Publications by authors named "Naoki Shimizu"

67 Publications

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan.

Pediatr Int 2021 Jul 7. Epub 2021 Jul 7.

The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan.

Background: Coronavirus disease 2019 (COVID-19) pandemic has affected the lives of young and old people. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than adults do. This is the first nationwide study that focused on pediatric cases reported by pediatricians, including those with no or mild symptoms, in Japan.

Methods: We analyzed the epidemiological and clinical characteristics, and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database that was voluntarily registered by the members of the Japan Pediatric Society.

Results: Almost half of patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively).

Conclusions: COVID-19 symptoms in pediatric cases are less severe than those in adult cases. School closure appeared to be limitedly effective, and controlling household transmission from adult family members is the most important measure for COVID-19 prevention among children.
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http://dx.doi.org/10.1111/ped.14912DOI Listing
July 2021

Comparative Analysis of Pediatric COVID-19 Infection in Southeast Asia, South Asia, Japan, and China.

Am J Trop Med Hyg 2021 Jun 15. Epub 2021 Jun 15.

Duke-NUS Medical School, Singapore.

There is a scarcity of data regarding coronavirus disease 2019 (COVID-19) infection in children from southeast and south Asia. This study aims to identify risk factors for severe COVID-19 disease among children in the region. This is an observational study of children with COVID-19 infection in hospitals contributing data to the Pediatric Acute and Critical Care COVID-19 Registry of Asia. Laboratory-confirmed COVID-19 cases were included in this registry. The primary outcome was severity of COVID-19 infection as defined by the World Health Organization (WHO) (mild, moderate, severe, or critical). Epidemiology, clinical and laboratory features, and outcomes of children with COVID-19 are described. Univariate and multivariable logistic regression models were used to identify risk factors for severe/critical disease. A total of 260 COVID-19 cases from eight hospitals across seven countries (China, Japan, Singapore, Malaysia, Indonesia, India, and Pakistan) were included. The common clinical manifestations were similar across countries: fever (64%), cough (39%), and coryza (23%). Approximately 40% of children were asymptomatic, and overall mortality was 2.3%, with all deaths reported from India and Pakistan. Using the multivariable model, the infant age group, presence of comorbidities, and cough on presentation were associated with severe/critical COVID-19. This epidemiological study of pediatric COVID-19 infection demonstrated similar clinical presentations of COVID-19 in children across Asia. Risk factors for severe disease in children were age younger than 12 months, presence of comorbidities, and cough at presentation. Further studies are needed to determine whether differences in mortality are the result of genetic factors, cultural practices, or environmental exposures.
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http://dx.doi.org/10.4269/ajtmh.21-0299DOI Listing
June 2021

Linoleic acid and squalene are oxidized by discrete oxidation mechanisms in human sebum.

Ann N Y Acad Sci 2021 May 31. Epub 2021 May 31.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.

Previous studies suggest that squalene (SQ) in sebum is oxidized by a photooxidation mechanism (i.e., singlet oxygen oxidation) to create SQ hydroperoxide (SQOOH), a compound that causes adverse skin conditions. However, oxidation of other lipids in sebum, such as linoleic acid (LA), has not been fully understood. Elucidating their oxidation, especially its mechanisms, may lead to a further understanding of the relationship between sebum oxidation and skin conditions. In this study, using HPLC-MS/MS, we aimed to detect LA hydroperoxide (LAOOH) directly from sebum and identify the oxidation mechanism of LA in sebum through analysis of LAOOH isomers. We developed extraction and HPLC-MS/MS analysis conditions that can sufficiently quantify each LAOOH isomer in sebum. Using this method, LAOOH was detected in samples from healthy individuals, demonstrating the presence of LAOOH in human sebum. Moreover, isomer analysis of LAOOH and SQOOH indicated that LA and SQ are oxidized in sebum by discrete oxidation mechanisms (LA oxidized by free radical oxidation, whereas SQ oxidized by singlet oxygen oxidation). Such results may further lead to the development of mechanism-specific ways to prevent oxidation of sebum via a selection of appropriate antioxidants, ultimately leading to the promotion of skin health.
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http://dx.doi.org/10.1111/nyas.14615DOI Listing
May 2021

Factors associated with parents' willingness to enroll their children in trials for COVID-19 vaccination.

Hum Vaccin Immunother 2021 06 23;17(6):1607-1611. Epub 2020 Nov 23.

Department of Pediatrics, Seattle Children's Hospital and University of Washington School of Medicine, Seattle, WA, USA.

The coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented global toll and vaccination is needed to restore healthy living. Timely inclusion of children in vaccination trials is critical. We surveyed caregivers of children seeking care in 17 Emergency Departments (ED) across 6 countries during the peak of the pandemic to identify factors associated with intent to participate in COVID-19 vaccine trials. Questions about child and parent characteristics, COVID-19 expressed concerns and parental attitudes toward participation in a trial were asked.Of 2768 completed surveys, 18.4% parents stated they would enroll their child in a clinical trial for a COVID-19 vaccine and 14.4% would agree to a randomized placebo-controlled study. Factors associated with willingness to participate were parents agreeing to enroll in a COVID-19 vaccine trial themselves (Odds Ratio (OR) 32.9, 95% Confidence Interval (CI) (21.9-51.2)) having an older child (OR 1.0 (1.0-1.01)), having children who received all vaccinations based on their country schedule (OR 2.67 (1.35-5.71)) and parents with high school education or lower (OR 1.79 (1.18-2.74)). Mothers were less likely to enroll their child in a trial (OR 0.68 (0.47-0.97)). Only one fifth of families surveyed will consider enrolling their child in a vaccine trial. Parental interest in participation, history of vaccinating their child, and the child being older all are associated with parents allowing their child to participate in a COVID vaccine trial. This information may help decision-makers and researchers shape their strategies for trial design and participation engagement in upcoming COVID19 vaccination trials.
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http://dx.doi.org/10.1080/21645515.2020.1834325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115755PMC
June 2021

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

Vaccine 2020 11 1;38(50):8049-8054. Epub 2020 Nov 1.

The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan; Division of Basic Nursing, Fukuoka Nursing College, Fukuoka, Japan.

Background: Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan.

Methods: This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups.

Results: We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01).

Conclusion: The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.049DOI Listing
November 2020

Caregiver willingness to vaccinate their children against COVID-19: Cross sectional survey.

Vaccine 2020 11 10;38(48):7668-7673. Epub 2020 Oct 10.

Emergency Department, University Children's Hospital Zurich, Zurich, Switzerland.

Background: More than 100 COVID-19 vaccine candidates are in development since the SARS-CoV-2 genetic sequence was published in January 2020. The uptake of a COVID-19 vaccine among children will be instrumental in limiting the spread of the disease as herd immunity may require vaccine coverage of up to 80% of the population. Prior history of pandemic vaccine coverage was as low as 40% among children in the United States during the 2009 H1N1 influenza pandemic.

Purpose: To investigate predictors associated with global caregivers' intent to vaccinate their children against COVID-19, when the vaccine becomes available.

Method: An international cross sectional survey of 1541 caregivers arriving with their children to 16 pediatric Emergency Departments (ED) across six countries from March 26 to May 31, 2020.

Results: 65% (n = 1005) of caregivers reported that they intend to vaccinate their child against COVID-19, once a vaccine is available. A univariate and subsequent multivariate analysis found that increased intended uptake was associated with children that were older, children with no chronic illness, when fathers completed the survey, children up-to-date on their vaccination schedule, recent history of vaccination against influenza, and caregivers concerned their child had COVID-19 at the time of survey completion in the ED. The most common reason reported by caregivers intending to vaccinate was to protect their child (62%), and the most common reason reported by caregivers refusing vaccination was the vaccine's novelty (52%).

Conclusions: The majority of caregivers intend to vaccinate their children against COVID-19, though uptake will likely be associated with specific factors such as child and caregiver demographics and vaccination history. Public health strategies need to address barriers to uptake by providing evidence about an upcoming COVID-19 vaccine's safety and efficacy, highlighting the risks and consequences of infection in children, and educating caregivers on the role of vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547568PMC
November 2020

Caregivers' Willingness to Accept Expedited Vaccine Research During the COVID-19 Pandemic: A Cross-sectional Survey.

Clin Ther 2020 11 3;42(11):2124-2133. Epub 2020 Oct 3.

Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.

Purpose: This study determined the predictors of caregivers' willingness to accept an accelerated regulatory process for the development of vaccines against coronavirus disease 2019 (COVID-19).

Methods: An international cross-sectional survey was administered to 2557 caregivers of children in 17 pediatric emergency departments (EDs) across 6 countries from March 26, 2020, to June 30, 2020. Caregivers were asked to select 1 of 4 choices with which they most agreed regarding a proposed COVID-19 vaccine-approval process, in addition to questions regarding demographic characteristics, the ED visit, and attitudes about COVID-19. Univariate analyses were conducted using the Mann-Whitney U test for comparing non-normally distributed continuous variables, an independent t test for comparing normally distributed continuous variables, and a χ or Fisher exact test for categorical variables. Multivariate logistic regression analysis was used for determining independent factors associated with caregivers' willingness to accept abridged development of a COVID-19 vaccine. A P value of <0.05 was considered significant.

Findings: Almost half (1101/2557; 43%) of caregivers reported that they were willing to accept less rigorous testing and postresearch approval of a new COVID-19 vaccine. Independent factors associated with caregivers' willingness to accept expedited COVID-19 vaccine research included having children who were up to date on the vaccination schedule (odds ratio [OR] = 1.72; 95% CI, 1.29-2.31), caregivers' concern about having had COVID-19 themselves at the time of survey completion in the ED (OR = 1.1; 95% CI, 1.05-1.16), and caregivers' intent to have their children vaccinated against COVID-19 if a vaccine were to become available (OR = 1.84; 95% CI, 1.54-2.21). Compared with fathers, mothers completing the survey were less likely to approve of changes in the vaccine-development process (OR = 0.641; 95% CI, 0.529-0.775).

Implications: Less than half of caregivers in this worldwide sample were willing to accept abbreviated COVID-19 vaccine testing. As a part of an effort to increase acceptance and uptake of a new vaccine, especially in order to protect children, public health strategies and individual providers should understand caregivers' attitudes toward the approval of a vaccine and consult them appropriately.
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http://dx.doi.org/10.1016/j.clinthera.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532744PMC
November 2020

First case of Legionella pneumonia in a female patient with anorexia nervosa.

J Paediatr Child Health 2021 06 14;57(6):950-952. Epub 2020 Aug 14.

Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1111/jpc.15108DOI Listing
June 2021

Concordance between the 2010 and 2015 Resuscitation Guidelines of International Liaison Committee of Resuscitation Councils (ILCOR) members and the ILCOR Consensus of Science and Treatment Recommendations (CoSTRs).

Resuscitation 2020 06 9;151:111-117. Epub 2020 Apr 9.

Imperial College NHS Healthcare Trust, London, UK; Centre for Reviews and Dissemination, University of York, UK.

Background: Cardiac arrests are associated with poor outcomes. The International Liaison Committee on Resuscitation (ILCOR) evaluates resuscitation science and produced, until 2015, five-yearly consensus on science and treatment recommendations (CoSTRs), informing global resuscitation guidelines. We aimed to identify similarities/differences in resuscitation guidelines from ILCOR members, noting concurrence over time, and CoSTRs influence on these guidelines.

Methods: We considered the component elements of paediatric and adult, basic and advanced resuscitation guidelines, published in 2010 and 2015, along with matching ILCOR CoSTRs to examine their influence. We contacted the responsible councils when guidelines were unavailable online.

Results: Complete resuscitation guidelines were found for six of the seven ILCOR council members. The Resuscitation Council of Asia only had adult basic life support (BLS) guidelines in English. Three members used the AHA guidelines. Therefore, five rather than seven sets of resuscitation guidelines were compared to the CoSTRs. Concurrence between CoSTRs recommendations and ILCOR council member's resuscitation guidelines has improved over time. Minor variations were identified in both basic and advanced life support, with most variance in paediatric guidelines, but these narrowed over time.

Conclusion: The improved concurrence across the resuscitation guidelines with the CoSTRs suggests that ILCOR members accept and hence incorporate CoSTRs recommendations to inform their own resuscitation guidelines. This is one step towards the development of international universal guidelines for adult and paediatric resuscitation.
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http://dx.doi.org/10.1016/j.resuscitation.2020.04.001DOI Listing
June 2020

Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice.

PLoS Genet 2020 02 26;16(2):e1008628. Epub 2020 Feb 26.

Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.
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http://dx.doi.org/10.1371/journal.pgen.1008628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062289PMC
February 2020

2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

Resuscitation 2019 12 14;145:95-150. Epub 2019 Nov 14.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research.
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http://dx.doi.org/10.1016/j.resuscitation.2019.10.016DOI Listing
December 2019

2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces.

Circulation 2019 12 14;140(24):e826-e880. Epub 2019 Nov 14.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research.
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http://dx.doi.org/10.1161/CIR.0000000000000734DOI Listing
December 2019

Component-resolved diagnostics can be useful for identifying hazelnut allergy in Japanese children.

Allergol Int 2020 Apr 1;69(2):239-245. Epub 2019 Nov 1.

Department of Allergy, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan; Course of Allergy and Clinical Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address:

Background: Cor a 9 and Cor a 14 are effective markers for predicting hazelnut allergy. However, there have been no reports on the component-resolved diagnostics (CRD) of hazelnut allergy using an oral food challenge (OFC) for diagnosis in Asia. We hypothesized that CRD would improve the accuracy of diagnosing hazelnut allergies in Japanese children.

Methods: We recruited 91 subjects (median age: 7.3 years) who were sensitized to hazelnuts and had performed a hazelnut OFC at the National Hospital Organization Sagamihara National Hospital between 2006 and 2017. All subjects were classified as allergic or asymptomatic to 3 g of hazelnuts. The sIgE levels (hazelnut/Cor a 1/Cor a 8/Cor a 9/Cor a 14/alder pollen) were measured using ImmunoCAP. We aimed to determine the predictive factors of hazelnut allergy.

Results: Nine subjects (10%) were allergic to ≤3 g of hazelnuts. Levels of sIgE for Cor a 9 in hazelnut-allergic subjects were significantly higher than those in asymptomatic subjects (4.47 vs. 0.76 kU/L, p = 0.039). Levels of sIgE to alder pollen and Cor a 1 in hazelnut-allergic subjects were significantly lower than those in asymptomatic subjects (<0.10 vs 13.0 kU/L, p = 0.004; <0.10 vs 5.03 kU/L, p = 0.025). The area under the receiver operating characteristics curve for hazelnut/alder/Cor a 1/Cor a 9 was 0.55/0.78/0.72/0.71, respectively, with p = 0.651/0.006/0.029/0.040, respectively.

Conclusions: The findings of a high sIgE level for Cor a 9 and a low sIgE level for Cor a 1 can improve the diagnostic accuracy to better identify Japanese children sensitized to hazelnuts.
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http://dx.doi.org/10.1016/j.alit.2019.10.001DOI Listing
April 2020

Analysis of oxidation products of α-tocopherol in extra virgin olive oil using liquid chromatography-tandem mass spectrometry.

Food Chem 2020 Feb 4;306:125582. Epub 2019 Oct 4.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980-8572, Japan; J-Oil Mills Innovation Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980-8572, Japan. Electronic address:

When α-tocopherol (α-Toc) exerts its antioxidative effect, a portion of α-Toc is converted to certain oxidation products. Although accumulation of such oxidation products is considered to cause a deterioration in the quality of foods, their distribution and generation in food samples have been still unknown. In this study, we tried to analyze α-Toc hydroperoxide (Toc-OOH) stereoisomers and tocopherylquinone (TQ) in extra virgin olive oil (EVOO) using liquid chromatography-tandem mass spectrometry. Photo-irradiation (5000 lx) to EVOO increased Toc-OOH stereoisomers but not TQ. In contrast, thermal oxidation (150 °C) of EVOO increased TQ but not Toc-OOH. We considered that the generation of Toc-OOH and TQ were due to the [4+2]-cycloaddition reaction and proton donation from the phenolic hydrogen, respectively. Our data and method would be helpful for understanding of α-Toc oxidation mechanisms in edible oil samples or the estimation of food quality.
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http://dx.doi.org/10.1016/j.foodchem.2019.125582DOI Listing
February 2020

Significance of Squalene in Rice Bran Oil and Perspectives on Squalene Oxidation.

J Nutr Sci Vitaminol (Tokyo) 2019 ;65(Supplement):S62-S66

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University.

As an intermediate metabolite during the biosynthesis of sterols, squalene is found ubiquitously in plants and animals. In rice, squalene is contained in rice bran, and consequently, squalene in rice bran oil has gained attention. Studies have shown that the intake of squalene from food sources demonstrate various physiological benefits such as the prevention of cancer and cardiovascular disease. Squalene is also known as an effective antioxidant in edible oils. However, due to its chemical structure, squalene is susceptible to oxidation, which may cause a decline in the nutraceutical and antioxidative effects of squalene in edible oils. Oxidative degradation of squalene also results in the formation of scission products (i.e., aldehydes and ketones) which may lead to off-flavor. Since the rate of squalene oxidation depends on the factors that induce its oxidation (i.e., light or heat), emphasis on oxidation mechanisms is necessary. It has been demonstrated in previous studies that the oxidation products formed by the singlet oxygen oxidation and free radical oxidation of squalene are different, and more recently, we demonstrated that different squalene monohydroperoxide isomers are formed by each oxidation mechanism. We herein discuss the significance of squalene in rice bran oil as well as the oxidative degradation of squalene in edible oils with focus on oxidation mechanisms.
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http://dx.doi.org/10.3177/jnsv.65.S62DOI Listing
March 2020

Evaluation of squalene oxidation mechanisms in human skin surface lipids and shark liver oil supplements.

Ann N Y Acad Sci 2019 12 26;1457(1):158-165. Epub 2019 Aug 26.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.

Squalene is a terpenoid found in human skin surface lipids (SSLs) and foods that possesses beneficial properties. However, since oxidation of squalene causes various complications, it is necessary to identify the mechanisms by which squalene is oxidized. In this study, we aimed to determine the oxidation mechanisms of squalene in SSLs and shark liver oil (SLO) supplements by the analysis of squalene monohydroperoxide (SQOOH) isomers, on the basis of our previous finding that different oxidation mechanisms yield different SQOOH isomers. Liquid chromatography-tandem mass spectrometry analysis of SQOOH isomers revealed that squalene in human SSLs was oxidized by singlet oxygen oxidation, whereas squalene in SLO was oxidized mainly by free radicals. As a result, we have presented the first evidence suggesting that the analysis of SQOOH isomers enables estimation of oxidation mechanisms. Estimating oxidation mechanisms by analyzing SQOOH isomers may provide a foundation for the prevention of skin diseases and food deterioration via regulation of squalene oxidation.
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http://dx.doi.org/10.1111/nyas.14219DOI Listing
December 2019

Middle-term prognosis in patients with ulcerative colitis who achieved clinical and endoscopic remission by budesonide rectal foam.

PLoS One 2019 5;14(8):e0220413. Epub 2019 Aug 5.

TMDU Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Budesonide foam is effective in inducing clinical remission in ulcerative colitis (UC) patients with active proctosigmoiditis. The aim of this study was to evaluate the duration of remission and predictors of relapse in UC patients who achieved clinical remission and mucosal healing by 6-week treatment with topical budesonide.

Methods: This is a retrospective, observational, multicenter study with a 2-year follow-up period. UC patients who were treated with budesonide foam in phase 2 or phase 3 clinical trials and achieved both clinical remission and mucosal healing were enrolled.

Results: Among 84 patients who met the eligibility criteria, 60 participated in the study. Eighteen of the 60 patients (30.0%; 95% confidence interval [CI]: 18.9-43.2) experienced no relapse (i.e., maintenance of remission) during the 2-year follow-up period. The median relapse-free survival time was 0.82 years (95% CI: 0.51-1.52). Of 37 patients with a Mayo endoscopic subscore of 0 after inducing remission with budesonide foam, 25 (67.6%) relapsed within 2 years. Patients with a disease duration of <1 year experienced a worse clinical outcome than patients with a disease duration of >5 years, and the hazard ratio was 2.38 (95% CI: 1.04-5.45).

Conclusion: This is the first study to evaluate the short- to middle-term prognosis in UC patients who achieved mucosal healing with topical preparations. After inducing remission by budesonide foam, treatment for maintaining remissions and strict follow-up may be needed for patients with shorter disease duration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681969PMC
March 2020

Comparison of Blood Profiles of γ-Oryzanol and Ferulic Acid in Rats after Oral Intake of γ-Oryzanol.

Nutrients 2019 May 25;11(5). Epub 2019 May 25.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980-8572, Japan.

γ-Oryzanol (OZ), a bioactive phytochemical abundant in cereals such as rice, has been reported to be mainly hydrolyzed to ferulic acid (FA) in the body. Meanwhile, in our previous study, we revealed that a part of OZ is absorbed into the body and exists in its intact form. However, the comprehensive absorption profile of OZ and its metabolites (e.g., FA) after OZ intake has not been fully elucidated yet. Therefore, in this study, we measured the concentrations of OZ, FA, and FA conjugates (i.e., FA sulfate and glucuronide) in the blood of rats with the use of HPLC-MS/MS after a single oral administration of 300 µmol/kg body weight of rice bran OZ (RBOZ). As a result, intact OZ along with FA and FA conjugates existed in the blood, which implied that these constituents may all contribute to the physiological effects under OZ intake. Additionally, when an equimolar amount of FA (300 µmol/kg body weight) was administered, it was found that the absorption profile of FA was significantly different from that when RBOZ was administered.
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http://dx.doi.org/10.3390/nu11051174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567117PMC
May 2019

Evaluation of lipid oxidation mechanisms in beverages and cosmetics via analysis of lipid hydroperoxide isomers.

Sci Rep 2019 05 14;9(1):7387. Epub 2019 May 14.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, 980-8572, Japan.

Understanding of lipid oxidation mechanisms (e.g., auto-oxidation and photo-oxidation) in foods and cosmetics is deemed essential to maintain the quality of such products. In this study, the oxidation mechanisms in foods and cosmetics were evaluated through analysis of linoleic acid hydroperoxide (LAOOH) and linoleic acid ethyl ester hydroperoxide (ELAOOH) isomers. Based on our previous method for analysis of LAOOH isomers, in this study, we developed a new HPLC-MS/MS method that enables analysis of ELAOOH isomers. The HPLC-MS/MS methods to analyze LAOOH and ELOOH isomers were applied to food (liquor) and cosmetic (skin cream) samples. As a result, LAOOH and ELAOOH isomers specific to photo-oxidation, and ELAOOH isomers characteristic to auto-oxidation were detected in some marketed liquor samples, suggesting that lipid oxidation of marketed liquor proceeds by both photo- and auto-oxidation during the manufacturing process and/or sales. In contrast, because only LAOOH and ELAOOH isomers specific to auto-oxidation were detected in skin cream stored under dark at different temperatures (-5 °C-40 °C) for different periods (2-15 months), auto-oxidation was considered to be the major oxidation mechanism in such samples. Therefore, our HPLC-MS/MS methods appear to be powerful tools to elucidate lipid oxidation mechanisms in food and cosmetic products.
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http://dx.doi.org/10.1038/s41598-019-43645-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517444PMC
May 2019

Relationship between institutional case volume and one-month survival among cases of paediatric out-of-hospital cardiac arrest.

