MCAM+CD161- Th17 Subset Expressing CD83 Enhances Tc17 Response in Psoriasis.

Recent studies have highlighted the pathogenic roles of IL-17-producing CD8+ T cells (T-cytotoxic 17 [Tc17]) in psoriasis. However, the underlying mechanisms of Tc17 induction remain unclear. In this study, we focused on the pathogenic subsets of Th17 and their mechanism of promotion of Tc17 responses. We determined that the pathogenic Th17-enriched fraction expressed melanoma cell adhesion molecule (MCAM) and CCR6, but not CD161, because this subset produced IL-17A abundantly and the presence of these cells in the peripheral blood of patients has been correlated with the severity of psoriasis. Intriguingly, the serial analysis of gene expression revealed that CCR6+MCAM+CD161-CD4+ T cells displayed the gene profile for adaptive immune responses, including CD83, which is an activator for CD8+ T cells. Coculture assay with or without intercellular contact between CD4+ and CD8+ T cells showed that CCR6+MCAM+CD161-CD4+ T cells induced the proliferation of CD8+ T cells in a CD83-dependent manner. However, the production of IL-17A by CD8+ T cells required exogenous IL-17A, suggesting that intercellular contact via CD83 and the production of IL-17A from activated CD4+ T cells elicit Tc17 responses. Intriguingly, the CD83 expression was enhanced in the presence of IL-15, and CD83+ cells stimulated with IL-1ß, IL-23, IL-15, and IL-15Rα did not express FOXP3. Furthermore, CCR6+MCAM+CD161-CD4+ T cells expressing CD83 were increased in the peripheral blood of patients, and the CD83+ Th17-type cells accumulated in the lesional skin of psoriasis. In conclusion, pathogenic MCAM+CD161- Th17 cells may be involved in the Tc17 responses via IL-17A and CD83 in psoriasis.

Efficacy and Safety of Admilparant, an LPA1 Antagonist in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed. OBJECTIVES: Assess efficacy and safety of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with IPF and PPF. METHODS: This phase 2, randomized, double-blind, placebo-controlled trial included parallel cohorts of patients with IPF (n = 278 randomized, n = 276 treated) or PPF (n = 125 randomized, n = 123 treated) who received 30-mg admilparant, 60-mg admilparant, or placebo (1:1:1) twice daily for 26 weeks. Background antifibrotics (both cohorts) and immunosuppressants (PPF only) were permitted. MEASUREMENTS AND MAIN RESULTS: Rates of change in percentage of predicted forced vital capacity (ppFVC) over 26 weeks for IPF were -2.7% (placebo), -2.8% (30-mg), and -1.2% (60-mg) and for PPF were -4.3% (placebo), -2.9% (30-mg), and -1.1% (60-mg). Treatment differences between 60-mg admilparant and placebo were 1.4% (95% CI, -0.1 to 3.0) for IPF and 3.2% (95% CI, 0.7 to 5.7) for PPF. Treatment effect was observed with or without background antifibrotics in both cohorts. Diarrhea occurred at similar frequencies in admilparant arms versus placebo. Transient day 1 post-dose blood pressure reductions were observed in all arms in both cohorts but greater with admilparant. Treatment discontinuations due to adverse events were similar across IPF arms and lower with admilparant (2.5% [30-mg]; 0% [60-mg]) versus placebo (17.1%) for PPF. CONCLUSIONS: In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60-mg admilparant slowed lung function decline and was safe and well tolerated, supporting further evaluation in phase 3 trials. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT04308681.

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.

Recent progress of Stevens-Johnson syndrome/toxic epidermal necrolysis: Diagnosis criteria, pathogenesis and therapy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms.

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.

Usefulness of intraoperative rapid immunohistochemistry in the surgical treatment of brain tumors.

