Multimodal Gated Mixture of Experts Using Whole Slide Image and Flow Cytometry for Multiple Instance Learning Classification of Lymphoma.

In this study, we present a deep-learning-based multimodal classification method for lymphoma diagnosis in digital pathology, which utilizes a whole slide image (WSI) as the primary image data and flow cytometry (FCM) data as auxiliary information. In pathological diagnosis of malignant lymphoma, FCM serves as valuable auxiliary information during the diagnosis process, offering useful insights into predicting the major class (superclass) of subtypes. By incorporating both images and FCM data into the classification process, we can develop a method that mimics the diagnostic process of pathologists, enhancing the explainability. In order to incorporate the hierarchical structure between superclasses and their subclasses, the proposed method utilizes a network structure that effectively combines the mixture of experts (MoE) and multiple instance learning (MIL) techniques, where MIL is widely recognized for its effectiveness in handling WSIs in digital pathology. The MoE network in the proposed method consists of a gating network for superclass classification and multiple expert networks for (sub)class classification, specialized for each superclass. To evaluate the effectiveness of our method, we conducted experiments involving a six-class classification task using 600 lymphoma cases. The proposed method achieved a classification accuracy of 72.3%, surpassing the 69.5% obtained through the straightforward combination of FCM and images, as well as the 70.2% achieved by the method using only images. Moreover, the combination of multiple weights in the MoE and MIL allows for the visualization of specific cellular and tumor regions, resulting in a highly explanatory model that cannot be attained with conventional methods. It is anticipated that by targeting a larger number of classes and increasing the number of expert networks, the proposed method could be effectively applied to the real problem of lymphoma diagnosis.

Are Online Simulations for Radiation Emergency Medical Preparedness Less Effective in Teaching Than Face-to-Face Simulations?

OBJECTIVE: The study clarified differences in understanding and satisfaction between face-to-face and online training on radiation emergency medical preparedness (REMP) training. METHODS: The training was held at Hirosaki University between 2018 and 2022, with 46 face-to-face participants and 25 online participants. RESULTS: Face-to-face training was significantly more understandable than online for the use of the Geiger counter (P < 0.05), but the educational effect of virtual reality (VR) was not significantly different from the actual practice. For the team exercise of taking care of the victims, online resulted in a significantly higher understanding (P < 0.05). CONCLUSIONS: Interactive exercises can be done online with equipment sent to learners, and VR is also as effective. The use of videos was more effective for first-timers to learn the practical process from a bird's-eye view, especially for team-based medical procedures.

SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma.

Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes and it is difficult to target these genes directly at a molecular level. We searched for the gene which showed synthetic lethal phenotype with LATS2, one of the MM causative genes and one of the kinases in the Hippo pathway. Here we showed that knockdown of SMG6 results in synthetic lethality in LATS2-inactivated cells. We found that this synthetic lethality required the nuclear translocation of YAP1 and TAZ. Both are downstream factors of the Hippo pathway. We also demonstrated that this synthetic lethality did not require SMG6 in nonsense-mediated mRNA decay (NMD) but in regulating telomerase reverse transcriptase (TERT) activity. In addition, the RNA-dependent DNA polymerase (RdDP) activity of TERT was required for this synthetic lethal phenotype. We confirmed the inhibitory effects of LATS2 and SMG6 on cell proliferation in vivo. The result suggests an interaction between the Hippo and TERT signaling pathways. We also propose that SMG6 and TERT are novel molecular target candidates for LATS2-inactivated cancers such as MM.

Development, implementation, and refinement of a comprehensive postcardiac arrest care training course in Japan.

Aim: In Japan, no training course is dedicated to postcardiac arrest care (PCAC), including venoarterial extracorporeal membrane oxygenation (VA-ECMO); thus, faculty members of the Japanese Circulation Society developed an original, comprehensive PCAC training course. This report reviews the development, implementation, and refinement of this PCAC training course. Methods: We examined the preserved data from the Japanese Circulation Society PCAC training courses between 2014 and 2020. Data related to the learning content and number of the attendees and instructors were collected and summarized. Results: Sixteen courses were held between August 2014 and February 2020, before the coronavirus disease 2019 (COVID-19) pandemic. A total of 677 health care providers participated: 351 doctors, 225 nurses, 62 perfusionists, five emergency medical professionals, and two pharmacists. Thirty-two attendees' data were missing. The core learning contents of all the courses included a standardized postcardiac arrest algorithm, targeted temperature management, VA-ECMO cannulation skills, and postcannulation management. Concerning curriculum evolution, extracorporeal cardiopulmonary resuscitation simulation, postarrest neurological examination and monitoring, and ultrasound-guided Seldinger technique training were added in the 4th, 5th, and 13th courses, respectively. Conclusion: The Japanese Circulation Society PCAC training course has been developed and refined to provide an organized, comprehensive opportunity for health care providers to acquire specific knowledge and skills in PCAC and VA-ECMO.

Wood-Splitter-Related Upper-Limb Injuries: A Single-Centered Case-Series Study.

(1) Background: Injuries to the upper limbs during wood splitting can affect social and economic life. We aimed to describe the clinical information concerning these injuries in Japan. (2) Methods: We identified patients from our patient database from April 2015-November 2021 and extracted data from their medical records, which includes age, gender, occupation, month, time and location of the injury, diagnosis, duration of hospitalization, ICU admission, treatment interventions including surgery, outcome, and medical costs. (3) Result: Seventeen cases were identified. Most of the patients were male (n = 15), with median age being 68 years old. Regarding the patients' backgrounds, six were apple farmers and three were unemployed. Injuries to the index finger was most common (n = 9), followed by injuries to the thumb in five cases (n = 5). Most of the incidents occurred at home or on the patient's farm estate. No injuries were due to incidents at work. (4) Conclusion: The wood splitter-related injuries required long-term treatment and frequently damaged the thumb, a functionally important digit. All the injuries were sustained during non-occupational use of a wood splitter. Therefore, we suggest that safety training should be provided to prevent traumatic injuries when these products are being sold.

Training of Medical Responders to Nuclear Disaster: Hybrid Program in the COVID-19 Pandemic.

OBJECTIVE: The spread of COVID-19 has made it difficult to provide training in medical treatment in a radiation disaster. In this study, we will examine the effects and challenges of using a hybrid approach that combines online and face-to-face components. METHODS: A total of 5 face-to face and 25 online medical staff participated in the training program. This program was conducted by using multiple cameras for live coverage, while protective clothing and decontamination kits had been sent in advance to the participants so that they could experience face-to-face and online learning at the same time. RESULTS: Participants reported a high level of satisfaction and achievement with the style of delivery. They also experienced problems such as fatigue due to long hours, and dissatisfaction with the debriefing. CONCLUSIONS: In designing new online training, it is necessary to consider the quantity and content of the program, and to take participant fatigue into consideration.

Japanese medical students' awareness of cardiopulmonary resuscitation in the context of the COVID-19 pandemic.

Aim: To evaluate Japanese medical students' awareness of newly recommended cardiopulmonary resuscitation (CPR) and airway management procedures in the context of the coronavirus disease (COVID-19) pandemic. Methods: An online survey was sent in December 2020 to all medical students at Hirosaki University in Japan. The survey included 15 questions and quizzes regarding prior experience of learning the new CPR guidelines in response to COVID-19, knowledge of conventional CPR, and COVID-19 context CPR and airway management procedures. Results: Of all medical students at the university, 457 (57.1%) responded to the survey. Among these, 22% reported that they were knowledgeable about CPR procedure in the COVID-19 pandemic setting. Prior knowledge of CPR in the context of COVID-19 was a significant positive predictor of quiz score regarding the CPR procedure (ß = 0.60, P < 0.01) and the airway management procedure (ß = 0.34, P = 0.02) in the context of the COVID-19 pandemic. Conclusions: Medical students with experience learning the new COVID-19 context CPR guidelines had sufficient knowledge of CPR and advanced airway management procedures in the setting of the COVID-19 pandemic. Implementation of a formal medical education curriculum based on the newly recommended CPR and advanced life support guidelines is needed to improve medical students' awareness and skills of CPR and airway management in the context of the COVID-19 pandemic.

