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There are few reports of multilocus sequence type (ST) 5/staphylococcal cassette chromosome (SCC) mec type IVc/toxic shock syndrome toxin (TSST)-1- positive methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections. We report a case of community-onset MRSA (CO-MRSA) bloodstream infection in a healthy 41-year-old Japanese man after nasal septoplasty, followed by pectoral abscess and costal osteomyelitis. The patient presented with right anterior chest pain and fever. After admission, MRSA was isolated from two sets of blood cultures, and vancomycin was administered. On the fifth day, contrast-enhanced computed tomography (CT) scan and contrast-enhanced magnetic resonance imaging (MRI) scan showed an abscess in the right anterior chest to the right subpleural region. The dosage of vancomycin (4 g/day) did not reach the effective blood concentration; therefore, there was a switch to daptomycin. On the 23rd day, contrast-enhanced MRI revealed osteomyelitis of the right first rib, and as a result, linezolid was initiated. Two weeks later, contrast-enhanced CT of the chest showed improvement in the abscess. The patient was treated for 6 weeks during hospitalization and then switched to minocycline for 10 weeks. Molecular characterization of this isolate showed that it was ST5/SCCmec type IVc/TSST-1-positive/Panton-Valentine leucocidin (PVL)-negative. PVL-negative CO-MRSA can lead to hematogenous osteomyelitis and abscess even if the patient is immunocompetent, and if isolated from blood cultures, it is important to repeat imaging studies, even if the initial imaging studies were normal. It is possible that this strain contributes to the pathogenesis of invasive CO-MRSA, but further case accumulation is needed.

Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

A 74-year-old man with diabetic nephropathy undergoing dialysis after total knee arthroplasty presented to our hospital with dyspnea and abnormal behavior such as wearing his pants on his head. The patient was in shock with ventricular tachycardia. Urine and blood cultures showed MAM with sterile pyuria. We administered amikacin and imipenem cilastatin, but repeated cultures were persistently positive. Although we initially chose not to administer azithromycin because of a higher risk of fatal arrhythmia, we had no choice but to administer azithromycin because of treatment failure. Upon close monitoring, we observed no arrhythmia, and the blood cultures became negative. The patient was discharged on day 106 without any symptoms. However, 2 months after discontinuation of antibiotics, he was readmitted and diagnosed with prosthetic joint infection due to MAM. He could not undergo total knee arthroplasty resection because of his low tolerance to surgery. We re-administered same antibiotics, and repeated draining and cleaning of his left knee for several weeks. The inflammation in the knee joint gradually improved, and the patient was discharged while treatment with azithromycin and amikacin was continued. After being discharged, the patient did not experience recurrent disease for at least 6 months. Our case suggests that MAM can cause sterile pyuria and infection in a patient with diabetic nephropathy. The macrolide agent is a key drug for MAM infection, and repeated joint lavage in addition to administering antibiotics may be an alternative treatment for prosthetic joint infection in patients with intolerance to surgery.

BACKGROUND For epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), administration of EGFR tyrosine kinase inhibitors (TKIs) is mandatory to prolong survival. To date, a comparison of second- and third-generation EGFR-TKIs has not been reported as far as we are aware. PATIENTS AND METHODS We retrospectively investigated the survival time of patients diagnosed with EGFR-mutated advanced or recurrent NSCLC who had received afatinib, a second-generation EGFR-TKI, or osimertinib, a third-generation EGFR-TKI, as the first-line treatment. RESULTS Among the 49 patients included in the study, 15 received afatinib and 34 received osimertinib. No significant differences in overall survival were observed between the two groups [afatinib vs. osimertinib=36 vs. 33 months (hazard ratio=2.917, 95% confidence interval=0.780-10.905; p=0.112)]. T790M mutation was detected in three of the patients in the afatinib group, and all three subsequently received osimertinib. The median overall survival of these three patients and of the 12 without the mutation were 63 and 36 months, respectively. CONCLUSION There was no apparent difference in the effect on survival between second- and third-generation EGFR-TKIs, whereas the sequential administration of second- followed by third-generation EGFR-TKIs appeared to confer a better long-term prognosis.

Although several prognostic factors in nivolumab therapy have been reported in recurrent or metastatic head and neck cancer (RM-HNC) patients, these factors remain controversial. Here, we conducted a multicenter retrospective cohort study to investigate the impact of clinico-hematological factors on survival in RM-HNC patients treated with nivolumab. We reviewed 126 RM-HNC patients from seven institutes. We evaluated the prognostic effects of clinico-hematological factors on survival. The median overall survival (OS) was 12.3 months, and the 1 year-OS rate was 51.2%. Patients without immune-related adverse events, lower relative eosinophil count, worse best overall response, higher performance status, and higher modified Glasgow Prognostic Score had worse survival. The score, generated by combining these factors, was associated with survival. Patients with score of 4–5 had worse survival than those with score of 2–3 and 0–1 [adjusted HR for PFS: score of 4–5, 7.77 (3.98–15.15); score of 2–3, 3.44 (1.95–6.06), compared to score of 0–1], [adjusted HR for OS: score of 4–5, 14.66 (4.28–50.22); score of 2–3, 7.63 (2.29–25.37), compared to score of 0–1]. Our novel prognostic score utilizing clinico-hematological factors might be useful to establish an individual treatment strategy in RM-HNC patients treated with nivolumab therapy.

In amyotrophic lateral sclerosis (ALS), early diagnosis is essential for both current and potential treatments. To find a supportive approach for the diagnosis, we constructed an artificial intelligence‐based prediction model of ALS using induced pluripotent stem cells (iPSCs). Images of spinal motor neurons derived from healthy control subject and ALS patient iPSCs were analyzed by a convolutional neural network, and the algorithm achieved an area under the curve of 0.97 for classifying healthy control and ALS. This prediction model by deep learning algorithm with iPSC technology could support the diagnosis and may provide proactive treatment of ALS through future prospective research. ANN NEUROL 2021, Deep LearningとALS iPS細胞を用いた疾患予測テクノロジー --人工知能のALS検知・診断への応用--. 京都大学プレスリリース. 2021-02-24., Deep learning amyotrophic lateral sclerosis by taking pictures. 京都大学プレスリリース. 2021-02-24.

