Safety of transbronchial lung cryobiopsy compared to transbronchial forceps biopsy in patients with diffuse lung disease: An observational study using a national database in Japan.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a new technique for obtaining high-quality and large-sized lung tissues, as compared to transbronchial forceps biopsy (TBFB), and is useful in the diagnosis of diffuse lung disease (DLD). We aimed to evaluate the safety of TBLC as compared to TBFB in DLD patients in Japan using a nationwide database. METHODS: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from April 1, 2020 to March 31, 2022. Eligible patients (n = 9673) were divided into the following two groups: those who underwent TBFB (TBFB group, n = 8742) and TBLC (TBLC group, n = 931). To compare the outcomes between the two groups, a stabilized inverse probability of treatment weighting (IPTW) was applied using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, complications (mechanical ventilation, pneumothorax, and bleeding), and length of hospital stay after bronchoscopy. RESULTS: The crude in-hospital mortality rates were 3.2% and 0.9% in the TBFB and TBLC groups, respectively. The stabilized IPTW analysis showed no significant difference in the in-hospital mortality rates between the two groups; the odds ratio of the TBLC group as compared with the TBFB group was 0.73 (95% confidence interval: 0.34-1.60; p = 0.44). Moreover, the secondary outcomes did not significantly differ between the two groups. CONCLUSIONS: TBLC for DLD patients had a similar mortality and complication rates as TBFB.

Improvement of the Ocular Prognosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A National Survey in Japan.

PURPOSE: To investigate the incidence and prognostic factors of ocular sequelae in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases arising between 2016 and 2018 in Japan, and compare the findings with those presented in the previous 2005-2007 survey. DESIGN: Retrospective, national trend survey. METHODS: Dermatologic case report forms (CRFs) (d-CRFs) were sent to 257 institutions that treated at least 1 SJS/TEN case, and 508 CRFs were collected from 160 institutions. Ophthalmologic CRFs (o-CRFs) regarding patient demographic data, onset date, ocular findings (first appearance, day of worst severity, and final follow-up), topical treatment (betamethasone), outcome (survival or death), and ocular sequelae (visual disturbance, eye dryness) were sent to the ophthalmologists in those 160 institutions. The results of this survey were then compared with that of the previous 2005-2007 survey. RESULTS: A total of 240 cases (SJS/TEN: 132/108) were included. The incidence of ocular sequelae incidence was 14.0%, a significant decrease from the 39.2% in the previous survey (SJS/TEN: 87/48). In 197 (82.1%) of the cases, systemic treatment was initiated within 3 days after admission, an increase compared to the previous survey (ie, treatment initiated in 82 [60.7%] of 135 cases). Of the 85 cases with an Acute Ocular Severity Score of 2 and 3, 62 (72.9%) received corticosteroid pulse therapy and 73 (85.9%) received 0.1% betamethasone therapy; an increase compared to the 60.0% and 70.8%, respectively, in the previous survey. Ocular-sequelae-associated risk factors included Acute Ocular Severity Score (P < .001) and specific year in the survey (P < .001). CONCLUSIONS: The ophthalmologic prognosis of SJS/TEN has dramatically improved via early diagnosis, rapid assessment of acute ocular severity, and early treatment.

Clinical Efficacy of Beta-1 Selective Beta-Blockers Versus Propranolol in Patients With Thyroid Storm: A Retrospective Cohort Study.

OBJECTIVES: Thyroid storm is the most severe manifestation of thyrotoxicosis. Beta-blockers are among the standard treatment regimens for this condition, with propranolol being the historically preferred option. However, 2016 guidelines issued by the Japan Thyroid Association and the Japan Endocrine Society recommend the use of beta-1 selective beta-blockers over nonselective beta-blockers, such as propranolol. Nevertheless, evidence supporting this recommendation is limited. Herein, we aimed to investigate the in-hospital mortality of patients with thyroid storms based on the choice of beta-blockers. DESIGN: Retrospective cohort study. SETTING: The Diagnosis Procedure Combination database, a national inpatient database in Japan. PATIENTS: Patients hospitalized with thyroid storm between April 2010 and March 2022. INTERVENTIONS: Propensity-score overlap weighting was performed to compare in-hospital mortality between patients who received beta-1 selective beta-blockers and those who received propranolol. Subgroup analysis was also conducted, considering the presence or absence of acute heart failure. MEASUREMENTS AND MAIN RESULTS: Among the 2462 eligible patients, 1452 received beta-1 selective beta-blockers and 1010 received propranolol. The crude in-hospital mortality rates were 9.3% for the beta-1 selective beta-blocker group and 6.2% for the propranolol group. After adjusting for baseline variables, the use of beta-1 selective beta-blockers was not associated with lower in-hospital mortality (6.3% vs. 7.4%; odds ratio, 0.85; 95% CI, 0.57-1.26). Furthermore, no significant difference in in-hospital mortality was observed in patients with acute heart failure. CONCLUSIONS: In patients with thyroid storm, the choice between beta-1 selective beta-blockers and propranolol did not affect in-hospital mortality, regardless of the presence of acute heart failure. Therefore, both beta-1 selective beta-blockers and propranolol can be regarded as viable treatment options for beta-blocker therapy in cases of thyroid storm, contingent upon the clinical context.

Potassium Iodide Use and Patient Outcomes for Thyroid Storm: An Observational Study.

PURPOSE: Iodine, combined with antithyroid drugs, is recommended as an initial pharmacologic treatment for thyroid storm according to some clinical guidelines. However, the clinical efficacy of iodine in managing thyroid storm remains unexplored. This study aimed to determine whether early potassium iodide (KI) use is associated with mortality in patients hospitalized for thyroid storm. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified patients hospitalized with thyroid storm between July 2010 and March 2022. We compared in-hospital mortality, length of stay, and total hospitalization costs between patients who received KI within two days of admission (KI group) versus those who did not (non-KI group). Prespecified subgroup analyses were performed based on the presence of the diagnosis of Graves' disease. RESULTS: Among 3,188 eligible patients, 2,350 received KI within two days of admission. The crude in-hospital mortality was 6.1% (143/2,350) in the KI group and 7.8% (65/838) in the non-KI group. After adjusting for potential confounders, KI use was not significantly associated with in-hospital mortality (odds ratio [OR] for KI use, 0.91; 95% confidence interval [CI], 0.62-1.34). In patients with the diagnosis of Graves' disease, in-hospital mortality was lower in the KI group than in the non-KI group (OR, 0.46; 95% CI, 0.25-0.88). No significant difference in in-hospital mortality was observed in patients without the diagnosis of Graves' disease (OR, 1.11; 95% CI, 0.67-1.85). Length of stay was shorter (subdistribution hazard ratio, 1.15; 95% CI, 1.05-1.27), and total hospitalization costs were lower (OR, 0.92; 95% CI, 0.85-1.00) in the KI group compared with the non-KI group. CONCLUSION: Our findings suggest that KI may reduce in-hospital mortality among patients hospitalized for thyroid storm with Graves' disease.

Berberine as a potential enhancer for 5-ALA-mediated fluorescence in glioblastoma: increasing detectability of infiltrating glioma stem cells to optimize 5-ALA-guided surgery.

OBJECTIVE: The prognosis of glioblastoma (GBM) correlates with residual tumor volume after surgery. In fluorescence-guided surgery, 5-aminolevulinic acid (ALA) has been used to maximize resection while avoiding neurological morbidity. However, not all tumor cells, particularly glioma stem cells (GSCs), display 5-ALA-mediated protoporphyrin IX (PpIX) fluorescence (5-ALA fluorescence). The authors searched for repositioned drugs that affect mitochondrial functions and energy metabolism, identifying berberine (BBR) as a potential enhancer of 5-ALA fluorescence. In this study, they investigated whether BBR can enhance 5-ALA fluorescence in GSCs and whether BBR can be applied to clinical practice as a 5-ALA fluorescence enhancer. METHODS: The effects of BBR on 5-ALA fluorescence in glioma and GSCs were evaluated by flow cytometry (fluorescence-activated cell sorting [FACS]) analysis. As 5-ALA is metabolized for heme synthesis, the effects of BBR on mRNA expressions of 7 enzymes in the heme-synthesis pathway were analyzed. Enzymes showing significantly higher expression than control in all cells were identified and protein analysis was performed. To examine clinical availability, the detectability and cytotoxicity of BBR in tumor-transplanted mice were analyzed. RESULTS: Fluorescence microscopy revealed much more intense 5-ALA fluorescence in both GSCs and non-stem cells with 5-ALA and BBR than with 5-ALA alone. FACS showed that BBR greatly enhanced 5-ALA fluorescence compared with 5-ALA alone, and enhancement was much higher for GSCs than for glioma cells. Among the 7 enzymes examined, BBR upregulated mRNA expressions of ALA synthetase 1 (ALAS1) more highly in all cells, and activated ALAS1 through deregulating ALAS1 activity inhibited by the negative feedback of heme. An in vivo study showed that 5-ALA fluorescence with 5-ALA and BBR was significantly stronger than with 5-ALA alone, and the sensitivity and specificity of BBR-enhanced fluorescence were both 100%. In addition, BBR did not show any cytotoxicity for normal brain tissue surrounding the tumor mass. CONCLUSIONS: BBR enhanced 5-ALA-mediated PpIX fluorescence by upregulating and activating ALAS1 through deregulation of negative feedback inhibition by heme. BBR is a clinically used drug with no side effects. BBR is expected to significantly augment fluorescence-guided surgery and photodynamic therapy.

The Proportion of Normalized Hips with Growth in Japanese Adolescents Aged > 10 years with Acetabular Dysplasia who Presented with Suspected Scoliosis.

Background: If asymptomatic acetabular dysplasia (AD) is incidentally identified in adolescence, it is difficult to determine the appropriate follow-up or treatment strategy because the acetabulum is still developing. We investigated the rate of AD normalization at the end of acetabular growth. Methods: This cross-sectional study involved 653 patients (1306 hips) aged 10-14 years with scoliosis or suspected scoliosis. All patients underwent plain standing whole-spine radiography (with the pelvis included) at the first visit. We measured the lateral center-edge angle, Sharp angle, Tönnis angle, and acetabular head index on radiographs. The criterion for AD was a lateral center-edge angle of < 20°. We extracted the data of patients aged < 12 (10-11) years and ≥ 12 (12-14) years with AD. Furthermore, we analyzed the radiographic follow-up data at 15 years of age to identify the AD normalization rate. Results: AD was diagnosed in 19 hips from patients aged < 12 years and in 36 hips from patients aged ≥ 12 years. The AD normalization rate at 15 years of age was 31.6% in those diagnosed at < 12 years of age and 5.6% in those diagnosed at ≥ 12 years of age. Conclusion: AD in adolescence was predictive of AD at the end of growth in 95% of cases diagnosed at ≥ 12 years of age compared with approximately 70% of cases diagnosed at < 12 years of age. Surgical treatment before completion of acetabular growth is beneficial for acetabular remodeling, but the decision to operate should be carefully evaluated in patients aged < 12 years. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-023-01065-4.

Proteinuria screening and risk of bone fracture: a retrospective cohort study using a nationwide population-based database.

Background and hypothesis: Proteinuria is associated with an increased risk of kidney function deterioration, cardiovascular disease, or cancer. Previous reports suggesting an association between kidney dysfunction and bone fracture may be confounded by concomitant proteinuria and were inconsistent regarding the association between proteinuria and bone fracture. Therefore, we aimed to evaluate the association using a large administrative claims database in Japan. Methods: Using the DeSC database, we retrospectively identified individuals with laboratory data including urine dipstick test between August 2014 and February 2021. We evaluated the association between proteinuria and vertebral or hip fracture using multivariable Cox regression analyses adjusted for various background factors including kidney function. We also performed subgroup analyses stratified by sex and kidney function and sensitivity analyses with Fine & Gray models considering death as a competing risk. Results: We identified 603 766 individuals and observed 21 195 fractures. With reference to the negative proteinuria group, the hazard ratio for hip or vertebral fracture was 1.10 [95% confidence interval (CI), 1.05-1.14] and 1.16 (95%CI, 1.11-1.22) in the trace and positive proteinuria group, respectively, in the Cox regression analysis. The subgroup analyses showed similar trends. The Fine & Gray model showed a subdistribution hazard ratio of 1.09 (95%CI, 1.05-1.14) in the trace proteinuria group and 1.15 (95% CI, 1.10-1.20) in the positive proteinuria group. Conclusions: Proteinuria was associated with an increased risk of developing hip or vertebral fractures after adjustment for kidney function. Our results highlight the clinical importance of checking proteinuria for predicting bone fractures.

The marine factor 3,5-dihydroxy-4-methoxybenzyl alcohol prevents TNF-α-mediated impairment of mineralization in mouse osteoblastic MC3T3-E1 cells: Impact of macrophage activation.

The phenolic antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), found in the Pacific oyster Crassostrea gigas, is a superior peroxyl radical scavenger compared to other materials, including Trolox. DHMBA may play an important role in the prevention of health disorders. This study elucidates whether DHMBA prevents the impairment of mineralization of mouse osteoblastic MC3T3-E1 cells under inflammatory conditions by using mouse macrophage RAW264.7 cells in vitro. Culturing with DHMBA (1-100 µM) did not affect the proliferation and death of MC3T3-E1 cells. DHMBA stimulated osteoblastic mineralization. DHMBA blocked the decrease in mineralization of MC3T3-E1 cells caused by culture with the inflammatory cytokine TNF-α. DHMBA inhibited the production of TNF-α by stimulation with lipopolysaccharide (LPS) in RAW264.7 cells. The growth of MC3T3-E1 cells was suppressed by coculture with macrophages under LPS stimulation through the crosstalk of both cells. Interestingly, the growth of MC3T3-E1 cells was suppressed by culturing with the conditioned medium obtained by culturing macrophages with LPS. The effect of the conditioned medium was blocked by the presence of DHMBA or Bay 11-7082, an inhibitor of the TNF-α pathway. The blocking effect of DHMBA was not further enhanced in the presence of Bay 11-7082. Mechanistically, DHMBA was found to decrease the levels of NF-κB p65 and the activity of NF-κB reporter expression in MC3T3-E1 cells. DHMBA was shown to prevent the impairment of osteoblastic mineralization via TNF-α signaling involved in macrophage activation in the bone marrow microenvironment. This study may provide a novel strategy for the therapy of osteoblastic impairment.

Cilostazol versus Aspirin or Clopidogrel for Reducing Post-Stroke Aspiration Pneumonia: A Nationwide Retrospective Cohort Study.

INTRODUCTION: The association between the use of cilostazol as a post-stroke antiplatelet medication and a reduction in post-stroke pneumonia has been suggested. However, whether cilostazol has a greater preventive effect against post-stroke aspiration pneumonia (AP) than other antiplatelet medications remains unclear. Thus, this study aimed to evaluate whether cilostazol has a greater preventive effect against post-stroke AP than aspirin or clopidogrel. METHODS: Through the Japanese Diagnosis Procedure Combination database, we identified patients who were hospitalized for ischemic stroke between April 2012 and September 2019. We performed 1:1 propensity score matching between patients who received cilostazol alone at discharge and those who received aspirin or clopidogrel alone at discharge. The primary outcome was the 90-day readmission for post-stroke AP. The occurrence of recurrent ischemic stroke within 90 days was also evaluated. RESULTS: Among the 305,543 eligible patients with ischemic stroke, 65,141 (21%), 104,157 (34%), and 136,245 (45%) received cilostazol, aspirin, and clopidogrel, respectively. Propensity score matching generated 65,125 pairs. The cilostazol group had a higher proportion of 90-day post-stroke readmissions with AP than the aspirin or clopidogrel groups (1.5% vs. 1.2%, p < 0.001). The proportion of patients with recurrent ischemic stroke within 90 days was also higher in the cilostazol group (2.4% vs. 2.2%, p = 0.017). CONCLUSION: The present study suggests that cilostazol may not have a greater effect on preventing post-stroke AP within 90 days than other antiplatelet medications. Nevertheless, further randomized controlled trials with longer follow-up periods are warranted.

Evaluation of skeletal muscle elasticity using color Doppler shear wave imaging.

PURPOSE: This study aimed to (1) assess the precision and reproducibility of color Doppler shear wave imaging (CD SWI) by comparing it with shear wave elastography (SWE) via elasticity phantom measurements, and (2) investigate the potential clinical applications of CD SWI in the upper limb muscles by assessing the reproducibility of skeletal muscle elasticity evaluations. METHODS: Four elastography phantoms of different stiffness (6.0-7.5 wt%) were used to assess the precision and reproducibility of CD SWI (compared with SWE) at depths. Typical upper limb muscles of 24 men were also assessed for this comparison. RESULTS: At superficial depths (0-2 cm), the phantom measurements obtained using CD SWI and SWE were similar at all levels of stiffness. Furthermore, both methods were highly reliable, with almost perfect intra- and inter-operator reliabilities. At greater depths (2-4 cm), measurements obtained using both methods were similar at all stiffness levels. Although standard deviations (SDs) of the phantom measurements obtained using both methods at lower stiffness were similar, those at higher stiffness were different. The SD of the CD SWI measurements was < 50% of that of the SWE measurements. However, both methods were highly reliable in the phantom test, with almost perfect intra- and inter-operator reliabilities. The intra- and inter-operator reliabilities of the shear wave velocity measurements for typical muscles of the upper limbs were also substantial in clinical settings. CONCLUSION: CD SWI is a valid method for measuring elasticity, with precision and reliability as high as those of SWE.

Therapeutic efficacy of the optimization of thyroid function, thrombophilia, immunity and uterine milieu (OPTIMUM) treatment strategy on pregnancy outcomes after single euploid blastocyst transfer in advanced age women with recurrent reproductive failure.

Purpose: To clarify the efficacy of the OPtimization of Thyroid function, Thrombophilia, IMmunity and Uterine Milieu (OPTIMUM) treatment strategy on pregnancy outcomes after euploid blastocyst transfer in advanced age women with recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL). Methods: Between January 2019 and May 2022, 193 consecutive women aged ≥40 years with RIF and/or RPL received single euploid blastocyst transfer. Before embryo transfer, 127 women underwent RIF/RPL testing. Chronic endometritis was treated with mainly antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. We compared pregnancy outcomes in the women who did and did not receive the OPTIMUM treatment strategy. Results: Women with RIF/RPL in the OPTIMUM group had significantly higher clinical pregnancy and livebirth rates than did those in the control group (clinical pregnancy rate of 71.7% and 45.5%, p < 0.001; livebirth rate of 64.6% and 39.4%, p = 0.001, respectively). However, preimplantation genetic testing for aneuploidy with and without OPTIMUM promoted low miscarriage rates with no significant difference between them (9.9%, and 13.3%, respectively; p = 0.73). Conclusions: The OPTIMUM treatment strategy improved clinical pregnancy rates after single euploid blastocyst transfer; but not miscarriage rates.

A large growing occipital meningocele with Dandy-Walker syndrome: A case report and review of the literature.

Background: Dandy-Walker syndrome (DWS) is a well-known developmental anomaly. An occipital meningocele (OMC) is recognized as a malformation that is relatively often associated with DWS, but the association of DWS with OMC has been reported in approximately 40 cases. We present herein a rare clinical course of DWS with OMC, in which the sac was small at birth and became progressively larger. Case Description: A 5-day-old baby boy was referred to our hospital due to OMC. He was born at 33 gestational weeks due to premature rupture of the membranes. He was diagnosed as having DWS associated with OMC. The OMC was covered with skin and its maximum diameter at birth was 3 cm. Magnetic resonance imaging showed an occipital bone defect and continuity of the fourth ventricle, posterior fossa cyst, and OMC sac. The aqueduct was patent, and no hydrocephalus was found. The OMC sac increased progressively with moderate hydrocephalus and reached 7 cm at the age of 54 days when his weight was 2508 g. A cystoperitoneal shunt and repair were performed after sinus venography by contrast computed tomography (CT). At the age of 1 year and 8 months, he had moderate developmental disabilities. Conclusion: In most cases reported, the OMC was relatively small, and large and giant sizes were reported in only six cases. Almost all cases remained the same size as at birth and underwent surgical intervention as early as possible. It was possible to understand the relationship between the occipital bone defect and abnormal running of sinuses such as the superior sagittal sinus, torcular Herophili, and transverse sinus preoperatively from the CT venography (CTV) image. CTV may be an effective and important method for safely performing repair and shunt.

Role of amide proton transfer imaging in maximizing tumor resection in malignant glioma: a possibility to take the place of 11C-methionine positron emission tomography.

BACKGROUND: Amide proton transfer (APT) imaging has been proposed as a technique to assess tumor metabolism. However, the relationship between APT imaging and other quantitative modalities including positron emission tomography (PET) has not been investigated in detail. This study aimed to evaluate the clinical usefulness of APT imaging in determining the metabolic status of malignant glioma and to compare findings with those from 11C-methionine (Met)-PET. METHODS: This research analyzed APT imaging data from 20 consecutive patients with malignant glioma treated between January 2022 and July 2023. Patients underwent tumor resection and correlations between tumor activity and intensity of APT signal were investigated. We also compared 11C-Met-PET and APT imaging for the same regions of the perifocal tumor invasion area. RESULTS: Clear, diagnostic APT images were obtained from all 20 cases. Mean APT intensity (APTmean) was significantly higher in the glioblastoma (GBM), IDH wild type group (27.2 ± 12.8%) than in other gliomas (6.0 ± 4.7%; p < 0.001). The cut-off APTmean to optimally distinguish between GBM and other malignant gliomas was 12.8%, offering 100% sensitivity and 83.3% specificity. These values for APTmean broadly matched the tumor-to-contralateral normal brain tissue ratio from 11C-Met-PET analysis (r = 0.66). The APT signal was also observed in the gadolinium non-contrast region on T1-weighted imaging, appearing to reflect the surrounding tumor-infiltrated area. CONCLUSIONS: APT imaging can be used to evaluate the area of tumor invasion, similar to 11C-Met-PET. APT imaging revealed low invasiveness in patients and was useful in preoperative planning for tumor resection, facilitating maximum tumor resection including the tumor invasive area.

Perioperative perampanel administration for early seizure prophylaxis in brain tumor patients.

Background: The efficacy of perioperative prophylactic antiepileptic drug therapy in "seizure-naïve" patients with brain tumor, including glioblastoma (GBM), remains controversial. This study investigated whether perampanel (PER) is effective and safe for preventing perioperative onset of epileptic seizures, so-called early seizure, in patients with brain tumors. Methods: Forty-five patients underwent tumor resection through craniotomy for a primary supratentorial brain tumor at Ehime University Hospital between April 2021 and July 2022. PER was administered from the 1st to the 6th day after surgery for seizure prophylaxis. Occurrence of early seizure, hematological toxicities, and various side effects were recorded on postoperative days 7 and 14. In addition, the clinical course of these patients was compared with 42 brain tumor patients under the same treatment protocol who received levetiracetam (LEV) for seizure prophylaxis between April 2017 and October 2018. Results: In 45 patients with brain tumor, including GBM, who received PER administration, no early seizures were identified within 7 days postoperatively. No adverse drug reactions such as hematological toxicity, liver or kidney dysfunction, or exanthematous drug eruption were observed in any cases. As side effects, somnolence was reported in 14 patients (31.1%), vertigo in 3 patients (6.7%), and headache in 3 patients (6.7%). Although somnolence and vertigo were difficult to assess in the case of intraparenchymal tumors, particularly GBM, these side effects were not identified in patients with extraparenchymal tumors such as meningiomas, epidermoid cysts, and pituitary adenomas. In addition, no significant differences were identified compared to patients who received LEV. Conclusion: The efficacy and safety of PER in preventing early seizures among patients with brain tumors were retrospectively evaluated. Perioperative administration of PER to patients with brain tumors may reduce the risk of early seizures without incurring serious side effects, showing no significant differences compared to patients who received LEV.

Identification of CD44 as a Reliable Biomarker for Glioblastoma Invasion: Based on Magnetic Resonance Imaging and Spectroscopic Analysis of 5-Aminolevulinic Acid Fluorescence.

Recurrent glioblastoma multiforme (GBM) is largely attributed to peritumoral infiltration of tumor cells. As higher CD44 expression in the tumor periphery correlates with higher risk of GBM invasion, the present study analyzed the relationship between CD44 expression and magnetic resonance imaging (MRI)-based invasiveness of GBM on a large scale. We also quantitatively evaluated GBM invasion using 5-aminolevulinic acid (5-ALA) spectroscopy to investigate the relationship between CD44 expression and tumor invasiveness as evaluated by intraoperative 5-ALA intensity. Based on MRI, GBM was classified as high-invasive type in 28 patients and low-invasive type in 22 patients. High-invasive type expressed CD44 at a significantly higher level than low-invasive type and was associated with worse survival. To quantitatively analyze GBM invasiveness, the relationship between tumor density in the peritumoral area and the spectroscopic intensity of 5-ALA was investigated. Spectroscopy showed that the 5-ALA intensity of infiltrating tumor cells correlated with tumor density as represented by the Ki-67 staining index. No significant correlation between CD44 and degree of 5-ALA-based invasiveness of GBM was found, but invasiveness of GBM as evaluated by 5-ALA matched the classification from MRI in all except one case, indicating that CD44 expression at the GBM periphery could provide a reliable biomarker for invasiveness in GBM.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Impact of meteorological and demographic factors on the influenza epidemic in Japan: a large observational database study.

Factors affecting the start date of the influenza epidemic season and total number of infected persons per 1,000,000 population in 47 prefectures of Japan were evaluated. This retrospective observational study (September 2014-August 2019; N = 472,740-883,804) evaluated data from a Japanese health insurance claims database. Single and multiple regression analyses evaluated the time to start of the epidemic or total infected persons per 1,000,000 population with time to absolute humidity (AH) or number of days with AH (≤ 5.5, ≤ 6.0, ≤ 6.5, and ≤ 7.0), total visitors (first epidemic month or per day), and total population. For the 2014/15, 2015/16, and 2016/17 seasons, a weak-to-moderate positive correlation (R2: 0.042-0.417) was observed between time to start of the epidemic and time to first day with AH below the cutoff values. Except in the 2016/17 season (R2: 0.089), a moderate correlation was reported between time to start of the epidemic and the total population (R2: 0.212-0.401). For all seasons, multiple regression analysis showed negative R2 for time to start of the epidemic and total visitors and population density (positive for time to AH ≤ 7.0). The earlier the climate becomes suitable for virus transmission and the higher the human mobility (more visitors and higher population density), the earlier the epidemic season tends to begin.

Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.