Radiation Emergency Medical Preparedness in Japan: A Survey of Nuclear Emergency Core Hospitals.

OBJECTIVE: Based on experiences following the Great East Japan Earthquake and nuclear power plant accident in 2011, Nuclear Emergency Core Hospitals (NECHs) were designated as centers for radiation disaster management in Japan. This study aimed to investigate their current status and identify areas for improvement. METHODS: This cross-sectional study was conducted in October 2018. Demographic data were collected by a questionnaire with free text responses about attitudes toward NECHs. Considerations regarding risk communications during a radiation disaster were analyzed using qualitative text mining analysis. RESULTS: A total of 36 hospitals participated in this study. Only 31% of NECHs anticipated a radiation disaster. The importance of business continuity plans and risk communications was shown. Text analysis identified 7 important categories for health care workers during a radiation disaster, including media response, communications to hospital staff, risk communications, radiation effects on children, planning for a radiation disaster in the region, rumors, and the role in the region. CONCLUSION: The radiation disaster medical system and NECHs in Japan were surveyed. The importance of risk communications, planning for a radiation disaster in each region, and the role in the region are identified as issues that need to be addressed.

Impact of air temperature on occurrence of bath-related cardiac arrest.

ABSTRACT: The mortality of the bath-related cardiac arrest (BRCA) is extremely high. While air temperature is reported to be associated with the BRCA occurrence, it is unclear whether daily minimum temperatures or the difference between maximum and minimum air temperatures influences BRCA occurrence the most.A retrospective cohort study of adult patients was conducted between January 2015 and February 2020 at Hirosaki University Hospital Emergency Department. The following data were collected: age, sex, day of cardiac arrest event, location of the event, initial cardiac rhythm, presence of return of spontaneous circulation, and overall mortality (status at 1 month after cardiac arrest event). Based on the day of the event and the location in which the event occurred, daily minimum and maximum temperatures were obtained from the Japan Meteorological Agency database.A total of 215 eligible cardiac arrest cases were identified, including 25 cases of BRCA. Comparing BRCA and non-BRCA, initial shockable cardiac rhythm (4.0% vs 44.7%), presence of return of spontaneous circulation (8.0% vs 34.7%), and overall mortality (96.0% vs 71.6%) differed significantly (P < .05 each). Daily minimum and maximum temperatures showed no significant relationships with BRCA or non-BRCA. Daily minimum temperature was a risk factor of BRCA occurrence after adjusting for age and temperature difference (risk ratio, 0.937; 95% confidence interval, 0.882-0.995).Daily minimum temperature represents a potential risk factor for BRCA occurrence.

Inspection of Perirectal Lymph Nodes by One-Step Nucleic Acid Amplification Predicts Lateral Lymph Node Metastasis in Advanced Rectal Cancer.

BACKGROUND: Lateral lymph node dissection (LLND) is performed for advanced rectal cancers in Japan; however, it can cause sexual and urinary dysfunction. The incidence of lateral LN metastasis is estimated at 7-13.9%; therefore, excessive rectal surgery with LLND should be avoided, especially for prophylactic purposes. To identify the patients who require LLND, we examined metastases in perirectal LNs by using a one-step nucleic acid amplification (OSNA) assay to predict lateral LN metastases. METHODS: Twenty-five patients who underwent surgery with bilateral LN dissection due to T3-T4 rectal cancers were prospectively included in this study. Twenty-two patients (88.0%) received preoperative chemotherapy. Among 1052 LNs from 25 patients (median 40 per case), 135 perirectal LNs (median 6 per patient) were divided into three pieces and analyzed by OSNA, reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen mRNA, and pathological examination after surgery. These results were compared with the pathological diagnosis of lateral LNs. RESULTS: Lateral LN metastases were present in 4 of 25 patients (16.0%). All of these patients were positive by OSNA for perirectal LN metastases. The OSNA assay had a sensitivity of 100%, specificity of 86%, positive predictive value of 57%, and negative predictive value (NPV) of 100% for predicting lateral LN metastases. CONCLUSIONS: The findings from this prospective study suggest that the OSNA assay of perirectal LNs may be useful for determining when LLND is necessary because of its high NPV, even in patients treated with preoperative chemotherapy.

The clinical importance of a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids in gastric cancer with clinical serosal invasion: a prospective, multicenter study.

PURPOSE: We have developed a novel molecular method of diagnosis using the technique of transcriptase-reverse transcriptase concerted reaction (TRC) for the detection of cancer micrometastasis. This study prospectively examined the clinical importance of the TRC diagnosis with peritoneal lavage fluids collected from gastric cancer operations at multiple institutes. METHODS: TRC amplification targeting carcinoembryonic antigen mRNA was applied to detect gastric cancer cells in peritoneal lavage fluids obtained during gastric cancer resections from nine different hospitals. A total of 137 patients with a clinical diagnosis of serosa-invading neoplasms were enrolled to investigate the correlation between the TRC diagnosis and patient prognosis. RESULTS: Of the 137 patients, 27 (20%) were positive by cytologic examination. In contrast, TRC targeting carcinoembryonic antigen mRNA was positive in 59 of 137 (54%) patients. TRC positivity was associated with a poorer overall survival in all patients and in the 104 patients who underwent a curative operation. TRC positivity also was associated with the peritoneal recurrence-free survival rate in the 104 curative cases. Multivariate analysis showed that TRC positivity and the pathologic N factor were prognostic factors for the overall survival time. CONCLUSION: Our prospective multicenter study showed that the TRC test using peritoneal lavage fluids could be a potential prognostic factor to predict patient survival and peritoneal recurrence with clinically diagnosed, serosa-invading gastric cancer.

Establishment of chemiluminescence enzyme immunoassay for apolipoprotein B-48 and its clinical applications for evaluation of impaired chylomicron remnant metabolism.

BACKGROUND: Apolipoprotein B-48 (apoB-48) is a constituent of chylomicron remnants synthesized in the small intestines. The serum concentration of apoB-48 at fasting has been reported to be a marker of postprandial hyperlipidemia, a presumed risk factor for atherosclerosis. METHODS: We evaluated the basal performance of a recently developed chemiluminescent enzyme immunoassay (CLEIA). We also examined the correlations between serum apoB-48 concentrations and other lipid concentrations or life style patterns, including smoking and drinking. We analyzed the data of 273 clinical samples by multiple regression analysis to examine the influence of other serum lipid values, age, sex, smoking, drinking status and BMI on serum apoB-48 values. RESULTS: Within-run and between-run precision was obtained with 1.7-2.7% and 1.2-7.3%, respectively. The correlativity of enzyme-linked immunosorbent assay was correlation coefficient r=0.953, and regression y=1.02×-1.59. Serum apoB-48 concentrations were higher in males than in females, and were correlated with the status of smoking as well as with remnant-like particle-cholesterol (RLP-C) concentrations. Patients with the metabolic syndrome showed higher values of serum apoB-48 compared with control subjects. CONCLUSION: Serum apoB-48 measurement by CLEIA was satisfactory for clinical use to assess abnormalities in the chylomicron remnant metabolism.

A solution for distinguishing Le(a-b-) sera in CA19-9 assays using SphereLight 180 and Architect i2000 assays.

BACKGROUND: Measurement of carbohydrate antigen (CA) 19-9 is not applicable in patients with Lewis (Le) blood type, Le(a-b-). It is important to distinguish cases with Le(a-b-) before CA19-9 measurement. Therefore, we prepared a cut-off solution that gives a clear index to distinguish Le(a-b-) sera. METHOD: The frequencies of Le blood types and the distribution of the CA19-9 values in each Le blood type were examined in 188 healthy subjects. The CA19-9 values for all Le(a-b-) sera and for a portion of Le(a-b+) sera exist below the limit of quantitation as measured by the SphereLight 180 kit. The cut-off solution, which gives a clear cut-off index (COI), was prepared to differentiate Le(a-b-) from Le(a-b+), and was evaluated using the SphereLight 180, Architect i2000, UniCel DxI 800, Elecsys 2010, and Lumipuls ƒ kits. RESULTS: The COI was calculated as the mean +3 SD of the CA19-9 values of a cut-off solution that is adjusted to the limit of detection. Both the sensitivities and specificities of the COIs were 100% using the SphereLight 180 kit and 100% and 91.7%, respectively, using the Architect i2000 kit, but these values were not satisfactory using the other CA19-9 assay kits. CONCLUSION: The COIs, determined by the cut-off solution, correctly identified all Le(a-b-) sera as Le(a-b-) and differentiated Le(a-b-) sera from other types of sera in CA19-9 assays using only the SphereLight 180 and Architect i2000 kits.

REGIV as a potential biomarker for peritoneal dissemination in gastric adenocarcinoma.

BACKGROUND: This study examined the clinical significance of regenerating islet-derived family member 4 (REGIV) in surgically resected gastric tumors. The potential of REGIV as a biomarker in gastric cancer was also assessed including its predictive value for prognosis and recurrence after surgery. METHODS: Immunohistochemistry was performed to assess the clinical significance of REGIV expression status in surgically resected specimens. The quantitative genetic diagnostic method, transcription-reverse transcription concerted reaction (TRC) that targeted REGIV mRNA was applied for prediction of peritoneal recurrence in gastric cancer. RESULTS: Positive immunostaining for REGIV was observed in 85 cases (52.5%), and correlated significantly with diffuse type histopathology (P = 0.001), advanced T stage (P = 0.022), and frequent peritoneal recurrence (P = 0.009). Multivariate analysis identified advanced T stage (P < 0.001) and REGIV expression (P = 0.034) as independent prognostic factors for peritoneal recurrence-free survival. Overexpression of REGIV protein was evident in the majority of peritoneal tumors (93.8%). REGIV mRNA assessed by TRC could be a predictive marker for peritoneal recurrence after curative operation. CONCLUSIONS: REGIV overexpression is common in primary gastric tumors and a potentially suitable marker of diffuse type histopathology and peritoneal dissemination. Overexpression of REGIV mRNA, assessed by the TRC method, is a potentially suitable marker of peritoneal recurrence after curative resection.

Effects of pravastatin and rosuvastatin on the generation of adiponectin in the visceral adipose tissue in patients with coronary artery disease.

Pravastatin increases the plasma adiponectin level. We examined whether this is a statins' class effect or specific to pravastatin. Of 50 patients undergoing cardiac surgery for coronary artery disease (CAD, n = 36) and valvular heart disease (VHD, n = 14), 23 with CAD and serum LDL-cholesterol level >100 mg/dL were randomized to pravastatin at 10 mg/day (PRAVA, n = 12) or rosuvastatin at 2.5 mg/day (ROSUVA, n = 11) for 2 months, and the other 13 with CAD and LDL-cholesterol ≤100 mg/dL were not treated with statin (Non-statin, n = 13). Patients with VHD did not have CAD and were not treated with statin. Blood was sampled at baseline and surgery. Visceral (VIS) and subcutaneous (SC) adipose tissues were harvested during surgery. At baseline, the plasma adiponectin level was low in patients with CAD compared with that of patients with VHD. At surgery, adiponectin level in PRAVA was increased to the level in VHD, whereas those in ROSUVA and Non-statin were unchanged. VIS contents and gene expressions of adiponectin in PRAVA and VHD were similar to each other and were both higher than those in Non-statin and ROSUVA. SC content and gene expression of adiponectin were similar among 4 groups. Protein carbonyl (PC) level, an indicator of oxidative stress, in VIS was lower in PRAVA and VHD than in ROSUVA and Non-statin. There was a negative correlation between the plasma adiponectin and VIS PC levels (r = -0.41, P < 0.05). Thus, pravastatin increases adiponectin generation, whereas rosuvastatin does not.

