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Background: Accidental hypothermia (AH) is a major cause of death in mountainous areas globally, and the second highest of mountaineering deaths in Japan, accounting for 37 % in Hokkaido. Managing AH is a significant challenge, particularly when adverse weather complicates the application of recommended rewarming and rapid transfer. To address this, the Hokkaido Police Organization (DOKEI) AH protocol was applied in Hokkaido's remote areas from 2011 to 2022, integrating high-temperature active external rewarming (HT-AER) with on-site sustained treatment., Methods: This study retrospectively analyzed the rescue reports and hospital records of hypothermia patients treated postprotocol, excluding patients with cold exposure, undetectable vital signs at rescue, and inadequate documentation. Protocol adherence and outcomes-hypothermia stage, cardiocirculatory collapse, survival, and neurological status-were assessed., Results: Among the 60 protocol-treated patients (19-74 years, 85 % male), 14 had stage 2 hypothermia, and 3 had stage 3 hypothermia. HT-AER was applied in 96.7 % of the patients. A total of 98.3 % of patients improved before handover without cardiac arrest (CA) or extracorporeal life support (ECLS). Comparatively, ten preprotocol patients (18-60 years, 70 % male) had two CAs, one fatal and six with no improvement., Conclusion: The DOKEI AH protocol demonstrates feasibility in managing stages 1-3 hypothermia, enhancing survival and neurological recovery, and can offer a vital option in challenging AH rescue scenarios., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human adenovirus (HAdV) infections present diverse clinical manifestations upon infecting individuals, with respiratory infections predominating in children. We surveyed pediatric hospitalizations due to respiratory HAdV infections across 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to March 2024, recording 473 admissions. While hospitalizations remained below five cases per week from July 2019 to September 2023, a notable surge occurred in late October 2023, with weekly admissions peaking at 15-20 cases from November to December. There were dramatic shifts in the age distribution of hospitalized patients: during 2019-2021, 1-year-old infants and children aged 3-6 years represented 51.4%-54.8% and 4.1%-13.3%, respectively; however, in 2023-2024, while 1-year-old infants represented 19.0%-20.1%, the proportion of children aged 3-6 years increased to 46.2%-50.0%. Understanding the emergence of significant outbreaks of respiratory HAdV infections and the substantial changes in the age distribution of hospitalized cases necessitates further investigation into the circulating types of HAdV in Hokkaido Prefecture and changes in children's neutralizing antibody titers against HAdV., (© 2024 Wiley Periodicals LLC.)

Background: Quick arterial cannulation is required in pediatric emergency situation, which require effective local anesthesia to avoid withdrawal movement. However, pediatric local anesthesia could be difficult because of withdrawal movement. Jet injectors, which are needleless and provide local anesthesia quickly, could be helpful for pediatric local anesthesia during arterial cannulation., Aims: This study aimed to examine whether new jet injector "INJEX50" could improve the success rate of local anesthesia for arterial cannulation in pediatric intensive care unit compared with the current standard of care, infiltration using a 26-gauge needle., Methods: This study was a randomized, double-blind, single-center study. Participants were infants and young children in the pediatric intensive care unit, who required an arterial line. Local anesthesia was performed with either a 26-gauge needle (group C) or INJEX50 (group I) before arterial cannulation. The primary outcome (success of local anesthesia) was the presence of withdrawal movement at the time of skin puncture for arterial cannulation. The secondary outcomes included rescue sedation during arterial cannulation. Data were analyzed using Fisher's exact test and the Mann-Whitney U-test, with values of p < .05 considered statistically significant., Results: Seventy patients were randomly assigned to groups C and I. The local anesthesia success rate in group I (30/35 [86%]) was significantly higher than that in group C (15/35 [43%], odds ratio, 8.00; 95% confidence interval, 2.51-25.5; p = .0005). In conclusion, INJEX50 could improve success rate of local anesthesia for arterial cannulation in pediatric intensive care unit compared with 26-gauge needle., (© 2024 John Wiley & Sons Ltd.)

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Tetsuo Takehara has received lecture fees and research grants from Chugai Pharmaceutical Co., Ltd, Eisai Co., Ltd. Takahiro Kodama has received lecture fees from Chugai Pharmaceutical Co., Ltd and AstraZeneca K.K. All other authors declare no conflicts of interest., (Copyright: © 2024 Kai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Following the coronavirus disease 2019 (COVID-19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID-19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and two patients had influenza A. However, in October to November 2022, there was a re-emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV-related hospitalizations dramatically increased to 317 patients, with the majority aged 3-6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre-COVID-19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks., (© 2023 Wiley Periodicals LLC.)

Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the "Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit" to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions., (© 2023. The Author(s).)