We analyzed the corneal topography before and after blepharoptosis surgery and examined whether there was a difference in the corneal topographic changes with and without deepening of the upper eyelid sulcus (DUES). Retrospective study. A total of 23 eyes of 23 patients (6 men and 17 women) were enrolled in this study. The patients were divided into two groups according to the presence or absence of DUES, and their clinical characteristics were compared. There were no significant differences between the DUES (n = 9) and non-DUES (n = 14) groups in any of the parameters examined before blepharoptosis surgery, including age, best-corrected visual acuity (BCVA), margin reflex distance-1 (MRD-1), spherical equivalent, average keratometry (AveK), cylindrical power (CYL), corneal higher order aberrations (HOAs) and central corneal thickness (CCT). In the non-DUES group, BCVA, spherical equivalent, AveK, CYL, and CCT were not significantly different between before and after surgery. On the other hand, in the DUES group, BCVA, spherical equivalent, and CCT were not significantly different before or after surgery, however, AveK, CYL and HOAs showed significant decreases after surgery. In addition, related to the post-surgical changes in CYL, the DUES group had a higher rate of reduced CYL. It is expected that in eyes with DUES blepharoptosis surgery can reduce AveK, CYL and HOAs in association with postoperative corneal flattening, and that will contribute to improvements in visual function.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

Purpose: To examine the clinical characteristics of patients who developed blepharoptosis after filtering surgery. Study Design: A retrospective, observational study. Methods: 96 eyes in 79 patient...

A nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugs-resistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.

OBJECTIVE Cases of pelvic high-grade serous carcinoma (HGSC) with incidentally detected cancer cells (ICCs) in endometrial and/or cervicovaginal cytology have been reported. This study aimed to clarify the incidence and characteristics of pelvic HGSC with ICCs and to determine whether ICCs have a negative prognostic impact. METHODS Patients with ovarian/tubal/peritoneal HGSC who underwent pre-treatment uterine (endometrial/cervicovaginal) cytology or biopsy between January 2007 and May 2017 were included. We reviewed the frequencies of ICCs and compared the clinicopathological features and survival outcome between the ICC-positive and ICC-negative groups. RESULTS Of the 160 patients evaluated, 69 (43.2%) had positive ICCs in at least one uterine specimen. There were no significant differences in clinicopathological characteristics, such as age, FIGO stage, serum CA125 level, ascites, and tubal lesion, between the two groups. Moreover, ICCs had no significant survival impact on progression-free survival or overall survival. CONCLUSION Our study showed a high rate of pelvic HGSC with ICCs in pre-treatment uterine specimens. The ICCs per se had no negative impact on survival outcomes of pelvic HGSC. Furthermore, uterine biopsy and cytology can be useful and less-invasive methods to obtain tubo-ovarian/peritoneal cancer cells before treatment.

Acinetobacter spp. are known to be a cause of nosocomial infections and to have diverse mechanisms of resistance to antimicrobials. Here, we report the case of a patient who presented to our emergency department with necrotizing fasciitis due to Acinetobacter junii as confirmed by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight mass spectrometry (MALDI-TOF MS). Patients with liver cirrhosis are susceptible to gram-negative infection. Moreover, although Acinetobacter spp. infection is best known to be a cause of combat-related-skin and soft-tissue infections, we propose that medical professionals need to consider the presence of these potentially multi-drug-resistant, gram-negative pathogens when treating patients with liver cirrhosis who present with severe soft-tissue infections. To our knowledge, this is the first case report of severe-skin and soft-tissue infections caused by A. junii.

This study aimed to identify the elderly generation with the worst prognoses for high-grade astrocytoma and find independent predictors of good outcomes. We conducted a retrospective analysis of 91 patients, ≥65 years old, with anaplastic astrocytoma or glioblastoma. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method and compared using log-rank test or multivariate Cox regression analysis. We included 21 (23%) and 70 (77%) patients aged 65–69 years and ≥70 years. In the two generations, significant differences were found in the Charlson comorbidity index, extent of resection, chemoradiotherapy (CRT) as adjuvant therapy, and radiation dose (all P < 0.05). The median PFS was 9.9 and 6.9 months in patients aged 65–69 and ≥70 years (P = 0.10). The median OS was 22.8 and 11.6 months in patients aged 65–69 and ≥70 years (P = 0.009). In the multivariate analyzes in patients ≥70 years, only postoperative Karnofsky performance status (KPS) scores ≥70 were significantly related to prolonged PFS (hazard ratio [HR]: 0.48, P = 0.04), and postoperative KPS, CRT as adjuvant therapy, and salvage therapy were significantly related to prolonged OS (HR: 0.45, P = 0.03, HR: 0.38, P = 0.002, and HR: 0.43, P = 0.01, respectively). In conclusion, in patients ≥70 with high-grade astrocytoma, OS was significantly shorter compared to those aged 65–69. Postoperative KPS score was significantly related to prolonged PFS and OS. Postoperative CRT and salvage therapy at recurrence may be effective in the selected elderly.

