The association between blood glucose levels on arrival at the hospital and patient outcomes after out-of-hospital cardiac arrest: A multicenter cohort study.

BACKGROUND: This study aimed to investigate the association between blood glucose levels on arrival at the hospital and 1-month survival and favorable neurological outcomes in patients with OHCA using a large Japanese dataset. METHODS: This study was a secondary analysis of data from the JAAM-OHCA Registry. Adult (≥18 years) patients with witnessed OHCA transported to emergency departments and registered in the database from June 2014 to December 2019 were included in the study. The primary and secondary endpoints were 1-month survival and 1-month favorable neurological outcomes (Glasgow-Pittsburgh Cerebral Performance Category score 1 or 2), respectively. Patients were categorized into the following four groups based on blood glucose levels on arrival at the hospital: <80 mg/dL, 80-179 mg/dL, 180-299 mg/dL, and ≥300 mg/dL. RESULTS: This study included 11,387 patients. Survival rates were 1.3%, 3.1%, 7.0%, and 5.7% in the <80 mg/dL, 80-179 mg/dL, 180-299 mg/dL, and ≥ 300 mg/dL blood glucose groups, respectively. The rates of favorable neurological outcomes in each group were 0.4%, 1.5%, 3.3%, and 2.5%, respectively. Multivariable analysis showed that 180-299 mg/dL glucose was significantly associated with 1-month survival and favorable neurological outcomes compared with 80-179 mg/dL glucose (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.34-2.31; p < 0.001 and OR, 1.52; 95 % Cl, 1.02-2.25; p = 0.035, respectively). In this study, blood glucose levels with the best outcomes likely ranged from 200 to 250 mg/dL based on the cubic spline regression model. CONCLUSIONS: Blood glucose level of 180-299 mg/dL on arrival at the hospital was significantly associated with 1-month survival and favorable neurological outcomes compared to blood glucose level of 80-179 mg/dL in patients with OHCA.

Evaluation of physical and psychological status of health care workers infected with COVID-19 during a hospital outbreak in Japan.

PURPOSE: COVID-19 causes physical and psychological impacts on health care workers (HCWs), especially when it occurs during an outbreak. As there are few reports on outcomes of HCWs infected with COVID-19 during a hospital outbreak, we investigated the physical and psychological impacts on HCWs infected with COVID-19 during an outbreak in our hospital. METHODS: During the outbreak in our hospital, 231 people were infected with COVID-19 including patients, HCWs and their families. Among them, 83 HCWs were enrolled in this study. Current quality of life (QOL) was assessed with the EuroQol-visual analogue scales (EQ-VAS), and motivation to keep on working was evaluated by a 10-point analogue scale. Physiological recovery rates including return to work (RTW) period were also analyzed. RESULTS: One nurse quit work due to anxiety regarding re-infection with COVID-19. The median period to RTW from the diagnosis was 14.0 (12.0-17.0) days. Motivation to keep on working was slightly reduced, and the EQ-VAS was 75.0 (65.0-83.6). There were no significant differences in QOL and motivation between male and female HCWs, nurses and other HCWs, treatment and non-treatment group, and supplemental and non-supplemental oxygen group. The most frequent persistent symptoms at 1,3 and 6 months after infection were anosmia followed by fatigue. CONCLUSION: Although QOL and motivation to keep on working were slightly reduced, only one HCW quit work. No severe persistent symptoms were observed, and the RTW period was relatively short.

PCO2 on arrival as a predictive biomarker in patients with out-of-hospital cardiac arrest.