In the treatment of primary central nervous system lymphoma (PCNSL), intraoperative rapid pathological diagnosis can dramatically change the surgical strategy, and more accurate diagnostic methods are required. In April 2020, we adopted intraoperative rapid immunohistochemistry (IHC) in addition to conventional rapid intraoperative diagnosis based on morphological assessment, mainly for patients with PCNSL. Here, we investigate the usefulness and significance of intraoperative rapid IHC based on our initial experience. We performed intraoperative rapid IHC using antibodies for cluster of differentiation (CD)20, CD3, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) using enzyme-labeled antibody methods in 25 patients, including PCNSL patients, from April 2020 to July 2022. We examined the utility of this approach in determining treatment strategies for brain tumors. Postoperative final pathological diagnoses from paraffin-embedded sections were as follows: diffuse large B-cell lymphoma, 16 cases; glioblastoma, six cases; pilocytic astrocytoma, one case; adenocarcinoma, one case; and inflammatory disorder, one case. The entire process took 32 min and staining for CD20, CD3, LCA, and GFAP was comparable to that using paraffin-embedded sections. In all cases, the results of intraoperative rapid IHC were consistent with final pathological diagnoses from paraffin-embedded sections. In addition, in two cases, the results of conventional intraoperative rapid pathological diagnosis based on morphological assessments using frozen sections were drastically changed by adding intraoperative rapid IHC. Intraoperative rapid IHC contributes to deciding appropriate treatment strategies and facilitating early initiation of chemotherapy for PCNSL. This may allow new therapeutic strategies not only for PCNSL but also for other brain tumors.

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.

Standard radiographic values for the acetabulum in Japanese adolescents: a cross-sectional study.

BACKGROUND: Most previous reports of normal acetabular radiographic values focused on adults or elderly people. Recent reports have described premature hip osteoarthritis in adolescents not caused by acetabular dysplasia. In addition, there is a certain failure rate of surgical treatment for young patients with borderline acetabular dysplasia. Accurate indices for treatment of adolescent hips are unclear because standard measurement values of the adolescent acetabulum have not been reported. METHODS: This cross-sectional study involved 552 Japanese adolescents aged 12-18 years who had scoliosis or suspected scoliosis and asymptomatic hips. All persons underwent plain standing anteroposterior whole-spine radiography, and measurements were obtained using the pelvic part of the radiograph. We excluded persons who were unable to correctly perform measurements because of conditions such as pelvic rotation or lateral inclination and persons in whom closure of the triradiate cartilage or closure of the secondary ossification centers of the acetabulum had not yet occurred. In 1101 hips, we measured the lateral center-edge angle (LCEA), Tönnis angle, Sharp angle, acetabular head index (AHI), lateral subluxation (LS), vertical subluxation (VS), and peak-to-edge distance (PED). We evaluated the correlation coefficient and coefficient of determination between each parameter and age, height, body weight, and body mass index (BMI) and assessed the intra- and inter-rater reliability of each radiographic parameter. RESULTS: Among all hips, the mean of each parameter was as follows: LCEA, 27.9° ± 4.8°; Tönnis angle, 5.0° ± 3.7°; Sharp angle, 44.1° ± 3.1°; AHI, 82.1% ± 5.5%; LS, 5.4 ± 1.4 mm; VS, 0.3 ± 1.2 mm; and PED, 14.0 ± 2.3 mm. The correlation between each parameter and age, height, body weight, and BMI was considerably low. Intra- and inter-rater reliability was moderate or good for almost all parameters. CONCLUSIONS: The values for each radiographic parameter of the acetabulum in this study are considered standard for the adolescent acetabulum without age-related changes. Some parameters differ slightly from the normal values for adults or elderly people in previous reports; thus, we suggest careful evaluation of these parameters for adolescents.

Hyaluronan-enriched transfer medium (HETM) can improve the implantation rate in morphologically poor euploid blastocyst transfer.