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (

Background To date, a few case reports have described the association between poststreptococcal acute glomerulonephritis (PSAGN) and hemolytic anemia/thrombocytopenia, both with or without a pathology similar to that of thrombotic microangiopathy (TMA). However, the detailed mechanism leading to the complication of TMA in PSAGN patients remains to be clarified. In contrast, infection with neuraminidase-producing Streptococcus pneumoniae is a well-known cause of TMA, and it has been reported that transient positivity of the direct Coombs test is observed in up to 90% of such patients. Case presentation A 44-year-old man was hospitalized for acute nephritic syndrome 3 weeks after developing pharyngitis. PSAGN was suspected owing to a low complement C3, increased antistreptolysin-O and serum creatinine (5.46 mg/dL), and hematuria/proteinuria. The throat antigen test for group A Streptococcus was positive. He developed hemolytic anemia with thrombocytopenia from hospital day 9. TMA was suspected owing to minimal coagulation abnormalities. ADAMTS-13 activity was normal, whereas the direct Coombs test was transiently positive. Renal biopsy demonstrated glomerular endocapillary proliferation without crescents, but with severe tubulitis and peritubular capillaritis on light microscopy. Immunofluorescence demonstrated C3 deposition along the glomerular capillary walls, and many subepithelial humps were observed on electron microscopy. The deposition of nephritis-associated plasmin receptor (NAPlr), a nephritogenic protein of Streptococcus pyogenes, was observed only in glomeruli. Thus, the histological diagnosis was typical PSAGN, but with atypical severe tubulointerstitial lesions. A positive direct Coombs test is often observed in pneumococcal TMA patients, which is attributed to the exposure of Thomsen–Friedenreich (T) antigen by neuraminidase. As Streptococcus pyogenes is one of the neuraminidase-producing bacteria other than Streptococcus pneumoniae, T-antigen exposure was analyzed in the renal tissue of this patient using labelled peanut lectin as a probe, which has strong and specific binding affinity for T-antigen. Exposure of T-antigen was found on tubular epithelial cells and small vessels in the tubulointerstitial area, but not in the glomeruli of this patient. Conclusion These findings suggest that 2 pathogenic proteins of Streptococcus pyogenes, i.e., NAPlr and neuraminidase, induced glomerular lesions of PSAGN and tubulointerstitial inflammation with TMA, respectively, resulting in severe acute kidney injury in this patient.

Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19. Importance Convalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

SUMMARYBackgroundWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified.MethodsIn the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined.FindingsSignificant rise in NT50s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation was seen between NT50s and AEs. NT50s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT50s>1,500-fold: the top 4% among all participants’ NT50s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.InterpretationBNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed.Research in contextEvidence before this studyWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Roseet al. N Engl J Med. 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined.Added value of this studyIn the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT50s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT50s and IgG levels were greater in women than in men. Following 28 days post-2ndshot, significant reduction was seen in NT50s, IgG, and IgM levels. The average half-life of NT50s was ∼68 days and the average time-length for participants’ serums to lose the detectable activity was ∼198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.Implications of all the available evidenceBNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1stshot on average. Individuals with moderate NT50s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.

Hemodialysis patients are vulnerable to severe and lethal COVID-19, and their protective immunity against COVID-19 is not yet fully understood. Therefore, we report a case of COVID-19 reinfection in a hemodialysis patient 81 days after the first episode and discuss the role of antibodies in SARS-CoV-2 infection. A hemodialysis patient developed asymptomatic COVID-19 due to an outbreak in a hospital on October 29th, 2020. As he was hospitalized and did not develop any symptoms, he was discharged on November 9th. On January 18th, he presented with symptomatic COVID-19 due to close household contact. Then, he developed respiratory failure and was transferred to National Center for Global Health and Medicine if he would need intensive care. He recovered with oxygen inhalation, favipiravir, and steroid treatment, and was discharged on February 12th. To evaluate anti-SARS-CoV-2 antibodies during two hospital stays, we measured immunoglobulin (Ig) G specific for S1 subunit of Spike (S) protein of SARS-CoV-2 (IgG-S1) , IgG specific for the full-length S protein (anti-Spike IgG) and neutralizing antibodies. No seroconversion occurred 5 days after initial infection, the seroconversion of IgG-S1 was observed 10 days after the second infection. Similar to IgG-S1 antibody titer results, anti-Spike IgG and neutralizing antibodies increased from 12 days after the second infection. In conclusion, we experienced a case of COVID-19 reinfection in a hemodialysis patient 81 days after the first episode and showed the kinetics and role of antibodies in SARS-CoV-2 infection. Further studies are needed to understand SARS-CoV-2 reinfection risk in hemodialysis patients and its clinical significance.

Patient: Male, 49-year-old Final Diagnosis: Chromobacterium violaceum infection Symptoms: No symptom Medication:— Clinical Procedure: — Specialty: Infectious Diseases Objective: Rare disease Background: Chromobacterium violaceum (C. violaceum) is a gram-negative and facultative anaerobic oxidase-positive bacillus generally seen in tropical or subtropical areas (latitudes between 35°N and 35°S). C. violaceum infection is a rare but serious infection with high morbidity and mortality rates. Most clinicians practicing in non-tropical counties, such as Japan, are unfamiliar with it. Case Report: We report the first fatal case of a 49-year-old man infected with C. violaceum after a traffic accident in Japan (latitude 34.8°N). The patient reported brief submergence in a marshy muddy rice field after the accident. There was some evidence of soil and water contamination of the patient’s skin and clothing, but he denied swallowing water or soil. There were no findings of pneumonitis or severe open wounds on admission. Until the night of the 7th day of hospitalization, his general conditions remained stable despite a persistent fever. However, he suddenly collapsed on the 8th day of hospitalization and died. C. violaceum bacteremia led to fatal sepsis on dissemination to the iliopsoas abscess, which is a rare combination for this infection. Conclusions: Episodes of exposure to contaminated water or soil, especially in summer, are important predisposing factors for C. violaceum infection. Thus, it is vital to include C. violaceum infections as a differential diagnosis, since the mortality rate of C. violaceum infections is high and the cases of this infection have increased in non-tropical counties.