BACKGROUND: Treating patients with out-of-hospital cardiac arrest (OHCA) requires early prediction of outcome, ideally on hospital arrival, as it can inform the clinical decisions involved. This study evaluated whether partial pressure of carbon dioxide (PCO2) on arrival is associated with outcome at one month OHCA patients. METHODS: This was a single-center retrospective study of adult OHCA patients treated between January 2016 and December 2020. Outcomes were defined along the Cerebral Performance Category (CPC) scale. Primary outcome was mortality (CPC 5) at one month. Secondary outcomes were death or unfavorable neurological outcome (CPC 3-5) and unfavorable neurological outcome (CPC 3-4) at one month. Multivariable analysis was adjusted for age, sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation, initial shockable rhythm, and time from call to emergency medical services to hospital arrival. RESULTS: Out of 977 OHCA patients in the study period, 19 were excluded because they were aged under 18 years, 79 because they underwent extracorporeal cardiopulmonary resuscitation, and 101 due to lack of PCO2 data. This study included 778 patients total; mortality (CPC 5) at one month was observed in 706 (90.7%), death or unfavorable neurological outcome (CPC 3-5) in 743 (95.5%), and unfavorable neurological outcome (CPC 3-4) in 37 (4.8%). In multivariable analysis, high PCO2 levels showed significant association with mortality (CPC 5) at one month (odds ratio [OR] [per 5 mmHg], 1.14; 95% confidence interval [CI], 1.08-1.21), death or unfavorable neurological outcome (CPC 3-5) (OR [per 5 mmHg], 1.29; 95% CI, 1.17-1.42), and unfavorable neurological outcome (CPC 3-4) (OR [per 5 mmHg], 1.21; 95% CI, 1.04-1.41). CONCLUSIONS: High PCO2 on arrival was significantly associated with mortality and unfavorable neurological outcome in OHCA patients.

Long-term outcomes and prognostic factors of extracorporeal cardiopulmonary resuscitation in patients older than 75 years: a single-centre retrospective study.

BACKGROUND: Few studies have assessed older adult patients who received extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest, and outcomes and prognostic factors of ECPR in this population remain unclear. This study aimed to assess the long-term outcomes and prognostic factors among patients older than 75 years who received ECPR after experiencing cardiac arrest. METHODS: This is a single-centre, retrospective case-control study conducted between August 2010 and July 2019. Consecutive patients older than 75 years who had in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) and received ECPR at the Emergency Department in the Hyogo Emergency Medical Center, Hyogo, Japan, were included. The primary outcome was a favourable neurological outcome, defined as a Cerebral Performance Category score of 1-2 at 1 year after the event. Univariate logistic regression was used to determine the association between variables and patient outcomes. RESULTS: Of the 187 patients with cardiac arrest who received ECPR, 30 were older than 75 years and 28 (15% of the cohort receiving ECPR) were examined in this study. The median age of the patients was 79 years (IQR 77-82), and there were 13 (46%) male patients. Neurological outcomes were favourable for seven (25%) patients, five of whom had IHCA and two with out-of-hospital OHCA. On univariate analysis, patients with a favourable outcome had a shorter median total collapse time (TCT) than those with an unfavourable outcome (favourable: 18.0 min (IQR 13.0-33.5) vs unfavourable: 44.0 min (IQR 25.0-53.0); p=0.049). CONCLUSION: In selected patients older than 75 years, ECPR could be beneficial by providing a shorter TCT, which may contribute to favourable neurological outcomes. Nevertheless, further studies are needed to validate these findings.

Singleton pregnancy using in vitro fertilization or intracytoplasmic sperm injection does not increase risk of bleeding in cesarean delivery: a retrospective cohort study.

