Forensic significance of intracardiac expressions of Nrf2 in acute myocardial ischemia.

When exposed to oxidative and electrophilic stress, a protective antioxidant response is initiated by nuclear factor erythroid 2-related factor 2 (Nrf2). However, the extent of its importance in the forensic diagnosis of acute ischemic heart diseases (AIHD), such as myocardial infarction (MI), remains uncertain. On the other hand, immunohistochemical analyses of fibronectin (FN) and the terminal complement complex (C5b-9) prove valuable in identifying myocardial ischemia that precedes necrosis during the postmortem diagnosis of sudden cardiac death (SCD). In this study, we investigated the immunohistochemical levels of Nrf2, FN, and C5b-9 in human cardiac samples to explore their forensic relevance for the identification of acute cardiac ischemia. Heart samples were obtained from 25 AIHD cases and 39 non-AIHD cases as controls. Nrf2 was localized in the nuclei of cardiomyocytes, while FN and C5b-9 were detected in the myocardial cytoplasm. The number of intranuclear Nrf2 positive signals in cardiomyocytes increased in AIHD cases compared to control cases. Additionally, the grading of positive portions of cardiac FN and C5b-9 in the myocardium was also significantly enhanced in AIHD, compared to controls. Collectively, these results indicate that the immunohistochemical investigation of Nrf2 combined with FN, and/or C5b-9 holds the potential for identifying early-stage myocardial ischemic lesions in cases of SCD.

A case of hemoperitoneum after percutaneous radiofrequency ablation in a patient with hepatocellular carcinoma.

We report a case of hemoperitoneum after percutaneous radiofrequency ablation in a patient with hepatocellular carcinoma. A 60-year-old female was hospitalized for the treatment of thrombasthenia and cirrhosis caused by chronic Hepatitis C, and computed tomography revealed hepatocellular carcinoma, which was treated by percutaneous radiofrequency ablation. After the ablation, hemoperitoneum was suspected because of the low hemoglobin level with abdominal pain. Approximately 6 h after the ablation treatment, the patient suddenly fell into a shock state and died. In this case, medical treatment-related death including malpractice was suspected, and forensic autopsy was performed. The abdominal cavity contained 910 mL of dark red fluid blood and 210 g of soft hemocoagula. Moreover, several puncture marks were observed on the liver surface and diaphragm, and there was no clear damage to the main arteries and veins. Considering the macroscopic and microscopic findings, the cause of death was assumed as hemorrhagic shock due to the hemoperitoneum caused by the damage to the liver by radiofrequency ablation. It is important to consider all the indications and adverse effects of radiofrequency ablation.

An autopsy case of fatal Japanese spotted fever in Wakayama.

Japanese spotted fever (JSF) is potentially fatal infection transmitted by tick bites which vectors Rickettsia (R.) japonica. Since JSF was first described in 1984, the incidence has gradually been increased. We experienced a case of JSF of fatal outcome. A female in 70's was found dead on her bed, whose house was so called 'hoarding house' filled with many waists and unused items. The following day, the autopsy was performed. As representative symptom of external findings, skin rashes were seen on the trunk and extremities, and there were tick-bite eschars on the left upper arm. Internal findings showed no specific findings in each organ. Histopathological examination demonstrated massive inflammatory cell infiltrates mainly consisted of neutrophils in the dermis beneath the external eschar. Furthermore, destruction of glomeruli in kidney with microhemorrhage from mesangial regions was observed. The numerous inflammatory infiltrates were also observed in pulmonary interstitium, which were accompanied with histopathologic features of vasculitis. Biochemical examination showed severe systemic inflammation as monitored by elevated CRP of 16 mg/dL and renal dysfunction by BUN of 171.2 mg/dL and creatinine of 6.07 mg/dL. Subsequently polymerase chain reaction revealed specifically amplified signals for R. japonica from the samples of tick-bites eschar and blood. Thus, we diagnosed her cause of death as JSF which had been occurred multiorgan failure such as acute renal failure and possibly acute respiratory failure. (224 terms).

Reverse Shock Index multiplied by Glasgow Coma Scale score as a point-of-care severity assessment for initial trauma management: A nationwide cohort study.

BACKGROUND: Severe trauma patients often require emergent interventions, such as massive transfusion, resuscitative procedures, and surgical procedures, and consume considerable human and medical resources. However, few practical indices can be easily used for emergent interventions. In recent years, it has become clear that rSIG (Reverse Shock Index multiplied by Glasgow Coma Scale [GCS] score), which can be easily calculated from vital signs, is a promising predictor of mortality. However, it is unclear whether rSIG is useful for emergent interventions. METHODS: Data collected by the Japan Trauma Data Bank for adult patients admitted directly from the scene of trauma between April 2019 and December 2020 were analysed. The outcomes were massive transfusion, resuscitative procedures, surgical procedures and emergent interventions. Emergent interventions were defined as the composite outcome of massive transfusion, resuscitative procedures, and surgical procedures. The ability of rSIG to predict massive transfusion was compared with that of the ABC score and FASILA score by receiver-operating characteristic curve analysis. The ability of rSIG to predict resuscitative and surgical procedures was compared with that of the Shock Index (SI), GCS, Triage Revised Trauma score (T-RTS), and Previous Simple Prediction (PSP) score. The ability of rSIG to predict emergent interventions was compared with that of T-RTS, PSP, ABC, and FASILA. In addition to rSIG, rSIM (Reverse Shock Index multiplied by best motor response score) was also analysed as a supplement. RESULTS: The study included 32,201 patients, 6,371 of whom required emergent interventions. The area under the receiver-operating characteristic curve (AUROC) for massive transfusion was highest for rSIG (0.846 [95 % confidence interval 0.832-0.859]) and significantly higher for rSIG than for rSIM, ABC and FASILA (all p < 0.0001). AUROCs for resuscitative and surgical procedures were highest for rSIG (0.777 [0.769-0.785] and 0.731 [0.720-0.741], respectively) and significantly higher than those for rSIM, SI, GCS, T-RTS, and PSP (all p < 0.0001). The AUROC for emergent interventions was highest for rSIG (0.760 [0.753-0.768]) and significantly higher for rSIG than for rSIM, T-RTS, PSP, ABC, or FASILA (all p < 0.0001). CONCLUSIONS: rSIG is a simple and effective point-of-care predictor of emergent interventions during initial management of trauma.

Relationship between intrathrombotic appearance of HSP27 and HSP70 and thrombus ages in a murine model of deep vein thrombosis.

Heat shock proteins (HSPs) are molecular chaperones whose primary function is cytoprotection, supporting cell survival under (sub) lethal conditions. They have been implicated in various diseases such as inflammatory diseases and cancer due to their cytoprotective and immunomodulatory effects, and their biological mechanisms have been studied. Central family members include, HSP27, which is induced by various stimuli such as heat shock, hypoxia, hyperoxia, ultraviolet exposure, and nutritional deficiency, and HSP70, which is homeostatically expressed in many organs such as the gastrointestinal tract and has anti-cell death and anti-inflammatory effects. In this study, HSP27 and HSP70 were investigated during thrombus formation and dissolution in a deep vein thrombosis model by immunohistochemistry to determine their involvement in this process and whether their expression could be used as a forensic marker. In the process of thrombus formation and lysis, HSP27 and HSP70 were found to be expressed by immunohistochemical analysis. The role of inhibitors of HSP27 and HSP70 in the pathogenesis of thrombosis in mice was also investigated. When HSP27 or HSP70 inhibitors were administered, thrombi were significantly smaller than in the control group on day 5 after inferior vena cava ligation, indicating pro-thrombotic effects HSP27 and HSP70. If HSP27- or HSP70-positive cells were clearly visible and easily identifiable in the thrombus sections, the thrombus was presumed to be more than 10 days old. Thus, the detection of intrathrombotic HSP27 and HSP70 could forensically provide useful information for the estimation of thrombus ages. Collectively, our study implied that both HSP27 and HSP70 might be molecular targets for thrombus therapy and that the detection of HSP-related molecules such as HSP27 and HSP70 could be useful for the determination of thrombus ages.

Metastability due to a branching-merging structure in a simple network of an exclusion process.