This study aimed to identify factors associated with engaging in sports and exercise volunteering among older adults. We used cross-sectional data from the Japan Gerontological Evaluation Study (JAGES), a nationwide mail survey of 20,877 older adults from 60 municipalities. Multilevel mixed-effects logistic regression analysis was used to investigate the correlation between engaging in sports and exercise volunteering and 39 variables classified into five factors: (1) demographic and biological, (2) behavioral, (3) psychological, cognitive, and emotional, (4) social and cultural, and (5) environmental factors. Among the analyzed samples, 1580 (7.6%) participants volunteered a few times/year or more often. Factors that showed positive association with the volunteering were older age, a current drinking habit, excellent self-rated health, high proportion of sports group participants in a living area, low municipal population density, and rich social and cultural features (i.e., social cohesion, support, network, and participation). Meanwhile, those that had a negative association were women, low level of education, deteriorated instrumental activities of daily living, having a past or current smoking habit, poor self-rated health, and depressive symptoms. We clarified the characteristics of the population that is more likely to participate in sports and exercise volunteering as well as those of the population that is less likely to participate and requires support.

We aimed to estimate the frequency of intratumoral susceptibility signals (ITSS) in susceptibility-weighted imaging (SWI) in consecutive patients with primary central nervous system lymphoma (PCNSL), and to determine if pretreatment heterogeneity of PCNSL is predictive of response to chemotherapy by using ITSS on SWI. We retrospectively examined 29 immunocompetent patients with PCNSL who underwent SWI-MRI before treatment. A univariate analysis was conducted with Fisher's exact test. Progression free survival (PFS) was calculated by the Kaplan-Meier method and compared by the log rank test. The patients, including 16 males, were initially treated at a median age of 69 years. All tissue types were diffuse large B-cell lymphoma. Nineteen patients (66%) presented lesions with ITSS. Sixteen patients (55%) received initial treatment with R-MTX (rituximab plus high-dose methotrexate). Seven out of nine patients with ITSS exhibited a poor response, whereas all seven without ITSS exhibited a good response to R-MTX. Regarding the absence of ITSS, the sensitivity, specificity, and diagnostic accuracy for a good response to R-MTX were 0.78, 1.00, and 0.88, respectively. Patients without ITSS showed significantly longer PFS compared to patients with ITSS (median PFS: 28.9 vs 2.1 months, P 0.01). In conclusion, ITSS in PCNSL patients were more common than previously reported. We have to be careful to use ITSS for differentiating PCNSL and glioblastoma. Presence of ITSS correlated significantly with therapeutic response to R-MTX. ITSS may be a new marker for the response to chemotherapy in patients with PCNSL. A prospective multi-institutional analysis is needed.

Aim To report the effect of oval and round window reinforcement surgery performed in two patients with the Tullio phenomenon. Case 1: A male with bilateral superior canal dehiscence syndrome. Downbeat nystagmus with leftward horizontal eye movement was recorded in an electronystagmogram using a pure-tone sound of 110 dB at 2000 or 4000 Hz in the right ear. Case 2: A female who had undergone stapes surgery. Computed tomography revealed an ossicular prosthesis in the vestibule. An audiogram indicated mild to moderate hearing impairment in the right ear. Leftward horizontal nystagmus was recorded in an electronystagmogram using a pure-tone sound of 110 dB at 500 or 1000 Hz in the right ear. Surgical findings indicated that the prosthesis was inserted deep into the oval window, which was closed with thin connective tissue. Outcomes After oval and round window reinforcement surgery was performed in the right ear, and loud, pure-tone sounds elicited neither nystagmus nor dizziness in either patient.

Purpose It is unclear whether local therapy (LT) or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) should take precedence for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases (BMs). The number of BMs is important in the choice of LT, including whole-brain radiation therapy, stereotactic radiosurgery, and surgery. Methods We retrospectively evaluated cases of EGFR-mutant non-small cell lung cancer with BMs from a single site. Patients were divided into 2 groups based on upfront therapy—EGFR-TKI (TKI) or LTs—and subsequently stratified by the number of BMs. Results Among 176 patients, 61% received upfront EGFR-TKI, and 39% received upfront LT. The number of patients with 1 to 4 BMs was similar (56% vs 52%; P = .61). All patients with 1 to 4 BMs in the LT group, except for surgical cases, received stereotactic radiosurgery (n = 31). Among those with ≥5 BMs, most (n = 27; 82%) received whole-brain radiation therapy. There was no significant difference in OS between LT and TKI groups (median overall survival, 28 vs 23 months; hazard ratio, 0.75; 95% confidence interval, 0.52-1.07). In patients with 1 to 4 BMs, the LT group showed significantly better OS compared with the TKI group (median overall survival, 35 vs 23 months; hazard ratio, 0.54; 95% confidence interval, 0.32-0.90). There was no difference in OS between the LT and TKI groups for patients with ≥5 BMs. Multivariable analysis showed that upfront LT yielded significantly better OS for patients with 1 to 4 BMs. Conclusion Upfront LT followed by EGFR-TKI is more effective than upfront EGFR-TKI for the survival of untreated patients harboring EGFR mutations with 1 to 4 BMs.

Physical activity (PA) is a key factor of bone mass acquisition in peripubertal children. Sedentary behavior (SB) has been shown to influence bone outcomes. This study aimed to examine the association between objectively measured PA and SB and bone stiffness in Japanese children. Participants were fifth-grade children aged 10–11 years from Project Koshu. The stiffness index (SI) of the calcaneus was measured by quantitative ultrasound; PA and SB were evaluated by an accelerometer. Each PA parameter was divided into sex-specific tertile or stratified by recommended PA guideline [≥ 60 min/day of moderate-to-vigorous PA (MVPA)]. The SI was compared among PA and SB through analysis of covariance with Bonferroni correction. Of 174 children, complete data were obtained from 134 (60 boys and 74 girls). The SI in boys was higher in the highest tertile of MVPA than that in the other groups. A similar association was found in girls but was not significant. Children who met the PA guideline had higher SI than those who did not, but there was no significant difference. A negative relation was observed in girls, with the SI gradually decreasing along with increasing SB (p for trend = 0.038). This association was not observed among boys. This study suggests that MVPA is positively associated with bone stiffness in Japanese schoolchildren in boys and SB is negatively associated with that in girls. Reducing SB might be a brief modifiable factor for preventing lower peak bone mass in girls, in addition to increasing MVPA.