PURPOSE: Several studies indicate that assisted reproductive technology (ART) including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies carries increased risk of complications including postpartum hemorrhage (PPH). However, the association between IVF/ICSI and the bleeding risk particularly in cesarean delivery has not been systematically assessed. The aim of this study was to evaluate bleeding risk during and after cesarean delivery in parturients who conceived using IVF or ICSI. METHODS: This is a retrospective observational study analyzing data from 310 parturients who underwent cesarean delivery: 155 who had conceived using IVF or ICSI (IVF/ICSI group) and 155 age and year of delivery matched controls who had conceived spontaneously (control group). The primary outcome measure was the amount of blood lost during and within 24 h after cesarean delivery. Secondary outcome measure was the incidence of severe PPH. With 132 parturients in each group, we had 90% power to detect a 200 mL difference in the bleeding amount, at a 0.05 two-sided significance level. RESULTS: The amount of bleeding in the IVF/ICSI group was 1234 ± 669 mL, which was 124 mL (11.2%) greater than that in the control group (95% CI - 34 to 282; p = 0.12). The incidence of severe PPH in the IVF/ICSI group and in the control group was 23.9% and 16.8%, respectively (p = 0.16), and the unadjusted odds ratio was 1.6 (95% CI, 0.9-2.7; p = 0.12). No significant independent effect of IVF/ICSI on the bleeding amount and the incidence of severe PPH was observed in multivariable regression analyses (p = 0.22, p = 0.16). CONCLUSION: In this study, IVF and ICSI were not associated with increasing risk of bleeding in cesarean delivery.

Power spectral analysis of heart rate variability is useful as a screening tool for detecting sympathetic and parasympathetic nervous dysfunctions in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that causes motor symptoms and autonomic dysfunction. However, autonomic function tests commonly performed in PD can only evaluate either the sympathetic or parasympathetic nervous system. Therefore, the purpose of this pilot study is to investigate whether power spectral analysis of heart rate variability could detect both sympathetic and parasympathetic nervous dysfunctions in patients with PD. METHODS: Seventeen patients with PD and 11 healthy control subjects underwent electrocardiogram recording for the spectral analysis of heart rate variability to obtain values of low-frequency (LF) (0.04-0.15 Hz) and high-frequency (HF) (0.15-0.4 Hz) powers. Moreover, we examined the coefficient of variation of R-R intervals (CVRR) as a parameter of parasympathetic function in all participants and performed 123I-metaiodobenzylguanidine scintigraphy to measure the heart-to-mediastinum ratio as a parameter of cardiac sympathetic innervation in patients with PD. RESULTS: The median age of control subjects and PD patients was 63 and 66 years old, respectively. The median Hoehn and Yahr scale of PD patients was stage 2. The values of resting LF and HF powers widely varied. The median values of resting LF powers of control subjects and PD patients and those of HF powers were 169 and 70 ms2, 279 and 65 ms2, respectively, the difference was statistically insignificant. Approximately 41% of patients with PD had values below the first quartile of resting LF powers (< 58 ms2) or HF powers (< 50 ms2); however, no control subject had such low values. Positive correlations were found between resting LF powers and heart-to-mediastinum ratios of 123I-metaiodobenzylguanidine uptake (r = 0.6) and between resting HF powers and CVRRs (r = 0.7). The resting LF power was also associated with CVRRs and constipation. Furthermore, a positive correlation was observed between resting LF powers and resting HF powers in patients with PD (r = 0.8). CONCLUSIONS: The power spectral analysis of heart rate variability may be useful as a screening tool for detecting autonomic dysfunctions by detecting low resting LF and HF powers in patients with PD. Sympathetic and parasympathetic nerves may be concurrently damaged in patients with PD.

Prehospital emergency life-saving technicians promote the survival of trauma patients: A retrospective cohort study.