Intradialytic hypotension and arrhythmias are complications of hemodialysis. They are associated with decreased intravascular volume due to reduced ultrafiltration volume, cardiac function, and arterial tone. The vascular endothelial glycocalyx, which exists on the surface of healthy vascular endothelial cells and maintains vascular permeability, has been suggested to be impaired by hemodialysis. This single-center retrospective study evaluated the association between syndecan-1, an endothelial glycocalyx dysfunction marker, and complications of hemodialysis. We enrolled 92 patients who underwent outpatient hemodialysis at Gifu Seiryu Hospital from April to July 2022 (346 hemodialysis sessions). The median duration and time of hemodialysis were 40 months and 4.1 h, respectively. Median serum syndecan-1 levels were 67.7 ng/mL before and 98.3 ng/mL after hemodialysis. Hemodialysis complications were noted in 68 sessions, all of which were hypotension. No correlation between pre-hemodialysis syndecan-1 levels and the incidence of complications was observed. However, a positive correlation between the amount of change in syndecan-1 levels before and after hemodialysis and the incidence of hemodialysis complications was noted. Conversely, syndecan-1 levels did not correlate with brain or atrial natriuretic peptides, suggesting that impairment of the vascular endothelial glycocalyx may be a possible cause of intradialytic hypotension and may be useful in preventing intradialytic hypotension., (© 2023. Springer Nature Limited.)

Background: Many reports have reported a reduction in respiratory infectious diseases and infectious gastroenteritis immediately after the coronavirus disease 2019 (COVID-19) pandemic, but data continuing into 2022 are very limited. We sought to understand the current situation of various infectious diseases among children in Japan as of July 2022 to improve public health in the post-COVID-19 era., Methods: We collected data on children hospitalized with infectious diseases in 18 hospitals in Japan from July 2019 to June 2022., Results: In total, 3417 patients were hospitalized during the study period. Respiratory syncytial virus decreased drastically after COVID-19 spread in early 2020, and few patients were hospitalized for it from April 2020 to March 2021. However, an unexpected out-of-season re-emergence of respiratory syncytial virus was observed in August 2021 (50 patients per week), particularly prominent among older children 3-6 years old. A large epidemic of delayed norovirus gastroenteritis was observed in April 2021, suggesting that the nonpharmaceutical interventions for COVID-19 are less effective against norovirus. However, influenza, human metapneumovirus, Mycoplasma pneumoniae , and rotavirus gastroenteritis were rarely seen for more than 2 years., Conclusions: The incidence patterns of various infectious diseases in Japan have changed markedly since the beginning of the COVID-19 pandemic to the present. The epidemic pattern in the post-COVID-19 era is unpredictable and will require continued careful surveillance., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The main aim of the current trial was to explore our hypothesis that cooling head wraps lower the core temperature more effectively than ice packs on the head during forced-air warming after pediatric cardiac surgeries., Methods: This study was a single-center Randomized Controlled Trial. Participants were children with a weight ≤ 10 kg and hyperthermia during forced-air warming after cardiac surgeries. When the core temperature reached 37.5 °C, ice packs on the head (group C) or a cooling head wrap (group H) were used as cooling devices to decrease the core temperature. The primary outcome was the core temperature. The secondary outcomes were the foot surface temperature and heart rate. We measured all outcomes every 30 min for 240 min after the patient developed hyperthermia. We conducted two-way ANOVA as a pre-planned analysis and also the Bonferroni test as a post hoc analysis., Results: Twenty patients were randomly assigned to groups C and H. The series of core temperatures in group H were significantly lower than those in group C (p < 0.0001), and post hoc analysis showed that there was no significant difference in core temperatures at T0 between the two groups and statistically significant differences in all core temperatures at T30-240 between the two groups. There was no difference between the two groups' surface temperatures and heart rates., Conclusions: Compared to ice packs on the head, head cooling wraps more effectively suppress core temperature elevation during forced-air warming after pediatric cardiac surgery., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Introduction: Individuals with neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and specific learning disorders (SLD) have various types of sensory characteristics., Methods: This study investigated sensory issues in individuals with neurodevelopmental disorders using a web-based questionnaire for qualitative and quantitative analysis, categorized the contents of their three most distressful sensory issues, and evaluated their order of priority., Results: Auditory problems were reported as the most distressing sensory issue among the participants. In addition to auditory problems, individuals with ASD frequently reported more tactile problems, and individuals with SLD reported more visual problems. Among the individual sensory issues, in addition to aversion to sudden, strong, or specific stimuli, some participants reported confusions regarding multiple stimuli presenting concurrently. Additionally, the sensory issues related to foods (i.e., taste) was relatively more common in the minor group., Conclusion: These results suggest that the diversity of sensory issues experienced should be carefully considered when aiding persons with neurodevelopmental disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wada, Hayashi, Seino, Ishii, Nawa and Nishimaki.)

Aim: Alterations in microbial composition of gut microbiota due to antibiotics (ATB) may lead to resistance to immune checkpoint inhibitors (ICIs). This study aimed to assess the impact of ATB use on therapeutic response in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab., Methods: This study retrospectively analyzed 105 patients with HCC treated with atezolizumab plus bevacizumab as a primary systemic therapy from prospectively-registered, multicenter, cohorts. Nineteen patients who received prior ATB were included in the ATB (+) group; 86 patients who did not receive prior ATB were included in the ATB (-) group. The therapeutic outcomes were compared between the two groups., Results: Most of the patients' baseline characteristics were not significantly different between the two groups. The objective response rates according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (30.1% vs. 11.1%; p = 0.143) and modified RECIST (mRECIST) (44.6% vs. 27.8%; p = 0.190) were not significantly different between the ATB (-) and ATB (+) groups. The disease control rates were higher in the ATB (-) group than in the ATB (+) group according to RECIST v1.1 (74.7% vs. 44.4%; p = 0.012) and mRECIST (78.3% vs. 50.0%; p = 0.020). Prior ATB use was found to be independently associated with radiological progressive disease of the first therapeutic assessment. The median progression-free survival according to RECIST v1.1 (9.1 months vs. 3.0 months; p = 0.049) and mRECIST (9.1 months vs. 3.0 months; p = 0.036), and overall survival (not reached vs. 11.4 months; p = 0.015) were longer in the ATB (-) group than in the ATB (+) group., Conclusions: Prior ATB use was associated with reduced therapeutic responses in patients with HCC receiving atezolizumab plus bevacizumab., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Professor Tetsuo Takehara has received research grants and lecture fees from Chugai Pharmaceutical Co., Ltd. All other authors declare no conflict of interest., (Copyright: © 2023 Maesaka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A man in his 60s had end-stage alcoholic cirrhosis. About six months before his death, hepatic peribiliary cysts (HPBC) rapidly increased, and he developed jaundice and liver failure. The pathological autopsy performed after his death revealed that his intrahepatic bile duct was pressured due to multiple cysts caused by HPBC, which resulted in liver failure. Some cases of HPBC have been associated with alcoholic cirrhosis;however, no other cases of increased HPBC in a short period of time have been reported. Although identifying the cause of increased HPBC in a short time is difficult in this case, it may be have been caused by continuous alcohol drinking after the onset of HPBC. Most patients with HPBC have liver cirrhosis and obstructive jaundice that may promote liver failure as in this case. Therefore, patients with HPBC should not only be instructed for abstinence but also promptly consider effective treatments in the event of obstructive jaundice to prevent liver dysfunction.

An 89-year-old woman underwent examinations for leg edema. Blood tests indicated low nutrition and low pancreatic enzymes, and a stool examination indicated fatty stool. Computed tomography showed pleural effusion, ascites, and cystic lesions in the pancreatic head and mural nodules within the cysts. Pancreatic juice cytology revealed adenocarcinoma. The diagnosis was pancreatic exocrine insufficiency caused by intraductal papillary mucinous carcinoma. The patient did not wish to undergo surgery. Therefore, diuretics, component nutrients, and pancreatic exocrine replacement therapy using pancrelipase were initiated. After starting treatment, her leg edema, pleural effusion, and ascites disappeared, and her activities of daily living improved markedly.

An 80-year-old man underwent follow-up examinations after endoscopic submucosal dissection (ESD) for esophageal cancer. Computed tomography showed enlarged lymph nodes of the right recurrent nerve. The patient had esophageal stenosis due to repeated ESD for multiple esophageal tumors. The stenosis made the passage of an endoscopic ultrasound (EUS) scope through the esophagus difficult. Thus, an endobronchial ultrasound bronchoscope, which had a thinner diameter than that of the EUS scope, was used for transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration. This technique led to the diagnosis of mediastinal lymph node metastasis of esophageal cancer.

Background: Bifidobacterium breve is widely used as a probiotic in preterm infants and children with congenital surgical conditions, however, some cases of probiotics-induced bacteremia have been reported recently., Objectives: To examine the clinical and bacteriologic features of Bifidobacterium breve bacteremia caused by a probiotic (BBG-01) in term and preterm infants., Methods: We included 298 patients who were admitted to the neonatal intensive care unit of Miyagi Children's Hospital and were given BBG-01 as a probiotic within the period June 2014 to February 2019. We experienced six cases of B. breve bacteremia and assessed their features retrospectively., Results: The incidence rate of B. breve bacteremia in our hospital was 2% (6/298), higher than reported previously. The median age at onset, corrected age, and weight of the patients was 8 days (range: 5-27 days), 35 weeks (range: 26-39 weeks), and 1,940 g (range: 369-2734 g), respectively. The bacteremia triggers were gastrointestinal perforations in two cases, food protein-induced enterocolitis syndrome in two cases, adhesive ileus in one case, ileal volvulus in one case, and aspiration pneumonia following esophageal atresia repair in one case. B. breve was detected on blood cultures after a median of 5 days 13 hours (range: 4 days 18 hours-9 days 13 hours). No patient demonstrated serious symptoms, such as septic shock. All patients received antibiotics and recovered without any sequelae., Conclusions: Ileus and intestinal mucosal damage, such as enteritis, can cause B. breve bacteremia. The incidence of B. breve bacteremia may be higher than reported previously and detection via culture may require a longer time than typically needed for more common bacteria. It is associated with a good prognosis., Competing Interests: The authors declare no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The epidemic of coronavirus disease 2019 (COVID-19) rapidly spread worldwide, and the various infection control measures have a significant influence on the spread of many infectious diseases. However, there have been no multicenter studies on how the number of hospitalized children with various infectious diseases changed before and after the outbreak of COVID-19 in Japan., Methods: We conducted a multicenter, prospective survey for hospitalized pediatric patients in 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to February 2021. We defined July 2019 to February 2020 as pre-COVID-19, and July 2020 to February 2021 as post-COVID-19. We surveyed various infectious diseases by sex and age., Results: In total, 5300 patients were hospitalized during the study period. The number of patients decreased from 4266 in the pre-COVID-19 period to 701 (16.4%) post-COVID-19. Patients with influenza and RSV decreased from 308 to 795 pre-COVID-19 to zero and three (0.4%) post-COVID-19. However, patients with adenovirus (respiratory infection) only decreased to 60.9% (46-28) of pre-COVID levels. Patients with rotavirus, norovirus, and adenovirus gastroenteritis decreased markedly post-COVID-19 to 2.6% (38-1), 27.8% (97-27) and 13.5% (37-5). The number of patients with UTIs was similar across the two periods (109 and 90). KD patients decreased to 31.7% (161-51) post-COVID-19., Conclusions: We suggest that current infection control measures for COVID-19 such as wearing masks, washing hands, and disinfecting hands with alcohol are effective against various infectious diseases. However, these effects vary by disease., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Recent studies, using magnetic resonance imaging (MRI) to assess white matter injury in preterm brains, increasingly recognize punctate white matter lesions (PWML) as the primary lesion type. There are some papers showing the relationship between the size and number of PWML and the prognosis of infants. However, the histopathological features are still unknown. In this study, we experimentally induced periventricular leukomalacia (PVL) in a sheep fetus model, aiming to find whether MRI can visualize necrotic foci (small incipient lesions of PVL) as PWML. Three antenatal insults were employed to induce PVL in preterm fetuses at gestational day 101-117: (i) hypoxia under intrauterine inflammation, (ii) restriction of artificial placental blood flow, and (iii) restriction of artificial placental blood flow after exposure to intrauterine inflammation. MRI was performed 3-5 days after the insults, and standard histological studies of the PVL validated its findings. Of the 89 necrotic foci detected in histological samples from nine fetuses with PVL, 78 were visualized as PWML. Four of the lesions detected as abnormal findings on MRI could not be histologically detected as corresponding abnormal findings. The diagnostic sensitivity and positive predictive values of histologic focal necrosis visualized as PWML were 0.92 and 0.95, respectively. The four lesions were excluded from these analyses. These data suggest that MRI can visualize PVL necrotic foci as PWML 3-5 days after the injury induction. PWML can spontaneously become obscure with time after birth, so their accurate diagnosis in the acute phase can prevent overlooking mild PVL.

Background: Indium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown., Case Presentation: This is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years., Conclusions: It is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

Purpose: To identify associated factors of having at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases in health examinees, and to describe the characteristics of each subgroup classified by comorbidities., Subjects and Methods: This was an observational cross-sectional survey carried out in multiple regions of Japan. Subjects aged 40 years older, undergoing comprehensive health examination, were recruited. Airflow limitation was defined as having forced expiratory volume in 1 s/forced vital capacity lower than 70%. Associated factors of having at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases were examined by logistic regression analysis. Subgroup classification by comorbidity patterns was conducted by hierarchical cluster analysis., Results: In a total of 22,293 subjects, 1520 (6.8%) had at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases. With this objective variable, the following explanatory variables were significantly associated: older age, higher total score in the chronic obstructive pulmonary disease assessment test (CAT) and coexistence of lung cancer (common in ever-smokers and never-smokers), higher pack-years, lower body mass index, higher C-reactive protein, without coexistence of diabetes mellitus (specific in ever-smokers), male sex, coexistence of anxiety, and sleep disorder (specific in never-smokers). Among the 1520 subjects, 1512 subjects with smoking history data were classified by comorbidity patterns into subgroups of "no comorbidities," "mixed comorbidities," "inflammatory comorbidities," "overweight," "underweight," and "chronic kidney disease." "Inflammatory comorbidities" were specific in ever-smokers, and "underweight" was specific in never-smokers., Conclusion: Several factors were identified as associated factors of having at least one of airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases and they were different between ever-smokers and never-smokers. Different comorbidity patterns were observed by smoking history. These findings could provide information to assist the management of subjects with COPD or at risk for COPD in the general population., Competing Interests: GlaxoSmithKline (GSK) was the funding source and was involved in all stages of this study (WEUSKOP6290). GSK also funded all costs associated with the publishing of the present manuscript. HO, NH, TN, and TF received funding for this study from GSK. TK is an employee of GSK and owns stock of the company; receives pay for part-time lecture from Shiga University of Medical Science. TS is an employee of GSK. The authors report no other potential conflicts of interest for this work., (© 2020 Omori et al.)

Shrinkage-reducing agents have been developed to mitigate shrinkage and to control cracks in concrete. This study aims to evaluate the impact of a newly developed shrinkage-reducing agent (N-SRA) on concrete properties and to compare its properties with a conventional shrinkage-reducing agent (C-SRA). The hydration rate, compressive strength, splitting tensile strength, shrinkage, occurrence of cracking, and freezing and thawing were investigated. N-SRA showed higher surface tension than C-SRA and reduced shrinkage to the same degree as C-SRA with half the dosage of C-SRA. The addition of N-SRA or C-SRA did not influence the early compressive strength but slightly reduced splitting tensile strength at seven days. Concrete with N-SRA showed higher compressive strength at 28 days than those of concrete with C-SRA or without SRA. Furthermore, concrete with N-SRA extended the period for the occurrence of shrinkage cracking under restrained conditions. It was found that N-SRA provided excellent freezing and thawing resistance because of the formation of good air voids, while C-SRA demonstrated inefficient behaviour in such an environment.

Background and study aims  The best method for endoscopic placement of self-expandable metallic stents (SEMS) for distal malignant biliary obstruction (MBO) has not yet been determined. The aim of this study was to evaluate how SEMS placement above the papilla and without endoscopic sphincterotomy (EST) impacts the time to recurrent biliary obstruction (RBO) in patients with distal MBO. Patients and methods  We retrospectively reviewed data for 73 consecutive patients with unresectable distal MBO who underwent endoscopic SEMS placement for the first time at our institution between April 2014 and March 2016. We compared time to RBO of SEMS placement above the papilla (intraductal placement) with SEMS placement across the papilla (transpapillary placement). In the intraductal placement group, we also compared time to RBO of placement without EST with placement with EST. Results  Endoscopic SEMS placement was performed in 30 patients with intraductal placement and in 43 patients with transpapillary placement. The median time to RBO was significantly longer with intraductal placement (307 days) than with transpapillary placement (161 days) ( P  = 0.022). Complication rates did not differ between the two groups. In both univariate and multivariate analysis, intraductal placement was an independent factor contributing to prolonged time to RBO. In intraductal placement, time to RBO was significantly longer in SEMS placement without EST than with EST (363 days vs. 227 days, respectively; P  = 0.026). Conclusions  Intraductal SEMS placement, especially without EST for distal MBO contributed to longer time to RBO., Competing Interests: Competing interests The authors declare that they have no conflict of interest.

Purpose: The purpose of this study was to estimate the prevalence of subjects with chronic cough and phlegm and describe their characteristics including the presence or absence of airflow limitation among the general population in Japan., Subjects and Methods: This was an observational cross-sectional survey targeting multiple regions of Japan. Subjects aged 40 years or above who were undergoing comprehensive health examination were recruited. The existence of chronic cough and phlegm, airflow limitation, and treatment for respiratory diseases were examined. Chronic cough and phlegm were defined as having both symptoms for at least 3 months of the year and for at least 2 consecutive years, or as receiving any treatment for chronic bronchitis at the time of recruitment. Airflow limitation was defined as forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) less than 0.7., Results: In a total of 22,293 subjects, 380 subjects (1.7%) had chronic cough and phlegm. Among these 380 subjects, 21.8% received treatment for a respiratory disease, and 11.6% had airflow limitation. Compared to subjects without both chronic cough and phlegm but with airflow limitation, subjects with chronic cough and phlegm without airflow limitation were younger, more likely to be current smokers (39.6%), and had higher total scores on a chronic obstructive pulmonary disease (COPD) assessment test (CAT). Scores of CAT questions 1-4 (cough, phlegm, chest tightness, breathlessness, respectively) were higher in subjects with chronic cough and phlegm regardless of airflow limitation., Conclusion: This study demonstrated that subjects identified to have chronic cough and phlegm in comprehensive health examination settings were symptomatic, while most of them did not receive any treatment for respiratory diseases and did not have airflow limitation. Screening subjects for chronic cough and phlegm in a comprehensive health examination followed by a detailed examination of screened subjects could be an effective approach for better management of chronic cough and phlegm. Smoking cessation should be included in the management, in consideration that around 40% of subjects with chronic cough and phlegm were current smokers., Competing Interests: GlaxoSmithKline (GSK) was the funding source and was involved in all stages of this study (WEUSKOP6290). GSK also funded all costs associated with the publishing of the present manuscript. HO, NH, TN, and TF received funding for this study from GSK. TK is an employee of GSK and owns stock of the company. TK received pay for a part-time lecture from Shiga University of Medical Science. TS is an employee of GSK. The authors report no other conflicts of interest in this work., (© 2020 Omori et al.)

Aims: Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts., Methods and Results: Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5-methylcytosine (5-mC). We next investigated possible relations of the incidence of 5-mC-positive (%5-mC + ) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5-mC was detected in the cardiomyocytes and other cell types. The %5-mC + cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5-mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial non-cardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5-mC + cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end-diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = -0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)-that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted., Conclusions: The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib-regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.

We have developed a metallic micro-cavity array filter and an automated detection system for capturing circulating tumor cells (CTCs). In this single institutional pilot study, we assessed the ability of this device to detect CTCs in patients with lung cancer at each stage. Patients diagnosed with lung cancer, undergoing planned surgery for lung cancer, or suspected of having lung cancer were recruited (40 recruited and 2 excluded). Blood samples were obtained from the patients and 3 ml whole blood was applied to the device without any preparation. The captured cells were stained to differentiate the nucleus, and determine cytokeratin and CD45 expression. Subsequently, two operators blinded to clinical information counted the number of CTCs. Sample collection was performed at the time of recruitment, before treatment and ~3 months after initial blood collection. CTC counts at recruitment were 1.4±0.4, 1.8±1.2, 1.3±0.6 and 7.4±5.1 (mean ± SE) in clinical stages I, II, III and IV, respectively. No significant difference was observed among the stages. These data indicated the ability of this device to detect CTCs at early or non-metastatic stages of lung cancer. Further research on a larger scale is needed for a more accurate assessment of the device, and research on the utility of captured cells remains a future challenge., (Copyright © 2019, Spandidos Publications.)

Background/aim: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation., Patients and Methods: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people., Results: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment., Conclusion: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognostic factors and treatment strategies for hepatocellular carcinoma (HCC) patients with a large number of tumor nodules have not been fully elucidated. Clinical factors influencing prognosis were investigated in HCC patients with 30 or more tumor nodules., Methods: Forty-six HCC patients with 30 or more tumor nodules participated in this study. None of them had vascular invasion and extrahepatic metastasis. Kaplan-Meier curve and Cox proportional hazard model were used for analysis., Results: The median survival time of our patients was no more than 15 months, suggesting that patients with 30 or more tumor nodules may be regarded as a progressive subgroup showing poorer prognosis. In multivariate analysis, presence of between 30 and 59 tumor nodules (P = 0.002), male gender (P = 0.002), lower total bilirubin (total bilirubin < 1.0 mg/dL) (P = 0.011), transarterial chemoembolization (TACE) as an initial therapy (P = 0.027) and higher prothrombin time (P = 0.049) were significant independent factors for better overall survival. Among 39 patients who underwent TACE as an initial therapy, patients who received sorafenib therapy during follow-up showed better overall survival than those who did not (P = 0.026). Efficacy of sorafenib appeared to be more evident in patients who needed repeated transarterial treatment., Conclusions: In HCC patients with 30 or more tumor nodules, TACE as an initial therapy may be correlated with better prognosis. Sorafenib administration after the prior transarterial treatment may improve antitumor efficacy., Competing Interests: All authors declare no conflict of interest related to this article., (Copyright 2020, Abe et al.)

A 68-year-old woman with an 11-day history of sudden abdominal pain and severe watery diarrhea was transferred to our hospital due to an exacerbation of renal function despite hydration. After treatment for dehydration and acidemia was provided in our intensive care unit, patient's renal function improved. Contrast-enhanced abdominal computed tomography was finally performed, revealing a hypervascular pancreatic mass with multiple hepatic masses. This imaging finding along with her clinical symptoms indicated watery diarrhea hypokalemia achlorhydria (WDHA) syndrome caused by a pancreatic VIPoma. Somatostatin analog was administered immediately leading to the improvement of her diarrhea and her general condition. As a result, endoscopic ultrasonography-guided fine-needle aspiration could be performed. Consequently, she was diagnosed with a pancreatic neuroendocrine tumor. She then underwent surgical resection of the pancreatic tumor and liver metastasis. As revealed in the immunohistochemical analysis of the excised tumor tissue, VIP was highly expressed, resulting in the final diagnosis of pancreatic VIPoma. Therefore, the immediate use of a somatostatin analog is crucial for improving the patient's general condition and achieving a definitive diagnosis pathologically when a patient is suspected of having a pancreatic VIPoma.

Purpose: To detect early, curable lung cancer, screening using low-dose CT (CT screening) was initiated in Japan and Western countries around the early 1990s. Material and methods: In 2013, the National Lung Screening Trial (NLST) reported that annual CT screening for high-risk participants leads to a 16% reduction in lung cancer death. In Hitachi City, CT screening for citizens 50 years of age or older was started in 1998, and 30% of the citizens had received a CT examination at least once by 2006. Results: We reported excellent survival (5-year survival of 90%) of 210 patients with lung cancer detected by CT screening. Based on a time trend analysis, a significant reduction (24%) in lung cancer mortality was observed 4 to 8 years after the introduction of CT screening among Hitachi residents. CT images can detect numerous smoking-related factors represented by pulmonary emphysematous change (CT emphysema). If we can evaluate the risk of respiratory disease according to these images, the benefits of screening are expected to increase further. Conclusion: To establish the effectiveness of CT screening for the general population, an optimum screening schedule is desired based on the risk of individuals. In addition, long-term follow-up is necessary to evaluate the effects of radiation exposure.

Congenital central hypoventilation syndrome is a disorder of respiratory control caused by mutations in the paired-like homeobox 2B gene. Mutations in the paired-like homeobox 2B gene are also responsible for Hirschsprung's disease. Variant Hirschsprung's disease is a rarer disorder that does not meet the diagnostic criteria of Hirschsprung's disease, although severe functional bowel obstruction persists. We present a case of an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease. A male infant who was diagnosed to have fetal growth restriction and polyhydramnios was delivered by emergency cesarean section at 30 weeks and 3 days of gestational age due to non-reassuring fetal status. The birth weight was 979 g, and intensive care was started immediately following delivery. The patient exhibited refractory apnea and was diagnosed with congenital central hypoventilation syndrome by genetic testing of the paired-like homeobox 2B gene. The patient also exhibited refractory functional bowel obstruction and was diagnosed to have variant Hirschsprung's disease through pathological examination of his intestinal specimens. The patient grew slowly but surely with intensive care including mechanical ventilation and parenteral nutrition. However, the patient repeatedly suffered from sepsis and died of fungemia at 197 days of age. This is the first congenital central hypoventilation syndrome case that was accompanied with variant Hirschsprung's disease, and the paired-like homeobox 2B mutation detected in this case (NM&#95;003924.3: c.441G > C; p.(Gln147His)) is novel. This case suggests that the paired-like homeobox 2B mutation causes not only congenital central hypoventilation syndrome and Hirschsprung's disease, but also variant Hirschsprung's disease in humans. It also highlights the extreme difficulty in treating premature infants with severe and prolonged functional bowel obstruction., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background and Aim: Although previous studies compared the efficacy of infliximab (IFX) versus adalimumab (ADA) as the first-line biologics for Crohn's disease (CD), the difference in long-term prognosis based on which biologic was used first has scarcely been reported. In particular, the clinical courses after loss of response (LOR) of the first-line biologics are largely unknown., Methods: A multicenter, retrospective study was performed. Disease courses of biologic-naïve CD patients who were started on IFX or ADA treatment were evaluated, even after LOR of the initial biologics., Results: In total, 263 CD patients were eligible for analysis, 183 were treated with IFX first, and 80 were treated with ADA first. The median observation period was 64.2 months. The cumulative steroid-free remission rates and surgery-free rates did not differ significantly between the patients treated with IFX first and those treated with ADA first (log-rank test P = 0.42 and P = 0.74, respectively). In addition, no significant difference was observed in the rate of occurrence of events associated with ineffectiveness (modification of anti-tumor necrosis factor treatment including intensification, switch, discontinuation, or surgery) between the patient groups (log-rank test P = 0.62). The patients treated with IFX first were likely to discontinue the agent due to adverse events, whereas those treated with ADA first were likely to discontinue due to treatment failure or LOR., Conclusions: No significant difference was observed in the long-term prognosis between biologic-naïve patients with CD who were started treatment with IFX first and ADA first., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: To evaluate the effectiveness of lung cancer screening using low-dose computed tomography for the general population, we conducted a retrospective cohort study of screening for participants among Hitachi residents., Materials and Methods: Citizens aged 50-74 who underwent low-dose computed tomography screening at least once during 1998-2006 were defined as the computed tomography group, and those who underwent X-ray screening at least once during the same period, but did not receive low-dose computed tomography screening throughout the follow-up period, were defined as the XP group. We investigated the lung cancer incidence rate, mortality rate and all-cause mortality rate for both groups from the first lung cancer screening to the end of 2012., Results: In the computed tomography group (17 935 residents; 9790 males and 8145 females), 273 cases of lung cancer (1.5%), 72 cases of lung cancer death (0.4%), and 885 cases of all-cause death (4.9%) were observed. On the other hand, 164 cases (1.1%) of lung cancer, 80 cases (0.5%) of lung cancer death and 1188 cases (7.6%) of all-cause death were observed in the XP group (15 548 residents; 6526 males and 9022 females). The hazard ratios of the computed tomography group to the XP group adjusted for gender, age and smoking history were 1.23 for lung cancer incidence rate, 0.49 for lung cancer mortality rate and 0.57 for all-cause mortality rate. Non-smokers and light smokers (<30 pack-years) had a significantly lower lung cancer mortality (0.41 and 0.21, respectively)., Conclusion: low-dose computed tomography screening for a population including non-smokers and light smokers may be effective.

Background and Objective: Patients in critical care settings often require prolonged mechanical ventilation (MV) therapy and, occasionally, they cannot be weaned from MV. The authors evaluated the efficacy of acupuncture treatment for improving the respiratory status and promoting successful weaning from prolonged MV in patients at intensive care units (ICUs)., Design: Retrospective observational study., Setting: Gifu University Hospital, Gifu, Japan., Subjects: The authors included 16 tracheostomized patients receiving MV for >21 days at the ICU of Gifu University Hospital, who underwent acupuncture therapy for improving their respiratory status., Intervention: Acupuncture treatment was conducted in four sessions per week., Outcome Measures: The data of tidal volume (VT), respiratory rate (RR), heart rate (HR), oxygen saturation as measured by pulse oximetry (SpO 2 ), dynamic lung compliance (Cdyn), rapid shallow breath index (RSBI; RR/VT) values before and immediately after acupuncture were extracted from the medical records., Results: The median number of days on MV before acupuncture initiation was 31 days. VT and Cdyn were significantly increased immediately after acupuncture (all p < 0.001), whereas RR, HR, and RSBI were significantly decreased (all p < 0.05). Eleven patients were successfully weaned from MV after acupuncture initiation. In the weaning success group, VT and Cdyn were significantly increased (all p < 0.01), whereas RR, HR, and RSBI were significantly decreased (all p < 0.05) after acupuncture. Conversely, in the weaning failure group, these values were not changed significantly. The increase in Cdyn after acupuncture was larger in the weaning success group than in the weaning failure group (p < 0.05)., Conclusion: Acupuncture treatment might have beneficial effects on the respiratory status of ICU patients receiving MV and may help in weaning from prolonged MV. Further large prospective cohort studies are warranted.

Background: To determine whether response to transarterial chemoembolization (TACE) predicts survival and to identify pretreatment factors associated with TACE response and prognosis., Methods: Between April and September 2010, 50 patients underwent TACE for hepatocellular carcinoma. Response to TACE was assessed using post-treatment computed tomography (CT) and magnetic resonance imaging (MRI) scans and tumor marker levels and classified as Response Poor (P) and Non-poor (NP). Time zero was set to September 30, 2010, and survival rates were analyzed by landmarking. Cumulative survival rates were calculated using the Kaplan-Meier method and compared according to grades using the log-rank test; contributing factors to survival were analyzed using a Cox proportional hazards model. Pretreatment factors were analyzed for 109 TACE sessions performed until October 2017, using a multiple logistic regression model. Receiver operating characteristic (ROC) curves were generated to determine the best tumor number for predicting response P., Results: Response P patients showed significantly lower cumulative survival rates than Response NP patients (P < 0.001). On multivariate analysis, tumor number (hazard ratio (HR), 1.475), protein-induced vitamin-K absence-II (HR, 4.539), and the number of previous TACE sessions (HR, 1.472) were identified as pretreatment factors contributing to Response P. Further, pre-treatment platelet count (HR, 0.876) and tumor number (HR, 1.330) were factors contributing to survival in multivariate analysis. ROC curve analysis revealed that the optimal cut-off value to discriminate Response P was 7.5., Conclusions: Response to TACE can predict survival. Pretreatment tumor number is a useful factor for predicting both TACE response and prognosis., Competing Interests: We have no conflict of interest to declare.

Background/aim: To describe real clinical outcomes when using afatinib therapy to treat non-small cell lung cancer patients who have an acquired EGFR T790M mutation., Materials and Methods: A retrospective chart review was conducted from January 2013 to November 2017 sourced from 15 medical institutes that cover a population of three million people., Results: There were 74 patients who met the above-mentioned criteria. Treatment outcomes with afatinib, in patients with or without tyrosine kinase inhibitor (TKI) therapy prior to afatinib, were similar to previously reported clinical trials. Stratification of patients by the presence or absence of TKI pretreatment before afatinib, and the presence or absence of an acquired T790M mutation found no statistical difference in overall survival., Conclusion: This population-based study found that the disadvantages of pretreatment before afatinib, and absence of an acquired T790M EGFR mutation, could be overcome by an appropriate treatment strategy in clinical practice., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We describe a rare case of drug-induced hepatitis due to the smoking cessation agent varenicline in a 46-year-old Asian woman. The liver injury progressed in two steps. First, the liver injury started in the absence of viral/autoimmune responses, and withdrawal of varenicline lowered the increase in the levels of liver enzymes immediately. Such findings suggested varenicline-induced liver injury. Second, hepatitis recurred in association with conversion of antinuclear antibody from negative to positive about 8 weeks after the initial episode. Histology upon recurrence of liver injury revealed interface hepatitis with lymphocytic and lymphoplasmacytic portal inflammatory infiltrates extending into lobules. Such findings suggested autoimmune hepatitis. Corticosteroid treatment was effective for recurrent hepatitis. The clinical course suggests that varenicline caused drug-induced liver injury and subsequent autoimmune hepatitis. Some autoimmune changes were probably involved in the mechanism of varenicline-induced liver injury.

Aim: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting., Materials and Methods: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people., Results: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42.5%) patients had acquired T790M mutations in EGFR. Patients ≥75 years old and patients with an exon 19 deletion had higher rates of acquired T790M mutation than did younger patients and those with an exon 21 L858R mutation. In 75 patients treated with afatinib, 34 (45.3%) patients had acquired T790M mutation. The sensitivity of T790M mutation detection was lower in plasma specimens than in biopsy specimens., Conclusion: This population-based study confirms previous studies and highlights potential determinants of acquired T790M mutation to be considered in clinical practice., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV dilation and LV wall thinning in cardiac patients.Methods and Results:In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF ≥47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e', an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd ≥50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth ≥8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth ≥8 mm (P=0.020)., Conclusions: Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients.