17 yr old or younger) registered in the database between June 2014 and December 2019., Measurement and Main Results: We used logistic regression models with stabilized inverse probability of treatment weighting (IPTW) to estimate the associated treatment effect of a prehospital physician with 1-month neurologically intact survival. Secondary outcomes included in-hospital return of spontaneous circulation (ROSC) and 1-month survival after OHCA. A total of 1,187 patients (276 in the physician presence group and 911 in the physician absence group) were included (median age 3 yr [interquartile range 0-14 yr]; 723 [61%] male). Comparison of the physician presence group, versus the physician absence, showed 1-month favorable neurologic outcomes of 8.3% (23/276) versus 3.6% (33/911). Physician presence was associated with greater odds of 1-month neurologically intact survival after stabilized IPTW adjustment (adjusted odds ratio [aOR] 1.98, 95% CI 1.08-3.66). We also found an association in the secondary outcome between physician presence, opposed to absence, and in-hospital ROSC (aOR 1.48, 95% CI 1.08-2.04). However, we failed to identify an association with 1-month survival (aOR 1.49, 95% CI 0.97-2.88)., Conclusions: Among pediatric patients with OHCA, prehospital physician presence, compared with absence, was associated almost two-fold greater odds of 1-month favorable neurologic outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation., Methods: Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div)., Results: The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively., Conclusions: After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.

Objective: We assessed the combined effect of household air pollution from solid fuel use and from environmental tobacco smoke and child health outcomes in Indonesia., Methods: Survey subjects self-reported solid fuel use, frequency of indoor smoking, and health outcomes in children. We then evaluated the effect of a combined exposure using multivariate logistic regression., Results: Children exposed to high levels of pollution from solid fuel use had an increased risk of low birth weight, neonatal death, infant death, and acute lower respiratory infection. Exposure to environmental tobacco smoke increased the risk of acute lower respiratory infection. The combined effect of both pollution sources outweighed the independent risk of each exposure alone., Conclusions: Solid fuel use and environmental tobacco smoke independently increased the risk and child health outcomes and the combined exposure showed the additive effect.

Rationale: Tricho-hepato-enteric syndrome (THES) is a rare disorder caused by mutations in the TTC37 or SKIV2L genes and characterized by chronic diarrhea, liver disease, hair abnormalities, and high mortality in early childhood due to severe infection or liver cirrhosis., Patient Concerns: The patient is the second child of three siblings born to non-consanguineous healthy Japanese parents. She had intrauterine growth retardation and was delivered at 33 weeks of gestation due to placental abruption. She presented with watery diarrhea, elevated levels of liver enzymes, multiple episodes of recurrent bacterial infection, and mild mental retardation. She had facial dysmorphism, including prominent forehead and hypertelorism, and had woolly hair without trichorrhexis nodosa., Diagnosis: Clinical features led to consideration of THES. Novel compound heterozygous nonsense mutations, c.1420G>T (p.Q474*) and c.3262G>T (p.E1088*), in the SKIV2L gene were identified in the patient, and decreased levels of SKIV2L protein expression were revealed by flow cytometry and confirmed by western blot analysis using patient peripheral blood mononuclear cells (PBMCs)., Interventions: Total parenteral nutrition was required from day 30 to day 100. Trimethoprim-sulfamethoxazole prophylaxis was started at the age of 7 years after multiple episodes of bacterial pneumonia and otitis media., Outcomes: Chronic diarrhea persisted for more than 10 years, but the symptoms gradually improved with age. At the age of 13 years, she started a normal diet in combination with oral nutritional supplementation and her height and weight were just below the 3rd percentile for healthy individuals. She developed secondary sex characteristics, and menarche occurred at the age of 12 years. Facial dysmorphism, including prominent forehead and hypertelorism, and woolly hair without trichorrhexis nodosa became noticeable as she matured., Lessons: Physicians must be aware of THES when they encounter a patient with infantile diarrhea, hair abnormalities, immune deficiency, mental retardation, and liver disease. Moreover, flow cytometric detection of SKIV2L protein in PBMCs may facilitate early diagnosis.

Background: Factors influencing the susceptibility of the elderly to the adverse health effects of short-term exposure to desert dust have yet to be explored. We aimed to identify the disease histories that increase the susceptibility of the elderly to disease onset induced by dust events., Methods: We used a time-stratified case-crossover design using data on 17,874 elderly residents (≥65 years) of Okayama, Japan, who were transported to hospital emergency rooms because of cardiovascular and respiratory diseases between 2006 and 2010. We used conditional logistic models to calculate the odds ratios (ORs) per interquartile increase of Asian dust. We then conducted stratified analyses based on patients with or without a history of chronic disease., Results: Dust concentration was associated with a higher risk of cardiovascular (3-day lag), cerebrovascular (same day), and respiratory (3-day lag) disease onset. Patients with a history of respiratory disease had a higher risk of cardiovascular (OR: 1.09 [95% confidence interval (CI) = 1.00, 1.19] vs. 0.99 [0.97, 1.01]; P for interaction = 0.03) or cerebrovascular (1.15 [1.01, 1.31] vs. 0.99 [0.97, 1.01]; P = 0.02) disease onset (2-day lag) than those without. Patients with diabetes also had a higher risk of cerebrovascular disease onset (1.09 [1.00, 1.19] vs. 0.99 [0.97, 1.01]; P = 0.05) (2-day lag). In contrast, patients with a history of cerebrovascular disease had a lower risk of respiratory disease., Conclusions: People with a history of respiratory disease or diabetes might have a greater susceptibility to cardiovascular disease from Asian dust and would therefore benefit from proactive interventions during desert dust events.

Background: Evidence linking air pollution with adverse health outcomes is accumulating. However, few studies have adopted a quasi-experimental design to evaluate whether decline in air pollution from regulatory action improves public health. We evaluated the effect of a diesel emission control ordinance introduced in 2003 on mortality rates in 23 wards of the Tokyo metropolitan area, Japan, from October 2000 to September 2012, taking into account change in mortality rates in a reference population (Osaka) with a introduction of such a regulation in 2009., Methods: We obtained daily counts of all-cause and cause-specific mortality and concentrations of nitrogen dioxide (NO2) and particulate matter less than 2.5 μm in diameter (PM2.5) during the study period. We employed interrupted time-series analysis to analyze the data., Results: Decline in NO2 during the study period was similar in the two areas, while decline in PM2.5 and the improvement in age-standardized mortality rates were greater in Tokyo's 23 wards compared with Osaka. Even after adjusting for age-standardized mortality rates in Osaka, percent changes in mortality between the first 3-year interval (October 2000 to September 2003) and the last 3-year interval (October 2009 to September 2012) were -6.0% for all causes, -11% for cardiovascular disease, -10% for ischemic heart disease, -6.2% for cerebrovascular disease, -22% for pulmonary disease, and -4.9% for lung cancer. We did not observe a decline in mortality from other causes., Conclusions: This quasi-experimental study in Tokyo suggests that emission control was associated with improvements in both air quality and health outcomes.

Background: Recent studies suggest that prenatal exposure to outdoor air pollution is associated with unfavorable neurodevelopment in children. We examined associations between prenatal exposure to traffic-related air pollution and child behavioral development milestone delays, using data from a nationwide population-based longitudinal survey in Japan, where the participants were recruited in 2001 and followed., Methods: Particulate matter, nitrogen dioxide, and sulfur dioxide concentrations during the 9 months before birth were obtained at the municipality level and assigned to the participants who were born in the corresponding municipality. We analyzed data from singleton births with linked pollution data available (N = 33,911 at the maximum). We used responses to survey questions about age-appropriate behaviors at ages 2.5 and 5.5 years as indicators of behavioral development. We conducted multilevel logistic regression analysis, adjusting for individual and municipality-level variables., Results: Air pollution exposure during gestation was positively associated with the risk of some developmental milestone delays at both ages. Specifically, air pollution was associated with verbal and fine motor development at age 2.5 years, and with behaviors related to inhibition and impulsivity at 5.5 years. In the fully-adjusted models, odds ratios following one-interquartile-range increase in nitrogen dioxide and suspended particulate matter were 1.24 (95% confidence interval: 1.07, 1.43) for inability to compose a two-phrase sentence at ages 2.5 and 1.10 (1.05, 1.16) for inability to express emotions at age 5.5 years, respectively., Conclusions: Prenatal exposure to traffic-related air pollution was associated with behavioral development milestone delays of children in a nationally representative sample in Japan.

Objective: We aimed to evaluate the annual health impacts of particulate matter (PM) less than 10 μm diameter (PM10) and less than 2.5-μm diameter (PM2.5) in 27 cities in Southeast and East Asian countries (Japan, the Philippines, the Republic of Korea, Singapore, and Vietnam) for the year 2009 (n = 50,756,699)., Methods: We estimated the number of cases attributable to long-term exposure. We used a scenario that reduced the annual mean values for PM10 and PM2.5 to 20 and 10 μg/m, respectively., Results: A reduction in long-term exposure to PM10 and PM2.5 would have postponed 8% to 9% of all-cause mortality or about 37,000 deaths. One third of them were associated with cardiopulmonary mortality and one ninth of them were associated with lung cancer mortality., Conclusions: Current air pollution levels in Southeast and East Asian countries have a nonnegligible public health impact.

Objective: To evaluate the direct health effects of Asian dust on ambulance calls and its role as an effect modifier on the effects of anthropogenic air pollution in Japan., Methods: The subjects were 51,945 elderly residents who visited hospital emergency departments from 2006 to 2010. We evaluated the impact of Asian dust by time-series analyses and the excess risk from suspended particulate matter (SPM) stratified by Asian-dust exposure., Results: Asian dust was associated with daily ambulance calls due to all-cause, cardiovascular, and respiratory disease independently of SPM, for example, the relative risk per interquartile increase in Asian dust (3-day lag) was 1.021 (1.002 to 1.039) for cardiovascular disease. Furthermore, Asian dust modified the effects of SPM on cardiovascular and respiratory diseases., Conclusions: Asian dust had adverse effects and modified the effect of SPM.

Objectives: We evaluated the association between short-term exposure to outdoor air pollution and out-of-hospital cardiac arrest in Japan., Methods: We studied 558 residents of Okayama, Japan, who visited hospital emergency departments between January 2006 and December 2010 for out-of-hospital cardiac arrest using a time-stratified case-crossover design. We calculated city-representative average concentrations of different air pollutants and examined the association between air pollution and cardiac arrest., Results: Exposure to air pollution was associated with an elevated risk of cardiac arrest; for example, odds ratios was 1.17 (95% confidence interval, 1.02 to 1.33) per interquartile-range increase in suspended particulate matter concentrations in the previous 48 to 72 hours. We also observed different susceptibilities to suspended particulate matter and ozone exposures by age category., Conclusions: Short-term exposure to outdoor air pollution was associated with increased risk of cardiac arrest.

Background and Purpose: Few studies have examined the effect of hourly changes in air pollution on cardiovascular disease morbidity. We evaluated the associations between hourly changes in air pollution and the risks of several types of cardiovascular disease., Methods: We used a time-stratified case-crossover design. Study participants were 10,949 residents of the city of Okayama, Japan, aged≥65 years who were taken to hospital emergency rooms between January 2006 and December 2010 for onset of cardiovascular disease. We calculated city representative hourly average concentrations of air pollutants from several monitoring stations and examined the associations between air pollution exposure before the case event, focusing mainly on suspended particulate matter, and disease onset., Results: Suspended particulate matter exposure 0 to <6 hours before the case events was associated with risks of onset of cardiovascular and cerebrovascular disease; odds ratios after 1 interquartile range increase in suspended particulate matter exposure were 1.04 (95% confidence interval, 1.01-1.06) for cardiovascular disease and 1.04 (95% confidence interval, 1.00-1.08) for cerebrovascular disease. We observed an elevated risk of hemorrhagic as well as ischemic stroke, but the risk was slightly higher for hemorrhagic stroke, and this elevation was persistent. Women tended to have higher effect estimates., Conclusions: This study provides further evidence that particulate matter exposure increases the risks of onset of cardiovascular and cerebrovascular disease (including hemorrhagic stroke) shortly after exposure.