OBJECTIVE: Appropriate decisions by medical technicians at a trauma scene may influence a patient's prognosis. Emergency life-saving technicians (ELSTs) are certified specialists trained with the knowledge to provide advanced techniques for prehospital emergency care in Japan. However, the benefit of treatment by ELSTs compared to basic emergency medical technicians (BEMTs) remains unclear. The aim of this study is to determine whether treatment by ELSTs improves outcomes for trauma patients. METHODS: We retrospectively reviewed the Japan Trauma Data Bank for the years 2004 to 2017. Patients transferred to the hospital directly from the trauma scene and at least 16 years old were included in this study. The following criteria were used to exclude patients; presence of burns, untreatable severe traumas, unknown ELST attendance, and missing prognosis. We compared two groups (ELST group: patients transported by emergency medical services (EMS) with the presence of at least one ELST; BEMT group: patients transported only by BEMTs). Primary outcome was survival to discharge. Secondary outcomes were the need of definitive treatments defined by surgical intervention, intravascular radiology and blood transfusion at the receiving hospital within 24 h. A multivariable logistic regression model was used to calculate odds ratio (OR) and confidence intervals (CI) adjusted by age, sex, revised trauma score, and Injury severity score (ISS). RESULTS: Overall survival to discharge did not improve significantly (adjusted OR 1.13, 95% CI 0.99-1.30) with ELST intervention. In-hospital blood transfusion was more frequently required in the ELST group (adjusted OR 1.10, 95% CI 1.01-1.20). Emergency interventions (adjusted OR 1.03, 95% CI 0.97-1.09) were not different between the groups. In stratified analysis, the benefit of ELST attendance for survival was observed among patients with ISS <16 (adjusted OR 1.53, 95% CI 1.10-2.15), aged 65 years or older (adjusted OR 1.27, 95% CI 1.07-1.52), during the earlier study period (2004-2008, adjusted OR 1.50, 95% CI 1.14-1.97), and shorter transportation time (adjusted OR 1.21, 95% CI 1.03-1.41). CONCLUSIONS: Dispatch systems with ELST should be considered for trauma transports, which may benefit elderly or moderate severity trauma groups, with shorter transportation time conditions.

[A Case of Metastasis of Gastric Cancer to the Bladder].

A 62-year-old woman was diagnosed with peritoneal dissemination of gastric cancer and was treated with anticancer drugs. Eleven months after the start of the treatment, follow-up computed tomography newly showed thickening of the bladder wall and left hydronephrosis even though the chemotherapy reduced peritoneal dissemination. Therefore, she was referred to our hospital for further evaluation. Cystoscopy and magnetic resonance imaging showed the tumor arising from the bladder neck to trigone. A few days later, she was admitted to our hospital because of bladder tamponade. Transurethral coagulation was carried out, and we resected part of the bladder tumor for pathological examination at the same time. As the pathological features of the bladder tumor were similar to those of the primary stomach cancer and peritoneal dissemination, the diagnosis of the bladder tumor was metastatic gastric adenocarcinoma. She died three months after visiting our hospital.

Clinical features of inherited neuropathy with BSCL2 mutations in Japan.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

The third national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from complicated urinary tract infection patients.

The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2-64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 µg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum ß-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.

The psoas muscle index as a predictor of mortality and morbidity of geriatric trauma patients: experience of a major trauma center in Kobe.

PURPOSE: An association between the prognoses of trauma and sarcopenia has not been well documented. The purpose of this study was to compare the outcomes of elderly Japanese trauma patients with sarcopenia and those without sarcopenia. METHODS: The medical records of patients aged ≧ 65 years old and Injury Severity Scores above 15 treated for trauma between 2010 and 2017 were reviewed, retrospectively. We measured the psoas muscle index (PMI), defined as the psoas muscle area at the third lumbar vertebra level divided by the body surface area. Patients of each gender with a PMI less than the lower interquartile range were included in the sarcopenia group. A questionnaire was mailed to the patients or their families to collect data on 1-year mortality and activities of daily living. RESULTS: There were 405 patients included in this study: 304 in the non-sarcopenia group (Group NS) and 101 in the sarcopenia group (Group S). Mortality was significantly higher in Group S than in Group NS (NS; 7.9% vs. S; 15.8%, OR, 2.20; 95% CI, 1.12-4.32; p = 0.027). Only 175 of the questionnaires were completed and the responses did not reveal any significant differences between the groups. CONCLUSIONS: Sarcopenia as defined by the PMI may be used as an indicator for mortality risk for geriatric trauma patients.

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

Geriatric Trauma in Patients ≧85 Years Old in an Urban District of Japan.