PURPOSE: Hyaluronan-enriched transfer medium (HETM) could improve the clinical pregnancy rate (CPR) for patients with repeated implantation failures (RIF). In contrast, there have been seldom reports addressing the potentially beneficial effects of HETM for morphologically poor blastocysts (MPBLs). Our study aimed to evaluate whether the use of HETM would improve the CPR for the patients who were transferred with euploid MPBLs. METHODS: Patients who underwent single euploid blastocyst transfer between July 2020 and June 2022 were enrolled. We included only those blastocysts confirmed as euploid by PGT-A, and those blastocysts were transferred after thawing. The natural ovulatory cycle or hormone replacement cycle (HRC) protocol were used for endometrial preparation for frozen embryo transfer (FET). A total of 1,168 FET cycles were performed in the study period, including 954 cycles of morphologically good blastocysts (≥ 4BB in Gardner's classification), and 85 cycles of MPBLs, of which 47 were transferred using HETM in FET (the HETM group), and the remaining 38 were transferred with the medium without hyaluronan (the control group). We compared the CPR between these two groups. RESULTS: The characteristics of patients were similar between the HETM and control groups. The CPR in the HETM group was significantly higher than the control group (47.4% and 21.5%, respectively, p = 0.019). The multiple logistic regression analysis found that the use of HETM was a predictive factor of positive pregnancy outcomes (OR = 5.08, 95% CI = 1.62-16.0, p = 0.019). CONCLUSION: Our data suggests that HETM used in the euploid blastocyst transfer can improve the clinical pregnancy rates of morphologically poor blastocysts.

Radiation exposure in pediatric patients with early onset scoliosis: A longitudinal single-center study.

BACKGROUND: There is no consensus regarding the acceptable level of medical radiation exposure in patients with early-onset scoliosis. This study aimed to quantify radiation exposure in these patients and investigate factors associated with high exposure. METHODS: Patients with early-onset scoliosis who received care for their spine deformity and other comorbidities in our institution were retrospectively reviewed. Cumulative radiation exposure and total number of imaging studies were recorded. Patients with ≥30 mSv exposure were classified as high exposure and analyzed to clarify factors associated with high exposure. RESULTS: Thirty-five patients were included for analysis. The etiology of scoliosis was idiopathic in 8 patients, congenital in 7, syndromic in 8, and neuromuscular in 12. Fifteen patients underwent 19 spinal surgeries. The types of operation performed were definitive fusion (n = 12), vertebrectomy for hemivertebra (n = 2), growing rod (n = 1), lengthening (n = 3), and revision/partial implant removal (n = 1). The mean cumulative radiation dose was 22.3 mSv (range, 2.5-94.5 mSv). Spine radiography and computed tomography combined accounted for 15.0 mSv (range, 2.4-52.5 mSv, 67.3% of the mean cumulative dose). The mean radiation dose was significantly higher in patients who underwent spinal surgery than in those who did not (31.2 mSv vs. 15.6 mSv). The high-exposure group comprised 10 patients (1 idiopathic, 1 congenital, 5 syndromic, and 3 neuromuscular scoliosis) and 8 underwent 11 spinal operations. Among 8 patients who underwent spinal surgery, the cumulative radiation dose for spine was ≥30 mSv and spine computed tomography was performed an average of 4.0 times. CONCLUSIONS: Nearly one-third of patients with early-onset scoliosis and half of patients who underwent spinal surgery had >30 mSv radiation exposure due to multiple computed tomography. Medical radiation exposure and associated cancer risk should be considered when treating these patients.

A Pacific Oyster-Derived Antioxidant, DHMBA, Protects Renal Tubular HK-2 Cells against Oxidative Stress via Reduction of Mitochondrial ROS Production and Fragmentation.

The kidney contains numerous mitochondria in proximal tubular cells that provide energy for tubular secretion and reabsorption. Mitochondrial injury and consequent excessive reactive oxygen species (ROS) production can cause tubular damage and play a major role in the pathogenesis of kidney diseases, including diabetic nephropathy. Accordingly, bioactive compounds that protect the renal tubular mitochondria from ROS are desirable. Here, we aimed to report 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), isolated from the Pacific oyster (Crassostrea gigas) as a potentially useful compound. In human renal tubular HK-2 cells, DHMBA significantly mitigated the cytotoxicity induced by the ROS inducer L-buthionine-(S, R)-sulfoximine (BSO). DHMBA reduced the mitochondrial ROS production and subsequently regulated mitochondrial homeostasis, including mitochondrial biogenesis, fusion/fission balance, and mitophagy; DHMBA also enhanced mitochondrial respiration in BSO-treated cells. These findings highlight the potential of DHMBA to protect renal tubular mitochondrial function against oxidative stress.

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.

Comparison of Intra-Familial Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Oseltamivir Using an Influenza Transmission Model and a Health Insurance Claims Database.

BACKGROUND: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. METHODS: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018-19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. RESULTS: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th-97.5th percentiles, 1.68-1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. CONCLUSIONS: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

The marine factor 3,5-dihydroxy-4-methoxybenzyl alcohol suppresses growth, migration and invasion and stimulates death of metastatic human prostate cancer cells: targeting diverse signaling processes.

Prostate cancer is metastatic cancer and is the second leading cause of cancer-related death in men. It is needed to develop more effective treatment for metastatic prostate cancer. The present study investigates whether the novel factor 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), which was isolated from marine oyster, suppresses the activity of metastatic human prostate cancer PC-3 or DU-145 cells. Culture of DHMBA (1 or 10 µM) suppressed colony formation and growth of PC-3 or DU-145 cells in vitro. Suppressive effects of DHMBA on cell proliferation were not occurred by culturing with intracellular signaling inhibitors. Mechanistically, DHMBA (10 µM) reduced the levels of key proteins linked to promotion of cell growth, including Ras, PI3K, Akt, MAPK, and mTOR in PC-3 cells. Interestingly, DHMBA increased the levels of cancer suppressor p53, p21, Rb, and regucalcin. Moreover, culture of DHMBA simulated the death of PC-3 and DU-145 cells. This effect was implicated to caspase-3 activation in cells. Interestingly, the effects of DHMBA on cell proliferation and death were blocked by culturing with an inhibitor of aryl hydrocarbon receptor linked to transcriptional regulation. Furthermore, culture of DHMBA inhibited production of reactive oxygen species in PC-3 or DU-145 cells. Of note, DHMBA blocked migration and invasion by diminishing their related protein levels, including NF-κB 65, caveolin-1 and integrin ß1. The novel marine factor DHMBA was demonstrated to suppress metastatic prostate cancer cells via targeting diverse signaling pathways. This study may provide a new strategy for prostate cancer therapy with DHMBA.

Quantitative measurement of peritumoral concentrations of glutamate, N-acetyl aspartate, and lactate on magnetic resonance spectroscopy predicts glioblastoma-related refractory epilepsy.

BACKGROUND: Increased extracellular glutamate is known to cause epileptic seizures in patients with glioblastoma (GBM). However, predicting whether the seizure will be refractory is difficult. The present study investigated whether evaluation of the levels of various metabolites, including glutamate, can predict the occurrence of refractory seizure in GBM by quantitative measurement of metabolite concentrations on magnetic resonance spectroscopy (MRS). METHODS: Forty patients were treated according to the same treatment protocol for primary GBM at Ehime University Hospital between April 2017 and July 2021. Of these patients, 23 underwent MRS to determine concentrations of metabolites, including glutamate, N-acetylaspartate, creatine, and lactate, in the tumor periphery by applying LC-Model. The concentration of each metabolite was expressed as a ratio to creatine concentration. Patients were divided into three groups: Type A, patients with no seizures; Type B, patients with seizures that disappeared after treatment; and Type C, patients with seizures that remained unrelieved or appeared after treatment (refractory seizures). Relationships between concentrations of metabolites and seizure types were investigated. RESULTS: In 23 GBMs, seizures were confirmed in 11 patients, including Type B in four and Type C in seven. Patients with epilepsy (Type B or C) showed significantly higher glutamate and N-acetylaspartate values than did non-epilepsy patients (Type A) (p < 0.05). No significant differences in glutamate or N-acetylaspartate levels were seen between Types B and C. Conversely, Type C showed significantly higher concentrations of lactate than did Type B (p = 0.001). Cutoff values of lactate-to-creatine, glutamate-to-creatine, and N-acetylaspartate-to-creatine ratios for refractory seizure were > 1.25, > 1.09, and > 0.88, respectively. CONCLUSIONS: Extracellular concentrations of glutamate, N-acetylaspartate, and lactate in the tumor periphery were significantly elevated in patients with GBM with refractory seizures. Measurement of these metabolites on MRS may predict refractory epilepsy in such patients and could be an indicator for continuing the use of antiepileptic drugs.

Therapeutic effects of an oral gonadotropin-releasing hormone receptor antagonist, relugolix, on preventing premature ovulation in mild ovarian stimulation for IVF.

PURPOSE: Can relugolix, a novel oral gonadotropin-releasing hormone receptor (GnRH) antagonist, function as an alternative ovulation inhibitor to GnRH antagonist injections? METHODS: This single-center, cross-sectional retrospective study compared premature ovulation rates and clinical outcomes in IVF treatment after mild ovarian stimulation with 40 mg of relugolix (relugolix group) or 0.25-mg injections of ganirelix acetate or cetrorelix acetate (injection group) between March 2019 and January 2020. Of 247 infertile women (256 IVF cycles) aged ≤42 years, 223 women (230 cycles) were evaluated. In the relugolix and injection groups, we compared 104 and 85 cycles after GnRH antagonist use before the LH surge (LH levels <10 mIU/ml) and 22 and 19 cycles during the LH surge (LH levels ≥10 mIU/ml), respectively. RESULTS: Before the LH surge, the ovulation rates in the two groups were very low (p = 0.838), however; during the LH surge, the cycles using relugolix had a high ovulation rate of 40.9% compared with no ovulation in the injection group (p = 0.002). There were no significant differences in embryo culture findings and pregnancy outcomes between the two groups. CONCLUSIONS: Although relugolix had a high ovulation suppressive effect, when the LH surge occurred, its effect was insufficient.

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. METHODS: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. RESULTS: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively. CONCLUSIONS: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. METHODS: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. RESULTS: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). CONCLUSIONS: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. CLINICAL TRIALS REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN000038159).

Ventricular tachycardia in patients undergoing 24-h Holter monitoring as preoperative evaluation for noncardiac surgery.

The incidence of ventricular tachycardia (VT) in preoperative evaluation for noncardiac surgery in general hospitals has not been established. The aim of this study was to determine the incidence of VT, characteristics of patients with VT, characteristics of VT, and significance of VT in patients undergoing 24-h Holter monitoring as preoperative evaluation for noncardiac surgery. In 601 patients, VT was detected in 46 patients (7.7%). In patients with VT, left ventricular ejection fraction (LVEF) was lower (62.6 ± 9.3% vs. 66.6 ± 8.9%, p = 0.003), and B-type natriuretic peptide (BNP) was higher compared with patients without VT (median, 52.5 pg/mL vs. 32.8 pg/mL, p = 0.02). The maximum number of consecutive beats of VT was more frequent in the patients with LVEF < 50% than in the patients with LVEF ≥ 50% (median, 11.5 beats vs. 3.0 beats, p = 0.01). Forty patients (87%) underwent scheduled surgery without major complications.

Met-PET uptake index for total tumor resection: identification of 11C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and 11C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness-type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.