Objective: Evidence linking short-term exposure to outdoor air pollution with hemorrhagic stroke is inconclusive., Methods: We evaluated the effects of suspended particulate matter (SPM) on cardiovascular disease mortality, focusing on types of stroke, from March 2005 to December 2010, in five selected prefectures in western Japan. A multicity time-series analysis was used, and Asian dust was adjusted in the models., Results: Even after adjusting for Asian dust, the same-day SPM was positively associated with several types of stroke mortality. Following a 10-μg/m increase in SPM, rate ratios were 1.014 (90% confidence interval [CI]: 1.002 to 1.026) for stroke, 1.030 (90% CI: 1.004 to 1.056) for intracerebral hemorrhage, and 1.016 (90% CI: 1.003 to 1.030) for ischemic stroke mortality., Conclusions: Short-term exposure to outdoor air pollution may increase the risks of hemorrhagic stroke as well as ischemic stroke mortality.

Objective: Evidence linking short-term exposure to outdoor air pollution with hemorrhagic stroke is inconsistent., Methods: We evaluated the associations between outdoor air pollution and specific types of stroke in Tokyo, Japan, from April 2003 to December 2008. We obtained daily counts of stroke mortality (n = 41,440) and concentrations of nitrogen dioxide as well as particles less than 2.5 μm in diameter. Time-series analysis was employed., Results: Although same-day air pollutants were positively associated with ischemic stroke and intracerebral hemorrhage mortality, both air pollutants were more strongly associated with subarachnoid hemorrhage mortality: rate ratio was 1.041 (95% confidence interval: 1.011-1.072) for each 10 μg/m3 increase in the previous-day particles less than 2.5 μm., Conclusions: This study suggests that short-term exposure to outdoor air pollution increases the risks of hemorrhagic stroke mortality as well as ischemic stroke mortality.

Background: Preterm births cause a large public-health burden, and air pollution is considered to be a potential risk factor. We evaluated the association between proximity to major roads (as an index for air pollution) and preterm births, classified by gestational age and specific clinical manifestations., Methods: Data on parental information and birth outcomes were extracted from the database maintained by the perinatal hospital in Shizuoka, Japan. We restricted the analysis to mothers who delivered liveborn single births from 1997 to 2008 (n = 14,226). Using the geocoded residential information, each birth was classified on its proximity to major roads. We estimated the multivariate-adjusted odds ratios and their 95% confidence intervals (CIs) for the association of proximity to major roads with preterm births, using logistic regression., Results: We found positive associations between proximity to major roads and preterm births at all gestational ages. Living within 200 m increased the risk of births before 37 weeks by 1.5 times (95% CI = 1.2-1.8), birth before 32 weeks by 1.6 times (1.1-2.4), and births before 28 weeks by 1.8 times (1.0-3.2). Proximity specifically increased the risk of preterm births with preterm premature rupture of the membranes and with pregnancy hypertension., Conclusions: This study demonstrates that exposure to traffic-related air pollution increases even the risk of preterm births of less than 30 weeks' gestational age and proposes a possible mechanism.

Objective: To evaluate the effects of outdoor air pollution, taking into account indoor air pollution, in Indonesia., Methods: The subjects were 15,242 children from 2002 to 2003 Indonesia Demographic and Health Survey. The odds ratios and their confidence intervals for adverse health effects were estimated., Results: Proximity increased the prevalence of acute respiratory infection both in urban and rural areas after adjusting for indoor air pollution. In urban areas, the prevalence of acute upper respiratory infection increased by 1.012 (95% confidence intervals: 1.005 to 1.019) per 2 km proximity to a major road. Adjusted odds ratios tended to be higher in the high indoor air pollution group., Conclusion: Exposure to traffic-related outdoor air pollution would increase adverse health effects after adjusting for indoor air pollution. Furthermore, indoor air pollution could exacerbate the effects of outdoor air pollution.

Oseltamivir is a neuraminidase inhibitor that inhibits influenza virus proliferation, and is used as an antiviral drug against influenza A and B viruses. Recently, concerns have been raised about hallucinations, delirium, and abnormal activity after administration of oseltamivir for treatment of infection with influenza virus. A large epidemiologic study was conducted in Japan in the winter of 2006-2007 to assess the relationship between oseltamivir intake and adverse behaviors, and an interim report was released on 10 July 2008. In the report, the research group concluded that no positive associations were detected between oseltamivir intake and abnormal behaviors. However, the analytic method used in the study was flawed. A correct analysis (based on person-time) shows a rate ratio of 1.57 (95% confidence interval = 1.34-1.83). This example clearly illustrates the importance of person-time in the analysis of cohort studies.

Background: Large-scale methylmercury poisonings have occurred in Japan (Minamata and Niigata) and in Iraq. The current WHO threshold for adult exposure (hair level: 50 microg/g) was based on evidence from Niigata, which included only acute and severe cases. That study leaves open the possibility of more subtle effects at lower exposure levels., Methods: The Shiranui sea had been contaminated in the 1950s by the discharge of methylmercury from a factory near Minamata.In 1960, the hair mercury content of 1694 residents living on the coastline of the Shiranui sea was measured by researchers from the Kumamoto Prefecture Institute for Health Research. Independently, in 1971, a population-based study to examine neurologic signs was conducted in the Minamata and Goshonoura areas, on the coastline of the Shiranui Sea, and the Ariake area (reference), by researchers at Kumamoto University. We identified 120 residents from exposed areas who were included in both datasets, plus 730 residents of Ariake (an unexposed area) who were also examined for neurologic signs., Results: Hair mercury levels were associated with perioral sensory loss in a dose-response relationship. The adjusted prevalence odds ratios and 95% confidence intervals for perioral sensory loss, compared with the lowest exposure category (0-10 microg/g), were 4.5 (0.5-44), 9.1 (1.0-83), and 10 (0.9-110), for the dose categories >10 to 20, >20 to 50, and >50 microg/g, respectively. The prevalence of all neurologic signs was higher in the exposure area than in Ariake., Conclusions: An increased prevalence of neurologic signs, especially perioral sensory loss, was found among residents with hair mercury content below 50 microg/g.

Background: It is well known that large-scale poisonings caused by methylmercury occurred in Japan (Minamata, in the 1950s) and Iraq. However, in contrast to Iraq, there have been few sound epidemiologic studies in Minamata. We evaluated the effect of methylmercury on neurologic signs using data from a 1971 population-based study., Methods: Villages in 3 areas were selected for study: the Minamata area (a high-exposure area), the Goshonoura area (a medium-exposure area), and the Ariake area (a low-exposure area). We used place of residence as the exposure indicator. We examined associations between methylmercury exposure and the following neurologic signs measured on clinical examination: paresthesia of whole body, paresthesia of extremities, paresthesia around the mouth, ataxia, dysarthria, tremors, and pathologic reflexes., Results: Total population was 1120 in the high-exposure villages, 1845 in the medium-exposure villages, and 1165 in the low-exposure villages. In the Minamata area, 87% (n=833) of the eligible population (age 10 years and older) participated in the 1971 investigations, in the Goshonoura area, 93% (n = 1450), and in the Ariake area, 77% (n = 755). Compared with subjects in the Ariake area, the subjects in the Minamata area manifested neurologic signs more frequently. The highest prevalence odds ratio was observed for paresthesia around the mouth (110; 95% confidence interval = 16-820). Although residents in the Goshonoura area had been exposed less heavily than those in the Minamata area, Goshonoura residents also had increased prevalence of neurologic signs., Conclusion: Long-term exposure to methylmercury has a strong adverse impact on neurologic signs among residents in a local community.