Publications by authors named "Takashi Moriya"

76 Publications

Procalcitonin elevation induced by sympathomimetic drug overdose.

Acute Med Surg 2021 Jan-Dec;8(1):e687. Epub 2021 Aug 3.

Department of Emergency and Critical Care Medicine Saitama Medical Center Jichi Medical University Saitama Japan.

Background: Procalcitonin, a biomarker used to detect systemic bacterial infection, can be elevated in other conditions. Some case reports have suggested procalcitonin elevation induced by drug overdose.

Case Presentation: A 20-year-old woman with insignificant medical history presented with vomiting, fever, and impaired consciousness. Her vital signs showed an altered mental status (Glasgow Coma Scale score, 11 [E4V1M6]) and high fever (38.0°C), and no significant neurological signs were detected. Laboratory tests revealed that her serum procalcitonin level was significantly high (>10 ng/dL). Gradually, her level of consciousness improved, and she admitted that she had taken an overdose of sympathomimetic drugs. She was discharged from the hospital on day 5 without any problems.

Conclusion: Drug overdose is seldom mentioned as one of the causes of serum procalcitonin level elevation. Sympathomimetic drug overdose can be one of the causes of procalcitonin elevation.
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http://dx.doi.org/10.1002/ams2.687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331093PMC
August 2021

Cholinergic crisis caused by ingesting topical carpronium chloride solution: A case report.

Am J Emerg Med 2021 May 14. Epub 2021 May 14.

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Saitama-shi, Saitama 330-8503, Japan. Electronic address:

A cholinergic crisiss is a state characterized by excess acetylcholine owing to the ingestion of cholinesterase inhibitors or cholinergic agonists. We report the first case of a cholinergic crisis after the ingestion of a carpronium chloride solution, a topical solution used to treat alopecia, seborrhea sicca, and vitiligo. An 81-year-old woman with no prior medical history was transported to our emergency department because the patient had disturbance of consciousness after ingesting three bottles of FUROZIN® solution (90 mL, 4500 mg as carpronium chloride). A family member who found the patient called for emergency medical services (EMS) personnel, who contacted the patient ten minutes after ingestion. The patient's Glasgow Coma Scale score was 12 (E4V3M5), and vital signs were as follows: blood pressure, 80/40 mmHg; heart rate, 40 beats/min. The patient vomited repeatedly in the ambulance. On arrival to the ED, the patient's systolic blood pressure and heart rate temporarily decreased to 80 mmHg and 40 beats/min, respectively. Seventy-eight minutes after ingestion, gastric lavage was performed. The patient's symptoms, which included excess salivation, sweating, and hot flush, improved 24 h after ingestion, and the patient's vital signs stabilized without atropine or vasopressors. On the second day of admission, the patient was examined by a psychiatrist and discharged without suicidal ideation. Carpronium chloride has a chemical structure similar to that of acetylcholine; therefore, it exhibits both cholinergic and local vasodilatory activities. There is limited information on the pharmacokinetics of ingested carpronium chloride; therefore, physicians should be made aware that ingesting a carpronium chloride solution may cause a cholinergic crisis.
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http://dx.doi.org/10.1016/j.ajem.2021.05.027DOI Listing
May 2021

Clinical Outcomes of 2nd- and 3rd-Line Regorafenib for Advanced Hepatocellular Carcinoma.

Oncology 2021 17;99(8):491-498. Epub 2021 May 17.

Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan.

Introduction: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma.

Methods: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy.

Results: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients.

Conclusion: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.
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http://dx.doi.org/10.1159/000515280DOI Listing
August 2021

Machine learning-based mortality prediction model for heat-related illness.

Sci Rep 2021 May 4;11(1):9501. Epub 2021 May 4.

Department of Critical Care and Emergency Medicine, Tokyo Women's Medical University, Tokyo, Japan.

In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017-2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 [95% confidence interval (CI) 0.336-0.494], 0.395 [CI 0.318-0.472], 0.426 [CI 0.346-0.506], and 0.528 [CI 0.442-0.614], respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 [CI 0.222-0.351] as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses.
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http://dx.doi.org/10.1038/s41598-021-88581-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096946PMC
May 2021

Efficacy and Safety of Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy for Patients with Intermediate-Stage Hepatocellular Carcinoma.

Oncology 2021 4;99(8):507-517. Epub 2021 May 4.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Introduction: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC).

Methods: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated.

Results: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p =  0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable.

Conclusion: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.
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http://dx.doi.org/10.1159/000515865DOI Listing
August 2021

Impact of Enteral Nutrition Within 24 Hours Versus Between 24 and 48 Hours in Patients With Severe Acute Pancreatitis: A Multicenter Retrospective Study.

Pancreas 2021 03;50(3):371-377

Department of Emergency Medicine, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.

Objectives: In patients with severe acute pancreatitis (SAP), early enteral nutrition (EN) is recommended by major clinical practice guidelines, but the exact timing for the initiation of EN is unknown.

Methods: We conducted a post hoc analysis of the database for a multicenter (44 institutions) retrospective study of patients with SAP in Japan. The patients were classified into 3 groups according to the timing of EN initiation after the diagnosis of SAP: within 24 hours, between 24 and 48 hours, and more than 48 hours. The primary outcome was in-hospital mortality.

Results: Of the 1094 study patients, 176, 120, and 798 patients started EN within 24 hours, between 24 and 48 hours, and more than 48 hours after SAP diagnosis, respectively. On multivariable analysis, hospital mortality was significantly better with EN within 48 hours than with more than 48 hours (adjusted odds ratio, 0.49; 95% confidence interval, 0.29-0.83; P < 0.001) but did not significantly differ between the groups with EN starting within 24 hours and between 24 and 48 hours (P = 0.29).

Conclusions: Enteral nutrition within 24 hours may not confer any additional benefit on clinical outcomes compared with EN between 24 and 48 hours.
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http://dx.doi.org/10.1097/MPA.0000000000001768DOI Listing
March 2021

Traumatic retropharyngeal-posterior mediastinal hematoma following a motor vehicle accident.

Acute Med Surg 2021 Jan-Dec;8(1):e632. Epub 2021 Feb 6.

Department of Anesthesiology and Critical Care Saitama Medical Center Jichi Saitama Japan.

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http://dx.doi.org/10.1002/ams2.632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865091PMC
February 2021

Sternal osteomyelitis and infective endocarditis after old trivial chest trauma in untreated diabetes mellitus: A case report.

J Gen Fam Med 2020 Sep 7;21(5):188-190. Epub 2020 Jun 7.

Division of General Medicine Department of Comprehensive Medicine 1 Saitama Medical Center Jichi Medical University Saitama Japan.

An 82-year-old man with untreated diabetes mellitus (DM) had anterior chest wall swelling and ulcers 2 years following blunt chest trauma. Contrast-enhanced computed tomography revealed sternal fracture with osteolytic change and subcutaneous abscess. Blood and sternal cultures were positive for methicillin-susceptible (MSSA). Transesophageal echocardiogram showed vegetation on the right coronary cusp and moderate aortic regurgitation. The patient received a diagnosis of infective endocarditis associated with chronic sternal osteomyelitis complicated by subcutaneous abscess because of MSSA. This case report showed that trivial trauma in patients with uncontrolled DM can cause chronic sternal osteomyelitis resulting in infective endocarditis.
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http://dx.doi.org/10.1002/jgf2.347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521787PMC
September 2020

Real-world efficacy of sofosbuvir plus velpatasvir therapy for patients with hepatitis C virus-related decompensated cirrhosis.

Hepatol Res 2020 Nov 11;50(11):1234-1243. Epub 2020 Sep 11.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.

Aim: Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy.

Methods: Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing.

Result: Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12.

Conclusion: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis.
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http://dx.doi.org/10.1111/hepr.13555DOI Listing
November 2020

Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib.

Oncology 2020 3;98(11):787-797. Epub 2020 Sep 3.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,

Background: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy.

Methods: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled.

Results: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465-18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099-0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07-0.592, p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12-0.746, p = 0.01) were significant prognostic factors.

Conclusion: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.
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http://dx.doi.org/10.1159/000509387DOI Listing
November 2020

Comparison of in-hospital death following ST-elevation myocardial infarction between secondary emergency and tertiary emergency.

Cardiovasc Interv Ther 2021 Oct 30;36(4):444-451. Epub 2020 Aug 30.

Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.

In most areas in Japan, patients with ST-elevation myocardial infarction (STEMI) would be transferred to the secondary hospitals or tertiary hospitals according to the judgement of emergency medical service (EMS) staff members. We hypothesized that in-hospital outcomes would be worse in STEMI patients judged as tertiary emergency than in those judged as secondary emergency, which may support the judgement of the current EMS systems. The purpose of this study was to compare in-hospital outcomes of STEMI between patients judged as secondary emergency and those judged as tertiary emergency. We included 238 STEMI patients who were transferred to our institution using EMS hotline, and divided those into the secondary emergency group (n = 106) and the tertiary emergency group (n = 132). The primary endpoint was in-hospital death. The prevalence of shock was significantly higher in the tertiary emergency group than in the secondary emergency group (32.6% vs. 10.4%, p < 0.001). The GRACE score was significantly higher in the tertiary emergency group than the secondary emergency group [146 (118-188) vs. 134 (101-155), p < 0.001]. The incidence of in-hospital death was significantly higher in the tertiary emergency group than in the secondary emergency group (8.0% vs. 2.1%, p = 0.014). The multivariate logistic regression analysis revealed that the tertiary emergency was significantly associated with in-hospital death (OR 3.52, 95% CI 1.24-10.02, p = 0.018) after controlling age and gender. In conclusion, the tertiary emergency was significantly associated with in-hospital death. Our results might validate the judgement of levels of emergency by local EMS staff members.
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http://dx.doi.org/10.1007/s12928-020-00698-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456443PMC
October 2021

Clinical characteristics, prognostic factors, and outcomes of heat-related illness (Heatstroke Study 2017-2018).

Acute Med Surg 2020 Jan-Dec;7(1):e516. Epub 2020 Jun 16.

Department of Emergency Medicine Teikyo University School of Medicine Tokyo Japan.

Aim: Heat-related illness is common, but its epidemiology and pathological mechanism remain unclear. The aim of this study was to report current clinical characteristics, prognostic factors, and outcomes of heat-related illness in Japan.

Methods: We undertook a prospective multicenter observational study in Japan. Only hospitalized patients with heat-related illness were enrolled from 1 July to 30 September 2017 and 1 July to 30 September 2018.

Results: A total of 763 patients were enrolled in the study. Median age was 68 years (interquartile range, 49-82 years) and median body temperature on admission was 38.2°C (interquartile range, 36.8-39.8°C). Non-exertional cause was 56.9% and exertional cause was 40.0%. The hospital mortality was 4.6%. The median Japanese Association for Acute Medicine disseminated intravascular coagulation (JAAM DIC), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores on admission were 1 (0-2), 4 (2-6), and 13 (8-22), respectively. To predict hospital mortality, areas under the receiver operating characteristic curves were 0.776 (JAAM DIC score), 0.825 (SOFA), and 0.878 (APACHE II). There were 632 cases defined as heatstroke by JAAM heat-related illness criteria, 73 cases diagnosed as having DIC. A total of 16.6% patients had poor neurological outcome (modified Rankin Scale ≥ 4) at hospital discharge. In the multivariate analysis, Glasgow Coma Scale and platelets were independent predictors of mortality. Type of heatstroke, Glasgow Coma Scale, and platelets were independent predictors of poor neurological outcome. Body temperature was not associated with mortality or poor neurological outcome.

Conclusions: In this study, hospital mortality of heat-related illness was <5%, one-sixth of the patients had poor neurological outcome. The APACHE II, SOFA, and JAAM DIC scores predicted hospital mortality. Body temperature was not associated with mortality or poor neurological outcome.
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http://dx.doi.org/10.1002/ams2.516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298290PMC
June 2020

Relationship Between Institutional Volume of Out-of-Hospital Cardiac Arrest Cases and 1-Month Neurologic Outcomes: A Post Hoc Analysis of a Prospective Observational Study.

J Emerg Med 2020 Aug 25;59(2):227-237. Epub 2020 May 25.

Department of Emergency Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Background: The influence of institutional volume of out-of-hospital cardiac arrest (OHCA) cases on outcomes remains unclear.

Objectives: This study evaluated the relationship between institutional volume of adult, nontraumatic OHCA cases and 1-month favorable neurologic outcomes.

Methods: This study retrospectively analyzed data between January 2012 and March 2013 from a prospective observational study in the Kanto area of Japan. We analyzed adult patients with nontraumatic OHCA who underwent cardiopulmonary resuscitation by emergency medical service personnel and in whom spontaneous circulation was restored. Based on the institutional volume of OHCA cases, we divided institutions into low-, middle-, or high-volume groups. The primary and secondary outcomes were 1-month favorable neurologic outcomes and 1-month survival, respectively. A multivariate logistic regression analysis adjusted for propensity score and in-hospital variables was performed.