Japan's population has been skewing toward the elderly, but the outcomes of advanced elderly trauma are not clear. Here we compared the outcomes of very elderly trauma patients (≧85 years old) with those of 65- to 84-year-old trauma patients. We retrospectively reviewed the medical records of patients treated at Hyogo Emergency Medical Center from August 2010 to August 2016; 631 patients were entered in the study. We divided them into the younger geriatrics (YG group, 65-84 years old: n=534) and older geriatrics (OG group, ≧85 years old: n=97). The group's patient characteristics, mortality, 1-year survival rate, and Barthel index were tabulated and compared. The patients' mean age was 75.6±7.5 years. There was no significant difference in mortality between the YG and OG groups (9.6% vs. 15.1%, odds ratio [OR] 1.73; 95% confidence interval [CI] 0.93-3.23, p=0.083). The 1-year survival rate (94.4% vs. 77.8%, OR 0.19, 95% CI 0.07-0.51; p<0.01) and Barthel index (Median score; 100 (IQR: 85-100) vs. 80 (IQR: 15-95), OR 0.98, 95% CI 0.97 to 0.99, p<0.01) differed significantly between the groups. Our study did not find a significant difference in-hospital mortality between patients in the YG group and those in the OG group.

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

Feasibility and safety of general anesthesia for bronchial thermoplasty: a description of early 10 treatments.

Bronchial thermoplasty (BT) is a recently introduced bronchoscopic treatment for patients with asthma refractory to pharmacotherapy. Intraprocedural sedation management is important for successful performance of BT. However, the results of general anesthesia in patients undergoing BT have not been well described. The aim of this study was to evaluate the feasibility and safety of general anesthesia in patients undergoing BT. We retrospectively reviewed the records of 10 consecutive BT treatments performed under general anesthesia in 4 patients. The feasibility outcomes were coughing and body movement during the procedure, procedure abandonment, and the relative frequency of thermal activation failure. The safety outcomes were bronchospasm and hypoxemia during the procedure, respiratory symptoms, and the need for oxygen after the procedure. Coughing occurred in two treatments. Neither body movement nor procedure abandonment occurred in any treatments. Neither intraprocedural bronchospasm nor hypoxemia occurred in any treatments. Respiratory symptoms occurred in 7 of 10 treatments within 1 day after the procedure and resolved within 4 days, which is comparable with a previous report. These results indicate that general anesthesia is feasible and safe for patients undergoing BT.

Treatment outcomes and late toxicities of intensity-modulated radiation therapy for 1091 Japanese patients with localized prostate cancer.

AIM: This study aimed to evaluate the treatment result of intensity-modulated radiation therapy (IMRT) in a large number of Japanese patients with prostate cancer. BACKGROUND: A total of 1091 patients with localized prostate cancer were recruited between March 2006 and July 2014. The patients were stratified into low- (n = 205 [18.8%]), intermediate- (n = 450 [41.2%]), high- (n = 345 [31.6%]), and very high-risk (n = 91 [8.3%]) groups according to the National Comprehensive Cancer Network classification. All patients were irradiated via IMRT at a dose of 74-78 Gy with or without androgen-deprivation therapy. The mean follow-up period was 50 months (range, 2-120 months). RESULTS: The biochemical failure-free rate (BFFR), the clinical failure-free rate, and the overall survival rate at the 5-year follow-up for all patients was 91.3%, 96.2%, and 99.1%, respectively. In univariate analysis, the prostate-specific antigen (PSA) levels (≤20 vs. >20 ng/ml) were significantly correlated with BFFR. A trend toward higher BFFR was noted in patients with a Gleason score (GS) of ≤7 than in patients with GS ≥8. In multivariate analysis, only PSA (≤20 vs. >20 ng/ml) was significantly correlated with BFFR. The cumulative incidence rate of gastrointestinal and genitourinary toxicity (≥grade 2) at the 5-year follow-up was 11.4% and 4.3%, respectively. CONCLUSIONS: The findings of this study indicate that IMRT is well tolerated and is associated with both good long-term tumor control and excellent outcomes in patients with localized prostate cancer.

Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.

OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aß)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aß in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.