This study examined whether employment category was associated with insomnia-related symptoms (IRS). We analyzed the 2010 Comprehensive Survey of Living Conditions in Japan. The anonymous data of 43,865 people ranging from 20-59 yr of age were analyzed. We defined six employment categories: regularly employed, non-regularly employed, self-employed, others, unemployed and not in the labor force. Sex-specific odds ratios (ORs) and 95% confidence intervals (CIs) of IRS were calculated using multivariable logistic regression analysis, adjusted for confounding factors. We further conducted stratified analyses by mental illness, smoking status, and age. For men, the multivariable ORs (95% CI) of IRS for the unemployed and those who were not in the labor force were 2.5 (1.8-3.4) and 2.1 (1.2-3.7). For women, the multivariable ORs (95% CI) for the unemployed was 1.9 (1.5-2.5). After being stratified by mental illness, we found that the associations were not significant in persons with mental illness, and were more evident in persons without mental illness. Smoking and age did not modify the associations. In conclusion, we found a significantly higher OR of IRS for the unemployed, and men who were not in the labor force. These associations were particularly more evident for individuals without mental illness.

Although the underlying neural mechanisms remain unknown for both persistent developmental stuttering (PSD) and acquired neurogenic stuttering (ANS), few studies have examined similarities/differences between these two disorders. We evaluated in both PDS (n = 35) and ANS (n = 5) phonetic, word class, word length, and word position variables that are widely believed to influence at which loci within utterances PDS speakers’ stuttering is most likely to occur. For both groups, (a) word weights based on the combination of variables were greater for stuttered vs. fluent words, and (b) stuttered words were loaded more by individual variables. However, contrary to long-standing views regarding PDS, greater loading for stuttered words was not found for the position variable. Findings suggest similar loci of stuttering in adults with PDS and ANS, and, for both groups, the probability of stuttering on a given word was more influenced by motor production variables than language variables.

Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of HIV-1 infection. Certain protein kinase C (PKC) activators have been previously reported to be LRAs because they can reverse HIV latency. In the present study, we examined the activities of a panel of benzolactam derivatives against cells latently infected with HIV. Using determination of p24 antigen in cell supernatants or altered intracellular GFP expression to measure HIV reactivation from latently infected cells along with a cytotoxicity assay, we found that some of the compounds exhibited latency-reversing activity, which was followed by enhanced release of HIV particles from the cells. One derivative, BL-V8-310, displayed activity in ACH-2 and J-Lat cells latently infected with HIV at a concentration of 10 nm or higher, which was superior to the activity of another highly active PKC activator, prostratin. These results were confirmed with peripheral blood cells from HIV-infected patients. We also found that these drugs up-regulate the expression of caspase 3 and enhance apoptosis specifically in latently HIV-infected cells. Moreover, combining BL-V8-310 with a bromodomain-containing 4 (BRD4) inhibitor, JQ1, not only enhanced HIV latency-reversing activity, but also reduced the effect on cytotoxic cytokine secretion from CD4+ T-cells induced by BL-V8-310 alone. Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects.

Background The safety and effectiveness of neoadjuvant fractionated stereotactic radiotherapy (FSRT) before piecemeal resection of brain metastasis (BM) remains unknown. Methods We retrospectively reviewed 20 consecutive patients with BM who underwent neoadjuvant FSRT followed by piecemeal resection between July 2019 and March 2021. The prescribed dose regimens were as follows: 30 Gy (n = 11) or 35 Gy (n = 9) in five fractions. Results The mean follow-up duration was 7.8 months (range 2.2–22.3). The median age was 67 years (range 51–79). Fourteen patients were male. All patients were symptomatic. All tumors were located in the supratentorial compartment. The median maximum diameter and volume were 3.7 cm (range 2.6–4.9) and 17.6 cm3 (range 5.6–49.7), respectively. The median time from the end of FSRT to resection was 4 days (range 1–7). Nausea (CTCAE Grade 2) occurred in one patient and simple partial seizures (Grade 2) in two patients during radiation therapy. Gross total removal was performed in seventeen patients and sub-total removal in three patients. Postoperative complications were deterioration of paresis in two patients. Local recurrence was found in one patient (5.0%) who underwent sub-total resection at 2 months after craniotomy. Distant recurrence was found in six patients (30.0%) at a median of 6.9 months. Leptomeningeal disease recurrence was found in one patient (5.0%) at 3 months. No radiation necrosis developed. Conclusions Neoadjuvant FSRT appears to be a safe and effective approach for patients with BM requiring piecemeal resection. A multi-institutional prospective trial is needed.

Objectives: In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80–90% of leptomeningeal metastasis (LM) develops after failed initial epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) treatment. However, the efficacy of rechallenging previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and LM that develops after EGFR-TKI treatment failure remains unknown.Materials and Methods: We retrospectively reviewed the medical records of patients with EGFR-mutated NSCLC and LM from November 2011 to August 2019. Patients were classified into two groups according to LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) and rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI).Results: In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI, and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion: Our findings suggest that rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Introduction “Re-infection” with COVID-19 is a growing concern; re-infection cases have reported worldwide. However, the clinical characteristics of SARS-CoV-2 re-infection, including the levels and role of anti-SARS-CoV-2 Spike protein IgG antibodies and the half-maximal concentration (IC50) of neutralizing antibodies remain unknown. Methods Both the epidemiological and clinical information has been collected during two episodes of COVID-19 in a patient. Laboratory results, including RT-PCR, Ct values, anti-SARS-CoV-2 Spike protein IgG antibodies, and the IC50 of neutralizing antibodies levels were analyzed on the patient. Results The patient was a 58-year-old man who developed moderate COVID-19 pneumonia with oxygen demand (cannula 2 L/min) in the first episode. By day 30, he recuperated and was discharged after testing negative for SARS-CoV-2. After two and a half months, his three family members showed COVID-19 symptoms and tested positive for SARS-CoV-2. He tested positive for SARS-CoV-2 once again and was asymptomatic (the second episode). The IC50 of neutralizing antibodies against SARS-CoV-2 greatly increased from 50.0 μg/mL (after the first episode) to 14.8 μg/mL (after the second episode), and remained strongly reactive (20.1 μl/mL) after 47 days of the second episode. Conclusions Epidemiological, clinical, and serological analyses confirmed that the patient had re-infection instead of persistent viral shedding from first infection. Our results suggest that SARS-CoV-2 re-infection may manifest as asymptomatic with increased neutralizing antibody levels. Further studies such as the virus characteristics, immunology, and epidemiology on SARS-CoV-2 re-infection are needed.

The quantitative range and reproducibility of current serological tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are not optimized. Herein, we developed a diagnostic test that detects SARS-CoV-2 IgG and IgM with high quantitativeness and reproducibility and low interference. The system was based on the high-sensitivity chemiluminescence enzyme immunoassay (HISCL) platform and detects IgG and IgM specific to SARS-CoV-2 spike and nucleocapsid proteins. Quantification accuracy and reproducibility were evaluated using serially diluted samples from 60 SARS-CoV-2-infected patients. Assay performance was evaluated using serum samples from the SARS-CoV-2-infected patients and 500 SARS-CoV-2-negative serum samples collected before the emergence of SARS-CoV-2. The system showed high quantification accuracy (range, 102), high reproducibility (within 5%), and no cross-reaction between SARS1- and MERS-S proteins. Detection accuracy was 98.3% and 93.3% for IgG and IgM against spike proteins and 100% and 71.7% for IgG and IgM against nucleocapsid proteins, respectively. Mean antibody levels were > 10 times that in negative samples upon admission and > 100 times that at convalescent periods. Clinical severity upon admission was not correlated with IgG or IgM levels. This highly quantitative, reproducible assay system with high clinical performance may help analyze temporal serological/immunological profiles of SARS-CoV-2 infection and SARS-CoV-2 vaccine effectiveness.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

No specific therapy is available for COVID-19. We report the effectiveness and adverse effects of triple therapy with hydroxychloroquine, azithromycin, and ciclesonide in patients with COVID-19 pneumonia. The clinical condition of the patients improved within 5 days in response to the therapy.

Complications after surgical treatment of pediatric radial neck fractures are common. The purpose of this study was to evaluate the mid- to long-term clinical and radiographic outcomes after surgical treatment of pediatric radial neck fractures. We assessed 10 children who had been surgically treated for radial neck fractures. We mainly performed percutaneous intrafocal pinning to reduce the fracture; where this was inappropriate, we performed open reduction. Mid- to long-term clinical and radiographic outcomes were assessed, as well as whether these affected patient-related outcomes (Hand 20 questionnaire) at the final follow-up. Of the 10 patients (seven boys; mean age, 9 years; age range, 5-14 years; four fractures on the right-hand side, six on the left), four each were grades II and III, and two were grade IV, according to the Judet classification. The mean follow-up time was 6.7 (range, 3.6-11.2) years. Eight patients had restricted forearm pronation. The mean radial neck angulation on the fractured side was 36° (range, 5°-96°), preoperatively, and 2° (range, 0°-11°) at the final follow-up. There were eight cases of radial head overgrowth, three of premature physeal closure, two of notching of the radial neck, and one of heterotopic ossification. According to the Leung/Peterson Classification, four patients had "excellent," three had "good," and three had "fair" functionality. Eight patients had a perfect score upon completing the Hand 20 questionnaire. In conclusion, postsurgical patient-related outcomes for the 10 cases were satisfactory despite slightly restricted forearm range of motion and complications detected using radiography.

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.

IMPORTANCE: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. OBJECTIVE: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those 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 the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. INTERVENTIONS: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. RESULTS: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 vs −4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548311

Background The incidence of leptomeningeal metastasis (LM) is underestimated because of its non-specific signs and the low sensitivity of clinical diagnostic modalities. Cerebrospinal magnetic resonance (MR) imaging with and without contrast enhancement (CE) is a gold standard for the neuroradiological assessment of patients with suspected LM. Previous studies suggested that some LM cases show changes of the brainstem surface on non-contrast MR images without or before the appearance of abnormalities on CE images. We assessed the features of this non-contrast MR finding in a cohort of LM patients in this retrospective single-institution study. Methods We reviewed head MR images and clinical data of 142 consecutive patients in whom the final diagnosis was LM. Results We found that 11 of these 142 patients (7.7%) with LM had band-like hyperintensity on the brainstem surface on non-enhanced FLAIR images, which looked like bloomy rind on cheese. Three of seven patients who were examined using diffusion-weighted imaging showed restricted diffusion in the corresponding lesion site. The above-mentioned 11 patients included 10 women and 1 man, with a median age of 61 years. All 11 patients had primary lung adenocarcinoma. Seven patients had symptomatic hydrocephalus. Ten patients had EGFR-mutated and one had ALK-rearrangement adenocarcinomas. Before the diagnosis of LM, 10 patients had undergone systemic therapy with EGFR-TKI or pemetrexed, and 1 patient with ALK inhibitor and bevacizumab. Conclusions We present a series of patients with bloomy rind sign that is non-enhancing LM reliably detected by FLAIR hyperintensity on the brainstem surface. This finding is rare, but may reflect the spread of cancer cells in both the leptomeningeal membrane and the surface of the brain parenchyma specifically in patients with lung adenocarcinomas. Further study is needed to determine the clinical significance of this sign, and the pathophysiological factors associated with it may be clarified by analyzing serial MR images in a larger cohort of patients treated for LM.