Results: Of 2699 eligible patients, 889, 898, and 912 patients were transported to low-volume (40 institutions), middle-volume (14 institutions), and high-volume (9 institutions) centers, respectively. Using low-volume centers as the reference, transport to a middle- or high-volume center was not significantly associated with a favorable 1-month neurologic outcome (adjusted odds ratio [OR] 1.21 [95% confidence interval {CI} 0.84-1.75] and adjusted OR 0.77 [95% CI 0.53-1.12], respectively) or 1-month survival (adjusted OR 1.10 [95% CI 0.82-1.47] and adjusted OR 0.76 [95% CI 0.56-1.02], respectively).

Conclusions: Institutional volume was not significantly associated with favorable 1-month neurologic outcomes or 1-month survival in OHCA. Further investigation is needed to determine the association between hospital characteristics and outcomes in patients with OHCA.
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http://dx.doi.org/10.1016/j.jemermed.2020.04.039DOI Listing
August 2020

Placement accuracy of resuscitative endovascular occlusion balloon into the target zone with external measurement.

Trauma Surg Acute Care Open 2020 29;5(1):e000443. Epub 2020 Apr 29.

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) should be safely placed at zone 1 or 3, depending on the location of the hemorrhage. Ideally, REBOA placement should be confirmed via fluoroscopy, but it is not commonly available for trauma bays. This study aimed to evaluate the accuracy of REBOA placement using the external measurement method in a Japanese trauma center.

Methods: A retrospective review identified all trauma patients who underwent REBOA and were admitted to our trauma center from 2008 to 2018. Patient characteristics, REBOA placement accuracy, and complications according to target zones 1 and 3 were reviewed.

Results: During the study period, 38 patients met our inclusion criteria. The in-hospital mortality rate was 57.9%. REBOA was mainly used for bleeding from the abdominal (44.7%) and pelvic (36.8%) regions. Of these, 30 patients (78.9%) underwent REBOA for target zone 1, and 8 patients (21.1%) underwent REBOA for target zone 3. The proportion of abdominal bleeding source in the target zone 1 group was greater than that in the target zone 3 group (56.7% vs. 0%). Overall, the proportion of REBOA placement was 76.3% in zone 1, 21.1% in zone 2, and 2.6% in zone 3. The total REBOA placement accuracy was 71.1%. At each target zone, the REBOA placement accuracy for target zone 3 was significantly lower than that for target zone 1 (12.5% vs. 86.7%, p<0.001). No significant associations between non-target zone placement and patient characteristics, complications, or mortality were found.

Conclusions: The REBOA placement accuracy for target zone 3 was low, and zone 2 placement accounted for 21.1% of the total, but no complications and mortalities related to non-target zone placement occurred. Further external validation study is warranted.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1136/tsaco-2020-000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228664PMC
April 2020

Placement accuracy of resuscitative endovascular occlusion balloon into the target zone with external measurement.

Trauma Surg Acute Care Open 2020 29;5(1):e000443. Epub 2020 Apr 29.

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) should be safely placed at zone 1 or 3, depending on the location of the hemorrhage. Ideally, REBOA placement should be confirmed via fluoroscopy, but it is not commonly available for trauma bays. This study aimed to evaluate the accuracy of REBOA placement using the external measurement method in a Japanese trauma center.

Methods: A retrospective review identified all trauma patients who underwent REBOA and were admitted to our trauma center from 2008 to 2018. Patient characteristics, REBOA placement accuracy, and complications according to target zones 1 and 3 were reviewed.

Results: During the study period, 38 patients met our inclusion criteria. The in-hospital mortality rate was 57.9%. REBOA was mainly used for bleeding from the abdominal (44.7%) and pelvic (36.8%) regions. Of these, 30 patients (78.9%) underwent REBOA for target zone 1, and 8 patients (21.1%) underwent REBOA for target zone 3. The proportion of abdominal bleeding source in the target zone 1 group was greater than that in the target zone 3 group (56.7% vs. 0%). Overall, the proportion of REBOA placement was 76.3% in zone 1, 21.1% in zone 2, and 2.6% in zone 3. The total REBOA placement accuracy was 71.1%. At each target zone, the REBOA placement accuracy for target zone 3 was significantly lower than that for target zone 1 (12.5% vs. 86.7%, p<0.001). No significant associations between non-target zone placement and patient characteristics, complications, or mortality were found.

Conclusions: The REBOA placement accuracy for target zone 3 was low, and zone 2 placement accounted for 21.1% of the total, but no complications and mortalities related to non-target zone placement occurred. Further external validation study is warranted.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1136/tsaco-2020-000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228664PMC
April 2020

Effectiveness and Usage Trends of Hemorrhage Control Interventions in Patients with Pelvic Fracture in Shock.

World J Surg 2020 07;44(7):2229-2236

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, 330-8503, Japan.

Background: Hemorrhage control for pelvic fractures remains challenging. There are several kinds of hemostatic interventions, including angiography/angioembolization (AG/AE), external fixation (EF), and resuscitative endovascular balloon occlusion of the aorta (REBOA). However, no large studies have been conducted for the comparative review of each intervention. In this study, we examined the usage trend of therapeutic interventions in Japan for patients with pelvic fractures in shock and the influence of these interventions on mortality.

Methods: Data of adult patients with pelvic fracture who were in shock were obtained from the Japanese Trauma Data Bank (2004-2014). The primary endpoint was the influence of each intervention (AG/AE, EF, and REBOA) on in-hospital mortality. We also investigated the frequency of each intervention.

Results: A total of 3149 patients met all our inclusion criteria. Specifically, 1131 (35.9%), 496 (15.8%), and 256 (8.1%) patients underwent AG, EF, and REBOA interventions, respectively. Therapeutic AE was performed in 690 patients who underwent AG (61.0%). The overall mortality rate was 31.4%. Multiple regression analysis identified that AG/AE (OR 0.64, 95% CI 0.52-0.80) and EF (OR 0.75, 95% CI 0.58-0.98) were significantly associated with survival, whereas REBOA (OR 4.17, 95% CI 3.00-5.82) was significantly associated with worse outcomes.

Conclusions: In Japan, patients with pelvic fracture who were in shock had high mortality rates. AG/AE and EF were associated with decreased mortality. AG may benefit from the early detection of arterial bleeding, leading to decreased mortality of patients with pelvic fracture in shock.
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http://dx.doi.org/10.1007/s00268-020-05441-1DOI Listing
July 2020

Complications after Radiofrequency Ablation for Hepatocellular Carcinoma: A Multicenter Study Involving 9,411 Japanese Patients.

Liver Cancer 2020 Jan 22;9(1):50-62. Epub 2019 Oct 22.

bDepartment of Oncology and Laboratory, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Introduction: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period).

Methods: Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared.

Results: We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods ( = 0.38), but the complication rates was significantly lower during the recent period ( = 0.038).

Discussion And Conclusions: Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.
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http://dx.doi.org/10.1159/000502744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024979PMC
January 2020

An integrated screening system for the selection of exemplary substrates for natural and engineered cytochrome P450s.

Sci Rep 2019 12 2;9(1):18023. Epub 2019 Dec 2.

Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

Information about substrate and product selectivity is critical for understanding the function of cytochrome P450 monooxygenases. In addition, comprehensive understanding of changes in substrate selectivity of P450 upon amino acid mutation would enable the design and creation of engineered P450s with desired selectivities. Therefore, systematic methods for obtaining such information are required. Herein, we developed an integrated P450 substrate screening system for the selection of "exemplary" substrates for a P450 of interest. The established screening system accurately selected the known exemplary substrates and also identified previously unknown exemplary substrates for microbial-derived P450s from a library containing sp-rich synthetic small molecules. Synthetically potent transformations were also found by analyzing the reactions and oxidation products. The screening system was applied to analyze the substrate selectivity of the P450 BM3 mutants F87A and F87A/A330W, which acquired an ability to hydroxylate non-natural substrate steroids regio- and stereoselectively by two amino acid mutations. The distinct transition of exemplary substrates due to each single amino acid mutation was revealed, demonstrating the utility of the established system.
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http://dx.doi.org/10.1038/s41598-019-54473-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888865PMC
December 2019

T-wave alternans: a harbinger of polymorphic ventricular tachycardia.

Oxf Med Case Reports 2019 Sep 28;2019(9):omz095. Epub 2019 Sep 28.

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, 330-8503, Japan.

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http://dx.doi.org/10.1093/omcr/omz095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765371PMC
September 2019

Comparison between the Bouchama and Japanese Association for Acute Medicine Heatstroke Criteria with Regard to the Diagnosis and Prediction of Mortality of Heatstroke Patients: A Multicenter Observational Study.

Int J Environ Res Public Health 2019 09 16;16(18). Epub 2019 Sep 16.

Emergency and Critical Care Center, Tokyo Metropolitan Tama Medical Centre, Tokyo 183-8524, Japan.

Background: This study aims to compare the Bouchama heatstroke (B-HS) and Japanese Association for Acute Medicine heatstroke (JAAM-HS) criteria with regard to the diagnosis and prediction of mortality and neurological status of heatstroke patients.

Methods: This multicenter observational study recruited eligible patients from the emergency departments of 110 major hospitals in Japan from 1 July to 30 September, 2014.

Results: A total of 317 patients (median age, 65 years; interquartile range, 39-80 years) were included and divided into the B-HS, JAAM-HS, and non-HS groups, with each group consisting of 97, 302, and 15 patients, respectively. The JAAM-HS (1.0; 95% confidence interval [CI], 0.87-1.0) and B-HS (0.29; 95% CI, 0.14-0.49) criteria showed high and low sensitivity to mortality, respectively. Similarly, the JAAM-HS (1.0; 95% CI, 0.93-1.0) and B-HS (0.35; 95% CI, 0.23-0.49) criteria showed high and low sensitivity to poor neurological status, respectively. Meanwhile, the sequential organ failure assessment (SOFA) scores demonstrated good accuracy in predicting mortality among heat-related illness (HRI) patients. However, both JAAM-HS and B-HS criteria could not predict in-hospital mortality. The AUC of the SOFA score for mortality was 0.83 (day 3) among the HRI patients. The patients' neurological status was difficult to predict using the JAAM-HS and B-HS criteria. Concurrently, the total bilirubin level could relatively predict the central nervous system function at discharge.

Conclusions: The JAAM-HS criteria showed high sensitivity to mortality and could include all HRI patients who died. The JAAM-HS criterion was considered a useful tool for judgement of admission at ED. Further investigations are necessary to determine the accuracy of both B-HS and JAAM-HS criteria in predicting mortality and neurological status at discharge.
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http://dx.doi.org/10.3390/ijerph16183433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765926PMC
September 2019

Enhancement of swallowing motor activity by the ACE inhibitor imidapril in an arterially perfused rat preparation.

Eur J Pharmacol 2019 Oct 14;861:172601. Epub 2019 Aug 14.

Department of Oral Physiology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Pharmacological agents that elevate dopamine and substance P concentrations have been suggested to prevent aspiration pneumonia and improve impaired swallowing processes. However, little is known about the effects of such agents on swallowing activities induced in motor nerves innervating the pharyngeal and laryngeal muscles. In this study, we examined the effects of imidapril, cilostazol, and amantadine, which are often prescribed for swallowing disorders, on swallowing motor activity. We recorded the efferent activities of the cervical vagal nerve, hypoglossal nerve, and phrenic nerve using arterially perfused rats aged between 21-35 postnatal days. The vagal nerve activity was used for evaluation of swallowing motor activity. When 1.25 ml of distilled water was injected into the oral cavity, or the superior laryngeal nerve was electrically stimulated, synchronized swallowing bursts were evoked in the vagal and hypoglossal nerves, while inspiratory discharges were inhibited in all the recorded nerves. Administration of imidapril (60 ng/ml) but not cilostazol (2.5 μg/ml) and amantadine (200 ng/ml) to the perfusate increased the mean peak amplitude of orally evoked swallowing bursts in the vagal nerve. Such increase in the peak amplitude by imidapril was antagonized by the administration of the NK receptor antagonist aprepitant (5 μg/ml) or the D receptor antagonist LE300 (2.5 μg/ml). In contrast, neither imidapril nor cilostazol caused a significant increase in swallowing bursts evoked by electrical stimulation of the superior laryngeal nerve. These results suggest that imidapril treatment may improve impaired swallowing by enhancing pharyngeal muscle activities via an increase in substance P and dopamine concentrations.
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http://dx.doi.org/10.1016/j.ejphar.2019.172601DOI Listing
October 2019

Reperfusion therapy of acute ischemic stroke in an all-in-one resuscitation room called a hybrid emergency room.

Oxf Med Case Reports 2019 Jun 8;2019(6):omz042. Epub 2019 Jun 8.

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

Acute ischemic stroke (AIS) caused by major vessel occlusion has potentially poor outcomes. Early successful recanalization after symptom onset is an important factor for favorable outcomes of AIS. We present the case of a 74-year-old man with AIS who underwent the entire process from diagnosis to thrombolysis and endovascular treatment in a hybrid emergency room (ER) equipped with a multidetector computed tomography (CT) scanner and an angiography suite set-up. A hybrid ER can facilitate evaluation and definitive interventions in patients with AIS more quickly and safely and in one place, without the requirement for transfer to a CT scanner or angiography suite set-up. In the present case, the door-to-puncture time and door-to-reperfusion time were 85 and 159 min, respectively, which were shorter than those in the group conventionally treated for stroke in our institution. Further study is needed to confirm the effect of the hybrid ER system.
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http://dx.doi.org/10.1093/omcr/omz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555907PMC
June 2019

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for Severe Torso Trauma in Japan: A Descriptive Study.

World J Surg 2019 07;43(7):1700-1707

Department of Emergency and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama City, Japan.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has the potential to be an alternative to open aortic cross-clamping (ACC). However, its practical indication remains unknown. We examined the usage trend of REBOA and ACC in Japan for severe torso trauma and investigated whether these procedures were associated with the time of death distribution based on a large database from the Japan Trauma Data Bank (JTDB).

Methods: The JTDB from 2004 to 2014 was reviewed. Eligible patients were restricted to those with severe torso trauma, which was defined as an abbreviated injury scale score of ≥4. Patients were classified into groups according to the aortic occlusion procedures. The primary outcomes were the rates of REBOA and ACC use according to the clinical situation. We also evaluated whether the time of death distribution for the first 8 h differed based on these procedures.

Results: During the study period, a total of 21,533 patients met our inclusion criteria. Overall, REBOA was more commonly used than ACC for patients with severe torso trauma (2.8% vs 1.5%). However, ACC was more frequently used in cases of thoracic injury and cardiac arrest. Regarding the time of death distribution, the cumulative curve for death in REBOA cases was elevated much more slowly and mostly flat for the first 100 min.

Conclusions: REBOA is more commonly used compared to ACC for patients with severe torso trauma in Japan. Moreover, it appears that REBOA influences the time of death distribution in the hyperacute phase.
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http://dx.doi.org/10.1007/s00268-019-04968-2DOI Listing
July 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

Tombstone ST elevation in Takotsubo cardiomyopathy.

Acute Med Surg 2019 Jan 18;6(1):87-88. Epub 2018 Nov 18.

Department of Emergency and Critical Care Medicine Saitama Medical Center Jichi Medical University Saitama Japan.

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http://dx.doi.org/10.1002/ams2.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328907PMC
January 2019

Evaluation of a Novel Classification of Heat-Related Illnesses: A Multicentre Observational Study (Heat Stroke STUDY 2012).

Int J Environ Res Public Health 2018 09 8;15(9). Epub 2018 Sep 8.

Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.

The Japanese Association for Acute Medicine Committee recently proposed a novel classification system for the severity of heat-related illnesses. The illnesses are simply classified into three stages based on symptoms and management or treatment. Stages I, II, and III broadly correspond to heat cramp and syncope, heat exhaustion, and heat stroke, respectively. Our objective was to examine whether this novel severity classification is useful in the diagnosis by healthcare professionals of patients with severe heat-related illness and organ failure. A nationwide surveillance study of heat-related illnesses was conducted between 1 June and 30 September 2012, at emergency departments in Japan. Among the 2130 patients who attended 102 emergency departments, the severity of their heat-related illness was recorded for 1799 patients, who were included in this study. In the patients with heat cramp and syncope or heat exhaustion (but not heat stroke), the blood test data (alanine aminotransferase, creatinine, blood urea nitrogen, and platelet counts) for those classified as Stage III were significantly higher than those of patients classified as Stage I or II. There were no deaths among the patients classified as Stage I. This novel classification may avoid underestimating the severity of heat-related illness.
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http://dx.doi.org/10.3390/ijerph15091962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165559PMC
September 2018

Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C.

J Med Virol 2018 12 13;90(12):1834-1840. Epub 2018 Aug 13.

Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.

Background: Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response.

Methods: Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed.

Results: The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients.

Conclusion: Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.
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http://dx.doi.org/10.1002/jmv.25267DOI Listing
December 2018

Experimental Study on Involvement of the Central Nervous System in Inferior Alveolar Nerve Damage-Associated Hyperalgesia of the Mental Region.

J Oral Maxillofac Surg 2018 10 22;76(10):2089.e1-2089.e8. Epub 2018 Jun 22.

Professor, Department of Oral Physiology, School of Dentistry, Showa University, Tokyo, Japan.

Purpose: Involvement of the central nervous system in sensory disturbances of the mental region occurring after inferior alveolar nerve damage was investigated using a rat model of inferior alveolar nerve damage.

Patients And Methods: The rat inferior alveolar nerve was damaged by ligation with thread, and the course of behavioral changes after surgery was observed for 42 days. In addition, activation of microglia and astroglia in the trigeminal spinal subnucleus caudalis (Vc) was analyzed using immunohistochemistry. c-Fos-positive cells were quantitatively evaluated to analyze the state of neuron excitement.

Results: The withdrawal threshold was significantly decreased 5 days after surgery in the inferior alveolar nerve-ligated (IANL) group compared with that in the sham group and subsequently recovered over time. In addition, microglia and astroglia were activated in the Vc region 5 days after surgery in the model group, and c-fos-positive cells were also significantly more frequent in the IANL group. However, no significant difference in the withdrawal threshold was seen between the IANL and sham groups on day 42, nor were any significant differences seen in the amounts of microglia, astroglia, or c-fos-positive cells.

Conclusions: Interactions among microglia, astroglia, and neurons in the central nervous system might be involved in the progression of inferior alveolar nerve damage-associated mental hyperalgesia to a chronic state.
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http://dx.doi.org/10.1016/j.joms.2018.06.021DOI Listing
October 2018

Hyperglycemia and chorea.

J Gen Fam Med 2018 Jul 29;19(4):141-142. Epub 2018 May 29.

Department of Emergency and Critical Care Medicine Saitama Medical Center Jichi Medical University Saitama Japan.

(A) Computed tomography of the brain showing no abnormal finding. (B) Magnetic resonance imaging of the brain showing a T1-weighted area of hyperintensity in the left putamen, caudate nucleus, and globus pallidum with sparing of the internal capsule (arrow). (C) T2*-weighted image showing hypointensity in the left putamen, caudate nucleus, and globus pallidum (arrowhead). (D) T2-weighted image showing no abnormal finding.
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http://dx.doi.org/10.1002/jgf2.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030040PMC
July 2018

Characteristics distinguishing abusive head trauma from accidental head trauma in infants with traumatic intracranial hemorrhage in Japan.

Acute Med Surg 2018 Jul 29;5(3):265-271. Epub 2018 Apr 29.

Division of Emergency and Critical Care Medicine Department of Acute Medicine Nihon University School of Medicine Tokyo Japan.

Aim: To identify markers for detecting abusive head trauma (AHT) and its characteristics in the Japanese population.

Methods: We retrospectively reviewed the clinical records of 166 infants with traumatic intracranial hemorrhage between 2002 and 2013 in three tertiary institutions in Japan. The infants were classified into AHT (57), suspected AHT (24), and accidental (85) group based on the defined criteria. We compared clinical presentations and computed tomography findings among these three groups and also compared age distribution of infants with AHT in our study to those in the USA.

Results: Age distribution of AHT cases is significantly higher in our study than in the USA ( < 0.001). The rates of male sex, bruising, retinal hemorrhage, subdural hematoma, cerebral edema, and neurological sequelae were significantly higher, and those of skull fracture and scalp finding were significantly lower, in the AHT group than in the accidental group ( < 0.05). In the multivariable analysis of the infants with subdural hematoma, absence of skull fracture (odds ratio = 42.1; 95% confidence interval, 3.5-507.7, = 0.003) was associated with AHT.

Conclusions: The age range of AHT in Japan is significantly different from that of countries in Europe and North America because of familial and sociocultural situations. Absence of bruising, and rib or long bone fractures did not reduce the likelihood of AHT. Subdural hematoma without findings of an impact to the head strongly suggested AHT. Abusive head trauma is a global problem, however, diagnosis and defensive measures likely need to be tailored to accommodate cultural risk factors.
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http://dx.doi.org/10.1002/ams2.341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028795PMC
July 2018
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