We investigate a simple network, which has a branching-merging structure, using the totally asymmetric simple exclusion process, considering conflicts at the merging point. For both periodic and open boundary conditions, the system exhibits metastability. Specifically, for open boundary conditions, we observe two types of metastability: hysteresis and a nonergodic phase. We analytically determine the tipping points, that is, the critical conditions under which a small disturbance can lead to the collapse of metastability. Our findings provide insights into metastability induced by branching-merging structures, which exist in all network systems in various fields.

Red-light-mediated Barton decarboxylation reaction and one-pot wavelength-selective transformations.

In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.

[A CASE OF SUSPECTED ALLERGIC BRONCHOPULMONARY MYCOSIS CAUSED BY SCEDOSPORIUM APIOSPERMUM THAT SHOWED CLINICAL IMPROVEMENT AFTER BRONCHOSCOPIC REMOVAL OF A MUCUS PLUG].

A 69-year-old woman presented with a persistent cough and high fever. Thoracic computed tomography revealed atelectasis and high-attenuation mucus. The blood test results showed eosinophils at 18.2%, an absolute eosinophil count of 980 cells/µL, and a total serum immunoglobulin E of 1980IU/mL. Bronchoscopy revealed a mucous plug, which upon photomicrograph examination, showed eosinophils. A culture study of the mucus yielded Scedosporium apiospermum, leading to the suspicion of allergic bronchopulmonary mycosis (ABPM) caused by the fungus. After the bronchoscopic removal of the mucous plug, her symptoms quickly diminished. She was successfully treated without medication, and ABPM has not recurred for 2 years. To our knowledge, ABPM caused by Scedosporium apiospermum is rare, and close follow-up was effective without the administration of systemic steroids or antifungal drugs.

The GGDEF protein Dgc2 suppresses both motility and biofilm formation in the filamentous cyanobacterium Leptolyngbya boryana.

Colony pattern formations of bacteria with motility manifest complicated morphological self-organization phenomena. Leptolyngbya boryana is a filamentous cyanobacterium, which has been used as a genetic model organism for studying metabolism including photosynthesis and nitrogen fixation. A widely used type strain [wild type (WT) in this article] of this species has not been reported to show any motile activity. However, we isolated a spontaneous mutant strain that shows active motility (gliding activity) to give rise to complicated colony patterns, including comet-like wandering clusters and disk-like rotating vortices on solid media. Whole-genome resequencing identified multiple mutations in the genome of the mutant strain. We confirmed that inactivation of the candidate gene dgc2 (LBDG_02920) in the WT background was sufficient to give rise to motility and morphologically complex colony patterns. This gene encodes a protein containing the GGDEF motif which is conserved at the catalytic domain of diguanylate cyclase (DGC). Although DGC has been reported to be involved in biofilm formation, the dgc2 mutant significantly facilitated biofilm formation, suggesting a role for the dgc2 gene in suppressing both gliding motility and biofilm formation. Thus, Leptolyngbya is expected to be an excellent genetic model for studying dynamic colony pattern formation and to provide novel insights into the role of DGC family genes in biofilm formation. IMPORTANCE Self-propelled bacteria often exhibit complex collective behaviors, such as formation of dense-moving clusters, which are exemplified by wandering comet-like and rotating disk-like colonies; however, the molecular details of how these structures are formed are scant. We found that a strain of the filamentous cyanobacterium Leptolyngbya deficient in the GGDEF protein gene dgc2 elicits motility and complex and dynamic colony pattern formation, including comet-like and disk-like clusters. Although c-di-GMP has been reported to activate biofilm formation in some bacterial species, disruption of dgc2 unexpectedly enhanced it, suggesting a novel role for this GGDEF protein for inhibiting both colony pattern formation and biofilm formation.

The Glasgow Prognostic Score Predicts Survival Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer.

INTRODUCTION: The Glasgow prognostic score (GPS) is an inflammation-related score based on C-reactive protein and albumin concentrations. Few studies have assessed the correlation between the GPS and the efficacy of chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Therefore, this study aimed to evaluate the utility of the GPS in predicting the survival outcomes of patients with ES-SCLC. METHODS: This retrospective study evaluated patients with ES-SCLC who had undergone chemotherapy between February 2008 and November 2021. GPS values were evaluated before the initiation of first-line chemotherapy. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The GPS values of the 113 patients were zero (54 patients, 48%), 1 (37 patients, 33%), and 2 (22 patients, 19%). The median follow-up duration was 10.7 months. Median PFS was 6.2, 5.6, and 3.8 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable PFS than the GPS 2 group (p < 0.001). Median OS was 17.1, 9.4, and 5.6 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable OS than the GPS 2 group (p = 0.001). Multivariate analysis confirmed that a GPS of 2 independently predicted unfavorable PFS (hazard ratio [HR], 2.89; 95% confidence interval [CI]: 1.68-4.88; p < 0.001) and OS (HR, 3.49 [95% CI: 1.83-6.63], p < 0.001). CONCLUSION: The study's findings suggest that the GPS can predict the survival outcomes of patients with ES-SCLC who have undergone chemotherapy. The GPS is an easy-to-calculate biomarker and would be ideal for routine use in clinical settings.

The Glasgow Prognostic Score Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations Who Are Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

INTRODUCTION: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. METHODS: We evaluated 340 patients with NSCLC harboring sensitive EGFR mutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (p = 0.03, p = 0.001, respectively) or 2 (p < 0.001, p < 0.001, respectively). Multivariate analysis identified poor performance status, stage 4 at diagnosis, type of EGFR-TKI (gefitinib/erlotinib vs. afatinib), and GPS = 2 as predictors of a short PFS. Meanwhile, poor performance status, gefitinib/erlotinib administration, and GPS = 2 were predictors of a short OS. CONCLUSION: The GPS predicted the survival of NSCLC patients harboring sensitive EGFR mutations who were undergoing EGFR-TKI treatment. The GPS might be ideal for routine use in clinical practice, given that it is an easily calculated parameter.

Visualization of Wall Teichoic Acid Decoration in Bacillus subtilis.

Teichoic acids are important for the maintenance of cell shape and growth in Gram-positive bacteria. Bacillus subtilis produces major and minor forms of wall teichoic acid (WTA) and lipoteichoic acid during vegetative growth. We found that newly synthesized WTA attachment to peptidoglycan occurs in a patch-like manner on the sidewall with the fluorescent labeling compound of the concanavalin A lectin. Similarly, WTA biosynthesis enzymes fused to the epitope tags were localized in similar patch-like patterns on the cylindrical part of the cell, and WTA transporter TagH was frequently colocalized with WTA polymerase TagF, WTA ligase TagT, and actin homolog MreB, respectively. Moreover, we found that the nascent cell wall patches, decorated with the newly glucosylated WTA, were colocalized with TagH and WTA ligase TagV. In the cylindrical part, the newly glucosylated WTA patchily inserted into the bottom of the cell wall layer and finally reached the outermost layer of the cell wall after approximately half an hour. Incorporation of newly glucosylated WTA was arrested with the addition of vancomycin but restored with the removal of the antibiotic. These results are consistent with the prevailing model that WTA precursors are attached to newly synthesized peptidoglycan. IMPORTANCE In Gram-positive bacteria, the cell wall is composed of mesh-like peptidoglycan and covalently linked wall teichoic acid (WTA). It is unclear where WTA decorates peptidoglycan to create a cell wall architecture. Here, we demonstrate that nascent WTA decoration occurred in a patch-like manner at the peptidoglycan synthesis sites on the cytoplasmic membrane. The incorporated cell wall with newly glucosylated WTA in the cell wall layer then reached the outermost layer of the cell wall after approximately half an hour. Incorporation of newly glucosylated WTA was arrested with the addition of vancomycin but restored with the removal of the antibiotic. These results are consistent with the prevailing model that WTA precursors are attached to newly synthesized peptidoglycan.

Application and limitation of a biological clock-based method for estimating time of death in forensic practices.

Estimating time of death is one of the most important problems in forensics. Here, we evaluated the applicability, limitations and reliability of the developed biological clock-based method. We analyzed the expression of the clock genes, BMAL1 and NR1D1, in 318 dead hearts with defined time of death by real-time RT-PCR. For estimating the time of death, we chose two parameters, the NR1D1/BMAL1 ratio and BMAL1/NR1D1 ratio for morning and evening deaths, respectively. The NR1D1/BMAL1 ratio was significantly higher in morning deaths and the BMAL1/NR1D1 ratio was significantly higher in evening deaths. Sex, age, postmortem interval, and most causes of death had no significant effect on the two parameters, except for infants and the elderly, and severe brain injury. Although our method may not work in all cases, our method is useful for forensic practice in that it complements classical methods that are strongly influenced by the environment in which the corpse is placed. However, this method should be applied with caution in infants, the elderly, and patients with severe brain injury.

Early Detection of Adverse Drug Reaction Signals by Association Rule Mining Using Large-Scale Administrative Claims Data.

INTRODUCTION: Adverse drug reactions (ADRs) are a leading cause of mortality worldwide and should be detected promptly to reduce health risks to patients. A data-mining approach using large-scale medical records might be a useful method for the early detection of ADRs. Many studies have analyzed medical records to detect ADRs; however, most of them have focused on a narrow range of ADRs, limiting their usefulness. OBJECTIVE: This study aimed to identify methods for the early detection of a wide range of ADR signals. METHODS: First, to evaluate the performance in signal detection of ADRs by data-mining, we attempted to create a gold standard based on clinical evidence. Second, association rule mining (ARM) was applied to patient symptoms and medications registered in claims data, followed by evaluating ADR signal detection performance. RESULTS: We created a new gold standard consisting of 92 positive and 88 negative controls. In the assessment of ARM using claims data, the areas under the receiver-operating characteristic curve and the precision-recall curve were 0.80 and 0.83, respectively. If the detection criteria were defined as lift > 1, conviction > 1, and p-value < 0.05, ARM could identify 156 signals, of which 90 were true positive controls (sensitivity: 0.98, specificity: 0.25). Evaluation of the capability of ARM with short periods of data revealed that ARM could detect a greater number of positive controls than the conventional analysis method. CONCLUSIONS: ARM of claims data may be effective in the early detection of a wide range of ADR signals.

Mechanism of Reductive Fluorination by PTFE-Decomposition Fluorocarbon Gases for WO3.

Reductive fluorination, which entails the substitution of O2- from oxide compounds with F- from fluoropolymers, is considered a practical approach for preparing transition-metal oxyfluorides. However, the current understanding of the fundamental reaction paths remains limited due to the analytical complexities posed by high-temperature reactions in glassware. Therefore, to expand this knowledgebase, this study investigates the reaction mechanisms behind the reductive fluorination of WO3 using polytetrafluoroethylene (PTFE) in an Ni reactor. Here, we explore varied reaction conditions (temperature, duration, and F/W ratio) to suppress the formation of carbon byproducts, minimize the dissipation of fluorine-containing tungsten (VI) compounds, and achieve a high fluorine content. The gas-solid reaction paths are analyzed using infrared spectroscopy, which revealed tetrafluoroethylene (C2F4), hexafluoropropene (C3F6), and iso-octafluoroisobutene (i-C4F8) to be the reactive components in the PTFE-decomposition gas during the reactions with WO3 at 500 °C. CO2 and CO are further identified as gaseous byproducts of the reaction evincing that the reaction is prompted by difluorocarbene (:CF2) formed after the cleavage of C═C bonds in i-C4F8, C3F6, and C2F4 upon contact with the WO3 surface. The solid-solid reaction path is established through a reaction between WO3 and WO3-xFx where solid-state diffusion of O2- and F- is discerned at 500 °C.

The Glasgow Prognostic Score Predicts Outcomes of Pembrolizumab or Atezolizumab Monotherapy in Patients with Pretreated Non-Small Cell Lung Cancer.

INTRODUCTION: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors. METHODS: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, body mass index (BMI), and each of progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI <20.4 kg/m2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, p = 0.002) and 2 (1.8 months, p = 0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, p = 0.002) and 2 (4.7 months, p = 0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1-2 (26.2% vs. 7.9%, p = 0.03). CONCLUSION: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy.

Promising Response to Dabrafenib Plus Trametinib in a Patient with Peritoneal Carcinomatosis from Non Small Lung Cancer Harboring BRAF V600E Mutation.

Background: The prognosis of peritoneal carcinomatosis in patients with lung cancer is poor. However, some cases of peritoneal carcinomatosis from lung cancer harboring specific gene alterations have responded to molecular targeted drugs. B-Raf proto-oncogene (BRAF) mutations occur in about 2-4% of NSCLCs, with about half of these cases having the BRAF V600E mutation. Concomitant inhibition of BRAF with dabrafenib and inhibition of the downstream mitogen-activated protein kinase with trametinib showed efficacy in NSCLC patients with the BRAF V600E mutation. Herein, we report a patient with peritoneal carcinomatosis from lung cancer with the BRAF V600E mutation who responded to dabrafenib plus trametinib. Case Presentation: A 67-year-old Japanese male never-smoker was diagnosed with stage IA3 lung adenocarcinoma. He underwent thoracoscopic left lower lobectomy but developed recurrence of the cancer with peritoneal carcinomatosis 33 months after the operation. An Oncomine Dx target test of the resected specimen was positive for the BRAF V600E mutation. He was started on dabrafenib 150 mg twice per day and trametinib 2 mg once per day. He had a good clinical response to dabrafenib/trametinib therapy with resolution of abdominal distention. He continued dabrafenib/trametinib treatment without disease progression for 7 months, with no severe adverse effects. Conclusion: This case highlights the importance of assessing genetic alterations in lung cancer patients with peritoneal carcinomatosis and treating them with appropriate molecular targeted drugs.

Gender stereotypes about intellectual ability in Japanese children.

Japan has a large gender gap; thus, this study examined whether Japanese 4- to 7-year-old children exhibit a "brilliance = males" stereotype and whether parental attitudes toward gender roles were related to children's stereotypes. We also explored whether the children exhibited such stereotypes in response to various stimuli. We showed children photos (Study 1) and stick figures (Study 2) of men, women, boys, and girls, asking them to attribute traits (smart or nice) to each. Study 1 revealed overwhelming in-group positivity in girls, whereas the results for boys were rather mixed. In Study 2, girls generally attributed nice to their own gender compared to boys. However, "brilliance = males" stereotypical responses were observed from 7 years of age, when boys began to be more likely to attribute smartness to their own gender compared to girls. The new data in Study 3 replicated results of Study 1 and parts of the results of Study 2. Moreover, merging the Study 3 data with that of Studies 1 and 2 confirmed their findings. Furthermore, it replicated the "brilliance = males" stereotype among 7-year-olds in the stick figure task. Parental attitudes toward gender roles were unrelated to children's gender stereotypes. The results indicated that Japanese children may acquire "brilliance = males" stereotypes later than American children (6-years-old). Furthermore, the results were clearer when children were presented with stick figure stimuli.

Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra.

Background: Pirfenidone (PFD) is widely used in patients with idiopathic pulmonary fibrosis (IPF) and its adverse effects, such as nausea and photosensitivity, are well known. Many patients with IPF have reduced doses or even cessation of PFD because of its side-effects. No solutions have been found for these side-effects because the current mechanistic insights are insufficient. Methods: Using the results of real-world data analysis from the US Food and Drug Administration Adverse Events Reporting System, we hypothesised that PFD-related symptoms may be similar to pellagra. Reverse translational experiments using female BALB/c mice were performed to validate and estimate this hypothesis. Niacin and its metabolite responses were compared between patients with IPF treated with PFD and those treated without PFD. Results: The pellagra hypothesis was translated from real-world data analysis. Pharmacological and comprehensive genetic investigations showed that PFD caused pellagra-related nausea and photosensitivity in a mouse model, which may have been mediated by the actions of nicotinamide N-methyltransferase (NNMT). Higher NNMT substrate responses were observed in urine from patients and mice with PFD than in those without PFD. Conclusions: PFD may cause pellagra or pellagra-like symptoms such as photosensitivity. Further studies are required to investigate whether niacin prevents pellagra-like symptoms caused by PFD in patients with IPF.