Resuscitation 2019 04 22;137:161-167. Epub 2019 Feb 22.

Department of Emergency Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8606, Japan.

Aim: To evaluate volume-outcome relationship in paediatric out-of-hospital cardiac arrest (OHCA).

Methods: This post hoc analysis of the SOS-KANTO 2012 study included data of paediatric OHCA patients <18 years old who were transported to the 53 emergency hospitals in the Kanto region of Japan between January 2012 and March 2013. Based on the paediatric OHCA case volume, the higher one-third of institutions (more than 10 paediatric OHCA cases during the study period) were defined as high-volume centres, the middle one-third institutions (6-10 cases) were defined as middle-volume centres and the lower one-third of institutions (less than 6 cases) were defined as low-volume centres. The primary outcome measurement was survival at 1 month after cardiac arrest. Multivariate logistic regression analysis for 1-month survival and paediatric OHCA case volume were performed after adjusting for multiple propensity scores. To estimate the multiple propensity score, we fitted a multinomial logistic regression model, which fell into one of the three groups as patient demographics and prehospital factors.

Results: Among the eligible 282 children, 112, 82 and 88 patients were transported to the low-volume (36 institutions), middle-volume (11 institutions) and high-volume (6 institutions) centres, respectively. Transport to a high-volume centre was significantly associated with a better 1-month survival after adjusting for multiple propensity score (adjusted odds ratio, 2.55; 95% confidence interval, 1.05-6.17).

Conclusion: There may be a relationship between institutional case volume and survival outcomes in paediatric OHCA.
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http://dx.doi.org/10.1016/j.resuscitation.2019.02.021DOI Listing
April 2019

Evaluation of γ-oryzanol Accumulation and Lipid Metabolism in the Body of Mice Following Long-Term Administration of γ-oryzanol.

Nutrients 2019 Jan 6;11(1). Epub 2019 Jan 6.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 980-8572, Japan.

γ-Oryzanol (OZ), abundant in rice bran oil, has gained attention due to its physiological activities (e.g., lipid-lowering effects). However, the absorption and metabolism of orally ingested OZ have not yet been fully elucidated. In this study, diets containing normal or high contents of OZ were fed to obesity model mice for 8 weeks, and OZ concentrations in plasma and organs were analyzed by HPLC-MS/MS. To evaluate the relationship between OZ accumulation and lipid metabolism in vivo, lipid concentrations in the mice plasma and liver were also measured. As a result, the accumulation of intact OZ in plasma and organs was seen in mice fed diets containing OZ, where mice fed diets containing higher OZ contents demonstrated higher levels of OZ accumulation and lower amounts of plasma lipids. These results, in combination with our additional data from a single oral administration test, suggest the possibility that intact OZ, along with its metabolites (e.g., ferulic acid), is biologically-active.
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http://dx.doi.org/10.3390/nu11010104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356301PMC
January 2019

Use of ALK Immunohistochemistry for Optimal Therapeutic Strategy of Pulmonary Large-cell Neuroendocrine Carcinoma and Identification of a Novel Fusion Oncokinase.

Anticancer Res 2019 Jan;39(1):413-420

Department of Diagnostic Pathology and Laboratory Medicine, Kindai University Nara Hospital School of Medicine, Nara, Japan.

Background: Patients with adenocarcinoma of the lung are routinely screened for anaplastic lymphoma kinase (ALK) rearrangement because they can be treated by ALK-specific targeted therapy. The clinical and molecular characteristics of large-cell neuroendocrine carcinoma (LCNEC) associated with ALK rearrangement are still unclear. Herein, we assessed the ALK status in a series of patients with LCNEC by testing methods commonly used for adenocarcinoma.

Materials And Methods: ALK expression was first examined by immunohistochemistry. For a positively stained tumor, molecular analyses were then conducted. The ALK fusion partner found in a patient with ALK rearrangement was further identified by direct DNA sequencing. Patient clinicopathological features were also analyzed, focusing on the ALK rearrangement-positive case.

Results: Immunohistochemistry of seven patients identified strong ALK expression in one case of stage IV LCNEC. Molecular analysis identified a novel rearranged gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 17 to ALK exon 20. The patient was treated with ALK-specific inhibitors, crizotinib and later, alectinib, and has remained alive for more than 24 months without disease progression. Three of the remaining six patients without ALK rearrangement had stage IV cancer and received cytotoxic chemotherapies. Their average overall survival was 5.4 months.

Conclusion: To our knowledge, this is the first report of a KIF5B-ALK fusion gene in LCNEC. The patient was successfully treated with ALK inhibitors, suggesting that sensitivity to ALK inhibitor may define a specific LCNEC subtype. We propose that screening for ALK rearrangement in patients with LCNEC may assist in selecting potential candidates for targeted therapy.
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http://dx.doi.org/10.21873/anticanres.13127DOI Listing
January 2019

Determination of pyrroloquinoline quinone by enzymatic and LC-MS/MS methods to clarify its levels in foods.

PLoS One 2018 21;13(12):e0209700. Epub 2018 Dec 21.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.

Pyrroloquinoline quinone (PQQ) is believed to be a new B vitamin-like compound, and PQQ supplementation has received attention as a possible treatment for diseases including dementia and diabetes. However, the distribution of PQQ in foods is unclear, due to the difficulty in analyzing the compound. Therefore, in this study, enzymatic and LC-MS/MS methods were optimized to enable an accurate analysis of PQQ in foods. The optimized methods were applied to the screening of foods, in which PQQ contents were identified in ng/g or ng/mL levels. Furthermore, we newly found that some foods related to acetic acid bacteria contain PQQ at 1.94~5.59 ng/mL higher than beer, which is known to contain relatively high amounts of PQQ. These results suggest that the optimized methods are effective for the screening of foods containing PQQ. Such foods with high PQQ content may be valuable as functional foods effective towards the treatment of certain diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303014PMC
May 2019

2018 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary.

Circulation 2018 12;138(23):e714-e730

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the second annual summary of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations that includes the most recent cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation. This summary addresses the role of antiarrhythmic drugs in adults and children and includes the Advanced Life Support Task Force and Pediatric Task Force consensus statements, which summarize the most recent published evidence and an assessment of the quality of the evidence based on Grading of Recommendations, Assessment, Development, and Evaluation criteria. The statements include consensus treatment recommendations approved by members of the relevant task forces. Insights into the deliberations of each task force are provided in the Values and Preferences and Task Force Insights sections. Finally, the task force members have listed the top knowledge gaps for further research.
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http://dx.doi.org/10.1161/CIR.0000000000000611DOI Listing
December 2018

2018 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary.

Resuscitation 2018 12 5;133:194-206. Epub 2018 Nov 5.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the second annual summary of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations that includes the most recent cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation. This summary addresses the role of antiarrhythmic drugs in adults and children and includes the Advanced Life Support Task Force and Pediatric Task Force consensus statements, which summarize the most recent published evidence and an assessment of the quality of the evidence based on Grading of Recommendations, Assessment, Development, and Evaluation criteria. The statements include consensus treatment recommendations approved by members of the relevant task forces. Insights into the deliberations of each task force are provided in the Values and Preferences and Task Force Insights sections. Finally, the task force members have listed the top knowledge gaps for further research.
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http://dx.doi.org/10.1016/j.resuscitation.2018.10.017DOI Listing
December 2018

Absorption and Metabolism of Luteolin in Rats and Humans in Relation to in Vitro Anti-inflammatory Effects.

J Agric Food Chem 2018 Oct 19;66(43):11320-11329. Epub 2018 Oct 19.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science , Tohoku University , Sendai , Miyagi 980-0845 , Japan.

Luteolin is a flavonoid present in plants in the form of aglycone or glucosides. In this study, luteolin glucosides (i.e., luteolin-7- O-β-d-glucoside, luteolin-7- O-[2-(β-d-apiosyl)-β-d-glucoside], and luteolin-7- O-[2-(β-d-apiosyl)-6-malonyl-β-d-glucoside]) prepared from green pepper leaves as well as luteolin aglycone were orally administered to rats. Regardless of the administered luteolin form, luteolin glucuronides were mainly detected from plasma and organs. Subsequently, luteolin aglycone, the most absorbed form of luteolin in rats, was orally administered to humans. As a result, luteolin-3'- O-sulfate was mainly identified from plasma, suggesting that not only luteolin form but also animal species affect the absorption and metabolism of luteolin. When LPS-treated RAW264.7 cells were treated with luteolin glucuronides and luteolin sulfate (the characteristic metabolites identified from rats and humans, respectively), the different luteolin conjugates were metabolized in different ways, suggesting that such difference in metabolism results in their difference in anti-inflammatory effects.
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http://dx.doi.org/10.1021/acs.jafc.8b03273DOI Listing
October 2018

Longer Duration of Urinary Catheterization Increases Catheter-Associated Urinary Tract Infection in PICU.

Pediatr Crit Care Med 2018 10;19(10):e547-e550

Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Objectives: Catheter-associated urinary tract infections account for 30% of healthcare-associated infections. To date, few studies have addressed pediatric catheter-associated urinary tract infection in PICUs. The aim of our study was to assess the risk of catheter-associated urinary tract infection in relation to the duration of catheterization in the PICU.

Design: Retrospective cohort study.

Setting: PICU at a tertiary children's hospital.

Patients: Our study was conducted between April 2012 and June 2015 at Tokyo Metropolitan Children's Medical Center in Japan. Children in the PICU with an urethral catheter were included. Catheter-associated urinary tract infection cases were defined according to the National Healthcare Safety Network criteria. The patients' demographic data and isolated organisms were reviewed. Duration of catheterization and the catheter-associated urinary tract infection occurrence rate were analyzed.

Interventions: None.

Measurements And Main Results: Among 1,890 catheterizations, 23 catheter-associated urinary tract infection cases were identified. The overall occurrence rate was 2.35/1,000 catheter-days. Among the patients with catheter-associated urinary tract infection, 13 were boys. The median age was 11 months (interquartile range, 7-35 mo), and the median duration of catheterization was 7 days (interquartile range, 5-12 d). The isolated bacteria were Escherichia coli (26.5%), Enterococcus faecalis (17.6%), and Klebsiella pneumoniae (11.8%). Two species were isolated in each of 11 cases (47.8%). Each additional day of catheterization increased the risk of catheter-associated urinary tract infection (odds ratio, 1.06; 95% CI, 1.02-1.10, and odds ratio adjusted for contact precaution status and surgical procedures was 1.05; 95% CI, 1.01-1.09).

Conclusions: Longer duration of catheterization increased the risk of catheter-associated urinary tract infection by 5% each day at the PICU. Prompt removal of the urethral catheter is strongly recommended whenever feasible.
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http://dx.doi.org/10.1097/PCC.0000000000001628DOI Listing
October 2018

Oxidation of squalene by singlet oxygen and free radicals results in different compositions of squalene monohydroperoxide isomers.

Sci Rep 2018 06 14;8(1):9116. Epub 2018 Jun 14.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, 980-0845, Japan.

Oxidation of squalene (SQ) causes a decline in the nutritional value of SQ in foods, as well as an accumulation of SQ oxidation products in skin lipids which lead to adverse skin conditions. However, mechanistic insights as to how SQ is oxidized by different oxidation mechanisms have been limited, and thus effective measures towards the prevention of SQ oxidation have not been identified. In this study, we oxidized SQ by either singlet oxygen oxidation or free radical oxidation, and monitored the formation of the six SQ monohydroperoxide (SQOOH) isomers, the primary oxidation products of SQ, at the isomeric level. While singlet oxygen oxidation of SQ resulted in the formation of similar amounts of the six SQOOH isomers, free radical oxidation of SQ mainly formed two types of isomers, 2-OOH-SQ and 3-OOH-SQ. The addition of β-carotene during singlet oxygen oxidation, and the addition of α-tocopherol during free radical oxidation lead to a dose-dependent decrease in the formation of SQOOH isomers. Such results suggest that the analysis of SQOOH at the isomeric level allows for the determination of the cause of SQ oxidation in various samples, and provides a foothold for future studies concerning the prevention of SQ oxidation.
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http://dx.doi.org/10.1038/s41598-018-27455-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002538PMC
June 2018

Development of quantitation method for glycated aminophospholipids at the molecular species level in powdered milk and powdered buttermilk.

Sci Rep 2018 06 7;8(1):8729. Epub 2018 Jun 7.

Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, 980-0845, Japan.

The Maillard reaction is a nonenzymatic glycation reaction between a reducing sugar and a free amino group, known to naturally occur during heat processing of food. In this study, we especially focused on phosphatidylethanolamine (PE)-linked Amadori products (Amadori-PE) in powdered milk, since the analysis of these products at the molecular species level has not yet been evaluated. Analysis of Amadori-PE was conducted by using liquid chromatography-tandem mass spectrometry in three different modes. The main Amadori-PE species in a powdered milk sample were first identified as 34:1, 36:1, 36:2 and 36:3 in the total ion current mode. Additionally, by using the characteristic product ions observed in the presence of sodium, we quantified the main Amadori-PE species in the multiple reaction monitoring mode, and evaluated their total concentrations in the precursor ion scan (PIS) mode for the first time. Powdered milk contained much Amadori-PE with concentrations ranging from 4.3 to 8239 mg/100 g, quantified by the PIS mode. The newly developed methods represent powerful tools for detailed analysis of glycated lipids including Amadori-PE in powdered milk, which may further be applied to research relating to infant food and nutrition.
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http://dx.doi.org/10.1038/s41598-018-27010-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992167PMC
June 2018

Antimicrobial Stewardship Program in a Pediatric Intensive Care Unit.

J Pediatric Infect Dis Soc 2018 Aug;7(3):e156-e159

Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Japan.

We conducted an antimicrobial stewardship program in a pediatric intensive care unit. An interrupted time-series analysis revealed a significant reduction in level and trend of days of therapy per 1000 patient-days for antipseudomonal agents. No increase in adverse patient outcomes was found.
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http://dx.doi.org/10.1093/jpids/piy031DOI Listing
August 2018
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