Major Causes of Death among Older Adults after the Great East Japan Earthquake : A Retrospective Study

This retrospective study investigated the 3-year impact of the Great East Japan Earthquake (GEJE) of 2011 on deaths due to neoplasm, heart disease, stroke, pneumonia, and senility among older adults in the primarily affected prefectures compared with other prefectures, previous investigations having been more limited as regards mortality causes and geographic areas. Using death certificates issued between 2006 and 2015 (n = 7,383,253), mortality rates (MRs) and risk ratios (RRs) were calculated using a linear mixed model with the log-transformed MR as the response variable. The model included interactions between the area category and each year of death from 2010 to 2013. The RRs in the interaction significantly increased to 1.13, 1.17, and 1.28 for deaths due to stroke, pneumonia, and senility, respectively, in Miyagi Prefecture in 2011, but did not significantly increase for any of the other areas affected by the GEJE. Moreover, increased RRs were not reported for any of the other years. The risk of death increased in 2011; however, this was only significant for single-year impact. In 2013, decreased RRs of pneumonia in the Miyagi and Iwate prefectures and of senility in Fukushima Prefecture were observed. Overall, we did not find evidence of strong associations between the GEJE and mortality

Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi-center, open-label, 52-week phase 3 trial

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg‐dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open‐label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand‐grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN

Efficacy of Mucosal Cutting Biopsy for the Histopathological Diagnosis of Gastric Submucosal Tumors

Background: Gastrointestinal stromal tumors occur frequently. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is performed commonly for diagnosis. However, the success rate of histological diagnosis is insufficient when the submucosal tumor (SMT) is small. Recently, another technique, mucosal cutting biopsy (MCB) has been reported. The aim of this study is to evaluate the efficacy and safety of MCB. Method: Between January 2012 and August 2018, MCB and EUS-FNA were performed 16 and 31 times for diagnosing gastric SMT. The diagnostic rate, the rate of successful immunohistochemistry, and the safety were reviewed. Difficult locations for EUS-FNA were also evaluated. Results: The mean SMT sizes measured on MCB and EUS-FNA were 21.2 and 36.2 mm. The diagnostic rates of MCB and EUS-FNA were almost the same (88 vs. 81%), but successful immunohistochemistry was significantly higher in the MCB group (93 vs. 59%, p = 0.03). In the subgroup of SMTs < 20 mm, the successful histological diagnosis rate from EUS-FNA was relatively low. There were no complications. Failures of EUS-FNA were more frequent in the middle third of the stomach. Conclusions: MCB was an effective procedure for diagnosing gastric SMT, especially in the case of small SMTs located at the middle third of the stomach

発症早期ALS患者に対する超高用量メチルコバラミンの有効性・安全性について : ランダム化比較試験

Importance: Post hoc analysis in a phase 2/3 trial indicated ultra-high dose methylcobalamin slowed decline of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 16 as well as at week 182, without increase of adverse events, in patients with amyotrophic lateral sclerosis (ALS) who were enrolled within 1 year from onset. Objective: To validate the efficacy and safety of ultra-high dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design: A multicenter, placebo-controlled, double-blind, randomized phase 3 trial with 12-week observation and 16-week randomized period, conducted from October 2017 to September 2019. Setting: Twenty-five neurology centers in Japan. Participants: Patients with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in ALSFRS-R total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. The target number was 64 in both methylcobalamin and placebo groups. Of 203 patients enrolled in the observation, 130 patients (age, 61.0 ± 11.7 years; female, 56) met the criteria and were randomly assigned through an electronic web-response system to methylcobalamin or placebo (65 for each). Of these, 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Interventions: Intramuscular injection of methylcobalamin 50 mg or placebo twice weekly for 16 weeks. Main outcomes and measures: The primary endpoint was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: The least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 versus −4.63; 95% CI, 0.44–3.50; P = 0.012). The incidence of adverse events was similar between the two groups. Conclusions and relevance: Ultra-high dose methylcobalamin was efficacious in slowing functional decline and safe in the 16-week treatment period in ALS patients in the early stage and with moderate progression rate. Trial registration: UMIN-CTR Identifier: UMIN000029588 (umin.ac.jp/ctr); ClinicalTrials.gov Identifier: NCT03548311 (clinicaltrials.gov

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

Intracutaneous Distributions of Fluconazole, Itraconazole, and Griseofulvin in Guinea Pigs and Binding to Human Stratum Corneum

We have compared the distribution of fluconazole (FLC) with that of itraconazole (ITC) and griseofulvin (GRF) in the abdominal skin tissues after a single oral dose was administered to guinea pigs. The FLC concentrations in the stratum corneum reached a peak at 2 h after administration and were similar to those of ITC and higher than those of GRF in spite of the administration of a lower dose. GRF was eliminated from the stratum corneum faster than FLC and ITC. The FLC concentrations were also remarkably higher than those of ITC and GRF in the epidermis-cutis but lower in the subcutaneous fatty tissue. The distribution characteristics of each drug result from differences in their physicochemical properties. Following the administration of multiple doses, the FLC concentrations in the stratum corneum were highest in the abdominal skin tissues; those at 24 h after each administration increased gradually and were maintained at a level more than 10 times higher than that of the plasma concentrations. The FLC concentrations in the planta pedis stratum corneum and in the nail showed good dose proportionality and obvious accumulation and were 60 and 40 times as high as that in plasma on day 14. The extent of binding of FLC to human corneous keratin in vitro was about 10%, which is lower than those of ITC (94 to 97%) and GRF (36 to 38%). FLC, unlike ITC, therefore, is presumed to exist in the stratum corneum at high concentrations in an active nonbinding form. These excellent intracutaneous pharmacokinetic properties of FLC probably account in large part for the in vivo efficacy of FLC