Impact of telmisartan on coronary stenting in patients with acute myocardial infarction compared with enalapril.

OBJECTIVE: To determine whether telmisartan reduces in-stent restenosis (ISR) after coronary angioplasty using bare metal stent (BMS) in patients with acute myocardial infarction (AMI) compared with an angiotensin converting enzyme (ACE) inhibitor. BACKGROUND: The efficacy of inhibition of renin-angiotensin-aldosterone system in patients with AMI has been established, and the prescription of ACE inhibitor is recommended as class I indication for all AMI patients, whereas that of angiotensin II receptor blocker (ARB) as class IIa. Telmisartan is a unique ARB since it has a peroxisome proliferator-activated receptor (PPAR) gamma activating effect which is known to reduce neointimal tissue proliferation after coronary stenting. METHODS: In 64 patients, telmisartan (20-40 mg per day) was orally administered for 6 months after stenting (telmisartan group). The incidence of ISR after stenting in these patients was retrospectively compared with those in the other 60 patients administrated enalapril (2.5-5 mg per day) (enalapril group). RESULTS: There were no adverse events such as death, re-infarction and emergency bypass surgery in telmisartan group during a follow-up period for 6 months. The ISR rate was lower in telmisartan group (18.8%) than in enalapril group (33.3%) (p=0.06). However, percent diameter stenosis (%DS) at follow-up in telmisartan group was significantly smaller than in enalapril group (26.7+/-18.6% vs 38.0+/-23.9%, p=0.004). Late lumen loss was also significantly smaller in telmisartan group than in enalapril group (0.97+/-0.48 mm vs 1.19+/-0.68 mm, p=0.039). CONCLUSIONS: Telmisartan not only is tolerable in patients with AMI but has a potential to reduce neointimal tissue proliferation after AMI treated with coronary angioplasty using BMS compared with enalapril.

Decreased plasma and cardiac matrix metalloproteinase activities in patients with coronary artery disease and treated with pravastatin.

Matrix metalloproteinase (MMP), which is activated by oxidative stress, plays an important role in the development of ventricular remodeling in coronary artery disease. Pravastatin is shown to reduce oxidative stress. We tested the hypothesis that cardiac oxidative stress and MMP activity are reduced in patients with coronary artery disease and treated with pravastatin. Forty-eight patients who underwent coronary artery bypass graft surgery (CABG) were studied. Twenty-four patients had the serum low-density lipoprotein (LDL) cholesterol level >2.59 mM, and were treated with pravastatin (10 mg/day) for 2 months before CABG (pravastatin group). The other 24 had LDL cholesterol< or =2.59 mM, and were untreated (control group). The plasma and pericardial MMP-2 and MMP-9 activities were measured by gelatin zymography, and MMP-2 and MMP-9 levels, and pericardial 8-iso-prostagrandin F2alpha (8-iso-PGF2alpha) level, a maker of oxidative stress, by enzyme-linked immunosorbent assay. The plasma and pericardial MMP-2 and MMP-9 activities and levels were all lower by 20-30% in pravastatin than in control group (all P<0.05). The pericardial 8-iso-PGF2alpha level was lower in pravastatin than in control group (38+/-4 vs 64+/-7 pg/ml, P<0.05). The pericardial MMP-2 and MMP-9 activities were positively correlated with the pericardial 8-iso-PGF2alpha level (r=0.57 and 0.47, respectively, both P<0.01). Thus, cardiac oxidative stress and MMP activities are reduced in patients with coronary artery disease and treated with pravastatin, which may be beneficial in preventing and reducing ventricular remodeling.