Background/aim Glioblastoma multiforme (GBM) is an intractable tumor that has a very poor prognosis despite intensive treatment with temozolomide plus radiotherapy. Patients and methods Sixteen newly diagnosed patients with high-grade gliomas were enrolled in a phase II study of the α-type-1 DC vaccine. Briefly, DCs obtained from the culture of enriched monocytes in the presence of a cytokine cocktail, were pulsed with a cocktail of 5 synthetic peptides and cryopreserved until injection into patients. Results The amount of IL-12 produced by activated DCs was higher than that previously reported. Among 15 evaluable patients, 10 showed positive CTL responses to any peptides in an ELISPOT assay. After 6 years of observation, five patients were still alive, and two of these patients were relapse-free. Moreover, a significant survival-prolonging effect was verified in DC-treated glioma patients. Conclusion Peptide-cocktail-pulsed α-type-1 DC vaccines have a potential therapeutic effect on survival when used in combination with the standard regimen, which is partly based on IL-12-IFN-γ-mediated T-cell activation.

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., Gen Sobue, Masao Nagasaki and colleagues report a genome-wide association study for amyotrophic lateral sclerosis (ALS) in a large, multi-ethnic cohort comprising Japanese, Chinese, and European ancestry populations. They find a significant association to variants within the ACSL5 gene and identify novel associations with 4 additional genes using a gene-based approach.

T2-FLAIR mismatch sign is known as a highly specific imaging marker of IDH-mutant astrocytomas. This study was intended to clarify what the T2-FLAIR mismatch sign represents by pathological analysis of lower-grade gliomas rediagnosed in accordance with the WHO 2016 classification. We retrospectively analyzed the records of 64 patients diagnosed with WHO grade II and III diffuse gliomas between June 2009 and November 2018. T2-FLAIR mismatch sign was found in 10 (45%) out of 22 patients with IDH-mutant astrocytoma, 1 (5%) out of 20 with oligodendroglioma, and 1 (5%) out of 22 with IDH-wild-type astrocytoma. T2-FLAIR mismatch sign as a marker of IDH-mutant astrocytomas showed positive predictive value of 83%. Among 22 patients with IDH-mutant astrocytomas, microcystic change was found in eight, of which seven showed T2-FLAIR mismatch sign. Microcystic change was significantly associated with T2-FLAIR mismatch sign (P

Background In patients with lower lateral medullary infarction (LMI) located under the vestibular nucleus, proprioceptive impairment due to dorsal spinocerebellar tract (DSCT) is considered a pathological condition for body lateropulsion. In patients with brainstem infarction located at or above the level of the vestibular nucleus, other pathways, such as the crossed vestibulothalamic tract (CVTT), are considered responsible. Research question The clinical course of body lateropulsion between each anatomical level of infarction remains unclear. Further, whether body lateropulsion refers to a static or a dynamic symptom also remains unclear. Methods We examined 47 patients who exhibited body lateropulsion and categorized them into four groups: lower LMI under the vestibular nucleus, LMI at the level of the vestibular nucleus, pontine infarction, and midbrain infarction. The patients’ time to acquire static upright standing position and gait in a straight line were statistically analyzed by a log-rank test using the Kaplan–Meier method. Results Body lateropulsion in the static upright position was less frequent in the lower LMI group than in the other groups. Significance Lower LMI primarily affected body lateropulsion in gait. DSCT damage could affect ipsilateral hip joint or leg coordination, causing body lateropulsion in dynamic situation.

Background Stereotactic irradiation (STI) is a primary treatment for patients with newly diagnosed brain metastases. Some of these patients experience local progression, which is difficult to differentiate from radiation necrosis, and difficult to treat. So far, just a few studies have clarified the prognosis and effectiveness of salvage surgery after STI. We evaluated the diagnostic value and improvement of functional outcomes after salvage surgery. Based on these results, we reconsidered surgical indication for patients with local progression after STI. Methods We evaluated patients with brain metastases treated with salvage surgery for local progression from October 2002 to July 2019. These patients had undergone salvage surgery based on magnetic resonance imaging findings and/or clinical evidence of post-STI local progression and stable systemic disease. We employed two prospective strategies according to the eloquency of the lesions. Lesions in non-eloquent areas had been resected completely with a safety margin, utilizing a fence-post method; while lesions in eloquent areas had been treated with minimal resection and postoperative STI. Kaplan-Meier curves were used for the assessment of overall survival. Prognostic factors for survival were analyzed. Results Fifty-four salvage surgeries had been performed on 48 patients. The median age of patients was 63.5 years (range 36–79). The median interval from STI to surgery was 12 months. The median overall survival was 20.2 months from salvage surgery and 37.5 months from initial STI. Primary cancers were lung 31, breast 9, and others 8. Local recurrence developed in 13 of 54 lesions (24%). Leptomeningeal dissemination occurred after surgery in 3 patients (5.6%). Primary breast cancer (breast vs. lung: HR: 0.17), (breast vs. others: HR: 0.08) and RPA class 1–2 (RPA 1 vs. 3, HR:0.13), (RPA 2 vs 3, HR:0.4) were identified as good prognostic factors for overall survival (OS) in multivariate analyses. The peripheral neutrophil-to-lymphocyte ratio (NLR) of ≤3.65 predicted significantly longer OS (median 25.5 months) than an NLR > 3.65 (median 8 months). Conclusion We insist that salvage surgery leads to rapid improvement of neurological function and clarity of histological diagnosis. Salvage surgery is recommended for large lesions especially with surrounding edema either in eloquent or non-eloquent areas.

Objectives Very few longitudinal studies have investigated the question of whether differences in company size may give rise to health inequalities. The aim of this study was to examine the relationship between company size of the longest‐held job and mortality in older Japanese adults. Methods This study used longitudinal data from the Japan Gerontological Evaluation Study. Surveys were sent to functionally independent individuals aged 65 or older who were randomly sampled from 13 municipalities in Japan. Respondents were followed for a maximum of 6.6 years. The Cox proportional hazards model was used to calculate mortality hazard ratios (HRs) for men and for women. Analysis was carried out on 35 418 participants (197 514 person‐years). Results A total of 3935 deaths occurred during the 6‐year follow‐up period. Among men, in Model 1 that adjusted for age, educational attainment, type of longest‐held job, and municipalities, mortality HRs decreased significantly with increasing size of company (P for trend = .002). Compared to companies with 1‐9 employees, the mortality HR (0.78, 95% confidence interval: 0.68‐0.90) was significantly lower for companies with 10 000 or more employees. However, there were no significant differences among women (P for trend = .41). Conclusions In men, mortality in old age may decrease with increasing size of company of the longest‐held job. To reduce health inequalities in old age due to differences in size of company, studies should be conducted to determine the underlying mechanisms and moderating factors and those findings should be reflected in labor policies and occupational health systems.

This study aimed to evaluate the relationships between androgen receptor (AR) expression and clinicopathologic features of sebaceous gland carcinoma (SGC) of the eyelid. AR expression was evaluated via immunohistochemistry analysis of surgically derived samples from 11 patients with SGC of the eyelid. The expression of AR was evident in 9 of 11 patients (82%). We divided patients into high AR (7 patients) and low AR (4 patients: 2 patients with low expression and 2 patients with no expression) groups. The low AR group showed significantly greater progression than the high AR group with regard to T category and exhibited a lower grade of differentiation. In patients with SGC of the eyelid, a marked decrease in AR expression may be associated with a poor prognosis. AR may be a prognostic factor and a potential therapeutic target in cases of SGC of the eyelid.

Background Lower birth weight (BW) is associated with increased chronic disease risk later in life. Previous studies suggest that this may be mediated principally via physical activity (PA). However, the association between BW and PA in children has not been clarified. The purpose of this study was to examine the association between BW and PA in school-aged children in Japan. Methods Participants were children from a prospective birth cohort study (Project Koshu) who were born from 1996 through 2002 in rural Japan. BWs were obtained from the Maternal and Child Health Handbook. Data on PA during childhood were collected using a self-reported questionnaire when participants were 9-15 years of age in July 2011. Analysis of covariance was used to evaluate exercise duration; Poisson regression analysis was used to evaluate if the recommended PA amount was met. Results Data from 657 children (boys: 54.8%, follow-up rate: 77.6%) were analyzed. Compared with the normal BW group, only girls in the low-BW group had significantly lower PA level (normal BW, 11.4 [standard error, 1.0] hours/week; low BW, 5.8 [standard error, 3.6] hours/week, P = 0.010), and were more likely to not meet the recommended PA level (prevalence ratio 1.57; 95% CI, 1.14-2.16). Conclusion Low BW was associated with a lower PA level in school-aged girls but not boys. Earlier consideration of BW may be an important public health strategy to prevent physical inactivity in school-aged girls.

Objectives 4′-cyano-2′-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography–mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration. Methods An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated. Key findings A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other. Conclusions The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV.

The embolization of cancer cells to cerebral vessels occurs early in the multi-step metastatic process. We aimed to determine whether the presence of leukoaraiosis (LA) before treatment would predict the development of brain metastases (BM) in patients with lung cancer. Between January 2014 and June 2015, 1007 patients underwent initial (i.e., prior to any chemotherapy) or routine magnetic resonance (MR) imaging of the brain and exhibited no evidence of BM. Of these, 189 underwent repeat MR imaging; 34 of 189 patients (18%) developed new BM, whereas 155 patients did not. LA was retrospectively evaluated according to Fazekas scale on the initial screening MR images of these 189 patients. The frequency of grade 0 periventricular hyperintensity (PVH) was greater among patients with BM, compared to those without BM (p = 0.001). In a multivariate analysis, patients with adenocarcinoma (95% confidence interval [CI] 1.8–171.8) and small cell carcinoma (95% CI 1.4–172.4) respectively developed BM at 9.3- and 8.8-fold higher rates than those with squamous cell carcinoma. Patients with grade 0 PVH developed BM at a rate 3.5-, 8.6-, and 3.6-fold higher rates than those with grade 1 (95% CI 1.4–9.0), 2 (95% CI 2.4–41.9), and 3 (95% CI 1.02–15.0), respectively. Lung cancer patients with grade 0 PVH on initial MR images have a high subsequent incidence of BM. PVH is a useful method for evaluating risk of BM.

Patients with malignant brain tumors are possibly at increased risk for surgical site infections (SSIs) considering the various medical situations associated with the disease. However, the actual rate of SSI after malignant brain tumor resection has not been well established, despite the potential impact of SSI on patient outcome. To investigate the incidence of SSI following malignant brain tumor surgery, we performed a retrospective study in 3 neurosurgical units. Subsequently, aiming at the reduction of incidence of SSI, we performed a prospective study using a care bundle technique in the same units. The SSI incidence in the retrospective (n = 161) and prospective studies (n = 68) were 4.3% and 4.4%, respectively, similar to the previously reports on general craniotomies. A care bundle does not appear to enhance prevention of SSI. However, future, large studies with a new care bundle should be planned based on a zero tolerance policy.

Background Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed. Materials and methods The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line. Results The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC50: 78 μM for STX-0119, 30.5 μM for rapamycin and 11.3 μM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway. Conclusion These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas.