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Purpose This study aims to establish a Japanese-style healthcare program customized for Japan and Asia under ISO 9001: 2008 (ISO: International Organization for Standardization) to improve problem areas and to inspect the effectiveness of the program. Furthermore, the authors wanted to create this health program using the ISO widely available in Asian countries and make an international contribution. Design/methodology/approach The authors implemented a 6- to 10-month health program in Minowa Town, Matsumoto City and Nagano City in Japan. This study assessed findings from pedometric, anthropometric and blood pressure measurements and physical fitness, blood chemistry and brain function tests. Findings The comparisons were made by examining the interaction effects between groups of participants. Groups from three regions in Japan showed significant differences on the physical fitness tests; regarding the 10-meter obstacle walk, the results of the Minowa participants showed the greatest improvement and the Matsumoto participants showed the second greatest improvement. In the six-min walk, the time of the Minowa participants significantly improved. Research limitations/implications This health education program, which has been conducted by the Japanese authors since 1998, measures anthropometry, brain function and physical fitness and performs blood tests before and after the program and it measures energy consumption with a pedometer during the program. With the aim of improving exercise via encouragement from friends and a sense of community with fellow participants, participants learn together with hands-on training in tai chi and aerobics about the importance of ongoing exercise and proper nutrition. This health education met the Health Education ISO in 2014. Practical implications Since 2010, Nagano Prefecture, including Minowa Town, Matsumoto City and Nagano City, where our study was carried out, has been the area with the highest life expectancy rates in Japan. Social implications The authors want to make this health promotion through ISO widely available in Asian countries and an international contribution. Originality/value This study aimed to appropriately establish a Japanese-style healthcare program under the ISO 9001:2008 to improve problem areas and inspect its effectiveness.

Schools play a central role in the transmission of many respiratory infections. Heterogeneous social contact patterns associated with the social structures of schools (i.e., classes/grades) are likely to influence the within-school transmission dynamics, but data-driven evidence on fine-scale transmission patterns between students has been limited. Using a mathematical model, we analyzed a large-scale dataset of seasonal influenza outbreaks in Matsumoto city, Japan, to infer social interactions within and between classes/grades from observed transmission patterns. While the relative contribution of within-class and within-grade transmissions to the reproduction number varied with the number of classes per grade, the overall within-school reproduction number, which determines the initial growth of cases and the risk of sustained transmission, was only minimally associated with class sizes and the number of classes per grade. This finding suggests that interventions that change the size and number of classes, e.g., splitting classes and staggered attendance, may have a limited effect on the control of school outbreaks. We also found that vaccination and mask-wearing of students were associated with reduced susceptibility (vaccination and mask-wearing) and infectiousness (mask-wearing), and hand washing was associated with increased susceptibility. Our results show how analysis of fine-grained transmission patterns between students can improve understanding of within-school disease dynamics and provide insights into the relative impact of different approaches to outbreak control., Proceedings of the National Academy of Sciences, 118(46), art. no. e2112605118; 2022

A local epidemiological survey of psoriasis was conducted from 19 February to 30 June 2016 in Matsumoto city, Nagano Prefecture, Japan. Patients were predominantly male (268 cases, 71.5% males vs 107 cases, 28.5% females). We estimated that the prevalence of psoriasis was 0.097% in the Matsumoto area. The clinical types of psoriasis identified were psoriasis vulgaris (90.7%), psoriatic arthritis (5.9%), pustular psoriasis (2.1%), guttate psoriasis (1.0%) and psoriatic erythroderma (0.3%). The topical therapeutic agents included corticosteroids (84.0%), vitamin D3 analogs (61.5%), and a combination of calcipotriol and betamethasone dipropionate (31.0%). Current systemic treatments included cyclosporin (9.0%), etretinate (7.4%) and methotrexate (1.3%). Biologic treatments included adalimumab (4.0%), ustekinumab (2.7%), infliximab (1.3%) and secukinumab (0.8%). Ultraviolet B therapy (11.3%) was the predominant phototherapy in which narrow band ultraviolet B therapy accounted for the majority, followed by psoralen and ultraviolet A therapy (1.0%). According to the recent evolution of psoriasis treatment, the use of biologics has been increasing. This study demonstrates the changes of treatment trends of psoriasis in a non-metropolitan regional area.

Households are important settings for the transmission of seasonal influenza. Previous studies found that the per-person risk of within-household transmission decreases with household size. However, more detailed heterogeneities driven by household composition and contact patterns have not been studied. We employed a mathematical model that accounts for infections both from outside and within the household. The model was applied to citywide primary school seasonal influenza surveillance and household surveys from 10,486 students during the 2014/15 season in Matsumoto city, Japan. We compared a range of models to estimate the structure of household transmission and found that familial relationship and household composition strongly influenced the transmission patterns of seasonal influenza in households. Children had a substantially high risk of infection from outside the household (up to 20%) compared with adults (1–3%). Intense transmission was observed within-generation (between children/parents/grandparents) and also between mother and child, with transmission risks typically ranging from 5–20% depending on the transmission route and household composition. Children were identified as the largest source of secondary transmission, with family structure influencing infection risk., Author summary We characterised detailed heterogeneity in household transmission patterns of influenza by applying a mathematical model to citywide primary school influenza survey data from 10,486 students in Matsumoto city, Japan, one of the largest-scale household surveys on seasonal influenza. Children were identified as the largest source of secondary transmission, with family structure influencing infection risk. This suggests that vaccinating children would have stronger secondary effects on transmission than would be assumed without taking into account transmission patterns within the household.

Background Influenza virus transmission may be prevented by infection control measures, including vaccination, wearing a mask, gargling with water, and hand washing. It is unclear, however, whether these measures affect influenza epidemics in school settings. Methods A prospective epidemiological survey in all public elementary schools in Matsumoto City, Japan, during the 2014/2015 season evaluated the number of diagnosed patients in each school and calculated the reproduction number of schoolchildren. At the end of the prospective survey, a cross-sectional survey evaluated the implementation of infection control measures in these schools. Both results were combined and associations among infection control measures including vaccination, mask wearing, hand washing, water gargling, and epidemic level were evaluated. Results Of the 13,217 schoolchildren in 29 schools, 2548 were diagnosed with seasonal influenza. A significant negative association was observed between vaccination coverage and reproduction number at each school, but not between other infection control measures and the reproduction number. A regression curve with exponential function was most predictive. At 0% vaccination, the reproduction number was estimated to be 1.39. Conclusion These findings provide evidence that high vaccination coverage was associated with reduced epidemic levels in schools and suggest the need for increased vaccination of schoolchildren.

Measures of seasonal influenza control are generally divided into two categories: pharmaceutical and non-pharmaceutical interventions. The effectiveness of these measures remains unclear, because of insufficient study sample size and/or differences in study settings. This observational epidemiological study involved all elementary schoolchildren in Matsumoto City, Japan, with seasonal influenza during the 2014/2015 season. Questionnaires, including experiences with influenza diagnosis and socio-demographic factors, were distributed to all 29 public elementary schools, involving 13,217 children, at the end of February 2015. Data were obtained from 10,524 children and analyzed with multivariate logistic regression analysis. The result showed that vaccination (odds ratio 0.866, 95% confidence interval 0.786–0.954) and wearing masks (0.859, 0.778–0.949) had significant protective association. Hand washing (1.447, 1.274–1.644) and gargling (1.319, 1.183–1.471), however, were not associated with protection. In the natural setting, hand washing and gargling showed a negative association, which may have been due to inappropriate infection control measures or aggregating infected and non-infected children to conduct those measures. These results may indicate a pathway for influenza transmission and explain why seasonal influenza control remains difficult in school settings. The overall effectiveness of vaccination and mask wearing was 9.9% and 8.6%, respectively. After dividing children into higher (grades 4–6) and lower (grade 1–3) grade groups, the effectiveness of vaccination became greater in the lower grade group, and the effectiveness of wearing masks became greater in the higher grade group. These results may provide valuable information about designing infection control measures that allocate resources among children., Highlights • An influenza survey was conducted in all 29 elementary schools in Matsumoto City. • Vaccination and wearing of masks were effective in infection control. • Effectiveness of protection methods differed between old and young schoolchildren. • Communal hand washing and water gargling was associated with the risk of influenza.

Concurrent chemoradiotherapy (CCRT) is one of the most promising treatments for advanced head and neck cancer (HNC). On the other hand, CCRT may induce severe edema in laryngo-pharyngeal structures in association with radiation. This is a report of a 66-year-old man with severe obstructive sleep apnea (OSA) associated with edema in laryngo-hypopharynx after CCRT for advanced laryngeal and hypopharyngeal cancer. Tracheostomy was avoided and OSA was controlled by continuous positive airway pressure (CPAP). Subjective symptoms of sleepiness were improved. Though laryngeal edema appeared during the course of CCRT in this case, OSA was not evaluated until snoring had been pointed out and he complained of sleepiness. CCRT for laryngeal and hypopharyngeal cancer have a risk of occurrence of OSA due to irreversible mucous edema in the upper airway. Patients for whom CCRT is planned should be informed about the occurrence of OSA before the treatment because symptoms associated with OSA can negatively impact not only the daytime quality of life but also increase the risk of cardiovascular events. The OSA treatment for post CCRT would be expected to have a positive impact on not only cardiovascular and metabolic systems but also on the cancer treatment survival rate.

Background Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. Although the patients with OPLL are more common in the 60s and 70s, we know that there are markedly young patients (e.g., early 40s). However, to the best of our knowledge, there is few reports characterize young patients with cervical OPLL in terms of the imaging features, subjective symptoms, and ADL problems. Methods This is the multicenter cross-sectional study. Two hundred and thirty-seven Japanese symptomatic patients with cervical OPLL confirmed by standard X-rays collected from 16 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament formed by the Japanese Ministry of Health, Labor and Welfare were recruited. Whole spine CT data as well as demographic data such as age, gender, patients-based evaluations, and the 36-item Short Form Health Survey (SF-36) were evaluated. Results Young group (≦ 45 years old) consisted of 23 patients (8 females and 15 males), accounting for 9.7% of the total. Their characteristics were high body mass index (BMI), significant involvement of trauma in the onset and deterioration of symptoms, and the predominance of thoracic OPLL. The patient-based evaluations did not show a significant difference between the young and non-young groups, or between the genders in the young group except for bodily pain (BP) of SF-36. Female patients in young group had significantly lower BP score of SF-36 than that of male in young group. Conclusions Characteristics of young patients with cervical OPLL were high BMI, significant involvement of trauma in the onset and deterioration of symptoms, lower BP score of SF-36 in female, and the predominance of thoracic OPLL.

Background Malignant tumors occurring around both the spinal column and posterior chest wall are uncommon. Surgical resection of chest wall tumors adjacent to the spinal column is still challenging due to the surrounding anatomical structures. The purpose of the present study was to evaluate the long-term outcomes of surgical management in malignant tumors involving the spinal column and posterior chest wall. Methods Between 1999 and 2007, 10 consecutive patients underwent en bloc resection combined with the posterior chest wall in the treatment of malignant tumors around the spinal column. There were 6 males and 4 females with a mean age at the surgery of 40.9 years old (range, 14–62 years old). The mean postoperative follow-up period was 159.7 months (range, 84–245 months). The clinical history, physical examination, laboratory data, radiological findings, and operative findings for each patient were retrospectively reviewed. Results All surgeries were performed via a combined anterior and posterior approach. The mean numbers of partially resected vertebrae and ribs were 3.1 and 4.1, respectively. Lower or upper lobectomy was performed in four patients, and the diaphragm was partially resected in two patients. The surgical margin was wide in seven patients and marginal in two patients. Although five patients had postoperative respiratory problem, all patients improved immediately without life-threatening complications. There were no patients with respiratory insufficiency after surgery. One patient with osteosarcoma died of lung metastases 99 months after surgery. At the final follow-up, only one patient had local recurrence, five had been continuously disease-free, and three were alive with no evidence of disease. Conclusions En bloc resection and reconstruction in selected patients with malignant tumors involving both the spinal column and posterior chest wall demonstrated good long-term results for local control and the respiratory function.

Economic and decision-making theories suppose that people would disengage from an extremely difficult task, because such a task does not implicate any normative utility values (i.e. success probability is almost zero). However, humans are often motivated for an extremely challenging task with little chance of success, even without any extrinsic incentives. The current study aimed to address how the nature of the task (luck vs. skill) and the presence of extrinsic rewards modulate this challenge-based motivation, and its neural correlates. Participants played a game-like, skill-based task with three different probabilities of success (i.e., high, moderate, and extremely-low chance of success), in one group without performance-based rewards (no-reward group) and the other group with performance-based monetary rewards (reward group). Participants in the third group played a similar task but the reward outcome was determined in a probabilistic manner (gambling group). Participants in the no-reward group showed increased intrinsic motivation, as the chance of success decreased (i.e. the task becomes more difficult) even if the task was almost impossible to achieve. On the other hand, the reward group exhibited the highest intrinsic motivation when the task had a moderate chance of success, and participants in the gambling group showed decreased intrinsic motivation as the chance of success decreased. The ventral striatum and the ventral pallidum also showed similar patterns of activation. These results suggest that, both at the behavioral and neural levels, people are intrinsically motivated to challenge a nearly impossible task, but only when the task requires certain skills and extrinsic rewards are not available.

Study Design: This is a retrospective study.Purpose: This study aims to evaluate the risk factor associated with pseudoarthrosis after placement of lateral interbody fusion (LIF) cages for adult spinal deformity (ASD) treatment. Overview of Literature: LIF technique is widely used for ASD correction. Furthermore, pseudoarthrosis is a major complication of fusion surgery required for revision surgery.Methods: This study included 42 patients with ASD (two men and 40 women; 112 segments; mean, 68.5±8.4 years; and mean follow-up, 31.6±17.0 months) who underwent LIF and posterior correction surgery. The concave slot of the LIF cage was filled with an autologous iliac crest bone graft (IBG), and the convex slot with a porous hydroxyapatite/collagen (HAp/Col) composite was soaked with bone marrow aspirate. Endplate injury, the gap between vertebral endplate and cage in the coronal or sagittal plane, and fusion status were evaluated using computed tomography multiplanar reconstruction at 12 months after surgery. Moreover, the associated risk factors for pseudoarthrosis were analyzed.Results: Fusion at LIF segments were observed in 71.4% segments at 12 months after surgery. Fusion on the concave slot (autologous IBG side), convex slot (porous HAp/Col composite side), and both concave and convex slots were observed in 66.1%, 37.5%, and 36.6% of patients, respectively. Moreover, pseudoarthrosis was observed in 28.6% at 12 months after surgery. Consequently, logistic regression analysis of the fusion at the LIF segment revealed that the gap between the LIF cage and endplate in the coronal plane (p=0.030; odds ratio, 0.183; 95% confidence interval, 0.030–0.183) was significantly associated with pseudoarthrosis at the LIF segments.Conclusions: ASD surgery fusion rate using LIF cages was 71.4% at 12 months after surgery. The fusion rate was higher on the concave slot filled with autologous IBG than on the convex slot filled with a porous HAp/Col composite. The gap in the coronal plane was a risk factor for pseudoarthrosis at the LIF segment.

Background The K-line in the neck-flexed position (FK-line) on radiography reflects dynamic factors and cervical alignment. Although the FK-line has been reported to affect the neurological recovery after muscle-preserving selective laminectomy for cervical spondylotic myelopathy (CSM), its influence on surgical outcomes after expansive open-door laminoplasty (ELAP) has not been investigated. Methods We reviewed the surgical outcomes in 81 patients with multilevel CSM who underwent C4–C6 ELAP combined with C3 and C7 partial laminectomy using a laminoplasty plate and were followed up for at least 2 years. We defined the K-line (−) as some portion of a bony spur or the vertebral body crossing the FK-line, whereas the FK-line (+) was defined as that never crossing the FK-line. Patients were divided into the FK-line (+) (n = 61) and FK-line (−) groups (n = 20), and the surgical outcomes were compared between the groups. A multivariate analysis was performed to identify the factors that influenced the neurological outcomes. Results The FK-line (−) group had a smaller C2–C7 angle, smaller C7 slope, greater postoperative increase in the C2–C7 sagittal vertical axis, greater kyphosis in cervical flexion and less lordosis in cervical extension, and higher incidence of postoperative residual spinal cord compression. The preoperative-to-postoperative changes in the Japanese Orthopedic Association (JOA) score and JOA score recovery rate (RR) were lower in the FK-line (−) group. The multiple linear regression analysis revealed that the K-line (−) (β = −0.327, P = 0.011) and high signal intensity (SI) changes on T2-weighted imaging (WI) combined with the low SI changes on T1-WI in the spinal cord (β = −0.320, P = 0.013) negatively affected the JOA score RR. Conclusions The FK-line can be used for patients with CSM as a simple indicator of neurological outcomes after ELAP.

Breast cancer is the second most common cancer in Peruvian women. Due to limitations in national breast cancer screening programs, especially in rural areas, more than 50% of cases of breast cancer in Peru are diagnosed in advanced stages. In collaboration with a local clinic registered as a nongovernmental organization (CerviCusco), RAD-AID International aims to create a sustainable diagnostic structure to improve breast cancer screening in Cuzco. With the support of local, national, and international partners that have collaborated in analyzing radiological resources, raising awareness in the population, acquiring equipment, training clinical staff, and building referral networks, our teams of radiologists, included in the RAD-AID team, have participated in training CerviCusco staff in breast ultrasound, thus enabling additional training for radiology residents through a regulated international collaboration.

Background Patients with diffuse idiopathic skeletal hyperostosis (DISH) are susceptible to spinal column injuries with neurological deterioration. Previous studies indicated that the prevalence of diabetes mellitus (DM) in patients with DISH was higher than that in patients without DISH. This study investigates the impact of DM on surgical outcomes for spinal fractures in patients with DISH. Methods We retrospectively evaluated 177 spinal fractures in patients with DISH (132 men and 45 women; mean age, 75 ± 10 years) who underwent surgery from a multicenter database. The subjects were classified into two groups according to the presence of DM. Perioperative complications, neurological status by Frankel grade, mortality rate, and status of surgical site infection (SSI) were compared between the two groups. Results DM was present in 28.2% (50/177) of the patients. The proportion of men was significantly higher in the DM group (DM group: 86.0% vs. non-DM group: 70.1%) (p = 0.03). The overall complication rate was 22.0% in the DM group and 19.7% in the non-DM group (p = 0.60). Poisson regression model revealed that SSI was significantly associated with DM (DM group: 10.0% vs. non-DM group: 2.4%, Relative risk: 4.5) (p = 0.048). Change in neurological status, mortality rate, instrumentation failure, and nonunion were similar between both groups. HbA1c and fasting blood glucose level (SSI group: 7.2% ± 1.2%, 201 ± 67 mg/dL vs. non-SSI group: 6.6% ± 1.1%, 167 ± 47 mg/dL) tended to be higher in patients with SSI; however, there was no significant difference. Conclusions In spinal fracture in patients with DISH, although DM was an associated factor for SSI with a relative risk of 4.5, DM did not negatively impact neurological recovery. Perioperative glycemic control may be useful for preventing SSI because fasting blood glucose level was high in patients with SSI.

Objective To evaluate the gustatory function before and after vestibular schwannoma (VS) surgery. Methods In this retrospective study, we evaluated the gustatory function of 12 patients who underwent VS surgery at Tsukuba University Hospital between 2012 and 2018. Gustatory function was examined using electrogustometry before VS surgery and 3 months, 6 months and 1 year after surgery. Electrogustometry was tested at the area mapped to the chorda tympani nerve, glossopharyngeal nerve and greater superficial petrosal nerve (GSPN). Intergroup mean comparisons of the threshold were performed using a one-way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test. Results The gustatory function mapped to the chorda tympani nerve was significantly disturbed 6 months after the surgery as compared with the preoperative function (p = 0.033) and that the dysfunction recovered at 1 year. However, gustatory function mapped to the glossopharyngeal nerve and greater superficial petrosal nerve (GSPN) was not impaired. Conclusion The gustatory function mapped to the chorda tympani nerve is impaired after surgery for VS. The dysfunction peaked at 6 months after surgery, and recovered within 1 year.

BACKGROUND: We report results of an internet-based field study evaluating the diagnostic guidelines for the newly introduced ICD-11 grouping of obsessive-compulsive and related disorders (OCRD). We examined accuracy of clinicians' diagnostic judgments applying draft ICD-11 as compared to the ICD-10 diagnostic guidelines to standardized case vignettes.METHODS: 1,717 mental health professionals who are members of the World Health Organization's Global Clinical Practice Network completed the study in Chinese, English, French, Japanese, Russian or Spanish. Participants were randomly assigned to apply ICD-11 or ICD-10 guidelines to one of nine pairs of case vignettes.RESULTS: Participants using ICD-11 outperformed those using ICD-10 in correctly identifying newly introduced OCRD, although results were mixed for differentiating OCRD from disorders in other groupings largely due to clinicians having difficulty differentiating challenging presentations of OCD. Clinicians had difficulty applying a three-level insight qualifier, although the 'poor to absent' level assisted with differentiating OCRD from psychotic disorders. Brief training on the rationale for an OCRD grouping did not improve diagnostic accuracy suggesting sufficient detail of the proposed guidelines.LIMITATIONS: Standardized case vignettes were manipulated to include specific characteristics; the degree of accuracy of clinicians' diagnostic judgments about these vignettes may not generalize to application in routine clinical practice.CONCLUSIONS: Overall, use of the ICD-11 guidelines resulted in more accurate diagnosis of case vignettes compared to the ICD-10 guidelines, particularly in differentiating OCRD presentations from one another. Specific areas in which the ICD-11 guidelines did not perform as intended provided the basis for further revisions to the guidelines.

Kounis syndrome is an anaphylactic reaction leading to acute coronary syndrome. The acute treatment of anaphylaxis is epinephrine; however, epinephrine may cause coronary vasoconstriction, reduce coronary blood flow, increase myocardial oxygen demand, and worsen myocardial ischemia. On the other hand, coronary vasodilation, a treatment for acute coronary syndrome, can aggravate hypotension in patients with anaphylaxis. Herein, the authors report a case of type II Kounis syndrome, with vasospasm in a patient with coronary disease, requiring the administration of epinephrine and a coronary vasodilator for resuscitation. The authors administered intravenous epinephrine continuously from lower dosages and performed delicate titration. The coronary vasodilator nicorandil, which has little effect on hemodynamics, also was administered. These treatments improved hemodynamics without complications. Circulatory management that considers both anaphylaxis and coronary lesions is crucial to improve prognosis in this syndrome.

BACKGROUND Initial management of severe traumatic brain injury is important and includes treatment decision-making and prediction of prognosis. We examined whether biomarkers at admission could be useful prognostic predictors. We focused on electrolytes and blood glucose, which can be measured easily at any facility and for which results can be obtained promptly, before those of other biomarkers, such as D-dimer. METHODS All trauma patients with head injuries treated at Chiba Hokusoh Hospital between 2014 and 2017 were investigated. Cases of multiple trauma accompanied by fatal trauma, hemorrhagic shock, or cardiopulmonary arrest, and pediatric cases, were excluded from this study. Blood gas data at the initial hospital visit were reviewed retrospectively. A poor outcome was defined as death during hospitalization or a vegetative state due to head injury. Factors related to poor outcomes were analyzed. RESULTS Of the 185 male and 79 female patients studied, 34 had poor outcomes. Poor outcome was significantly correlated with potassium (P = 0.003), glucose (P < 0.001), and glucose-to-potassium ratio (P < 0.001) at arrival. The odds ratio was 4.079 for a glucose-to-potassium ratio of ≥50. CONCLUSIONS We evaluated blood gas data at the initial hospital visit, as these results can be obtained more quickly than those of other biomarkers assessed previously. Serum glucose-to-potassium ratio at admission may be a potential predictor of prognosis for severe traumatic brain injury.

Parenteral morphine is widely used for dyspnea of imminently dying cancer patients (terminal dyspnea). However, the efficacy of other opioids such as oxycodone remains largely unknown.To explore the efficacy of parenteral oxycodone vs. morphine by continuous infusion over 24 hours in cancer patients with terminal dyspnea.This was a pre-planned subgroup analysis of a multicenter prospective observational study. Inclusion criteria were advanced cancer patients admitted to palliative care units, Eastern Cooperative Oncology Group performance status = 3-4, and a dyspnea intensity ≥2 on the Integrated Palliative care Outcome Scale (IPOS) for which oxycodone or morphine was initiated by continuous infusion. We measured dyspnea IPOS scores over 24 hours.We analyzed 164 patients who received oxycodone (n = 26) and morphine (n = 138) for dyspnea (median survival = 5 days). The mean age was 70 years, 58 patients (35%) had lung cancer, and 97 (59%) had lung metastases. Complete case analysis revealed that mean dyspnea IPOS scores decreased from 3.0 (standard deviation = 0.7) to 1.5 (0.7) in the oxycodone group (difference in means = 1.5; P 0.001), and from 2.9 (0.7) to 1.6 (1.0) in the morphine group (difference in means = 1.3; P 0.001). No significant between-group differences existed in the IPOS scores at 24 hours (P = 0.753). Adverse events were seen in no and 5 patients in the oxycodone and morphine groups, respectively.Parenteral oxycodone may be equally effective and safe as morphine in the treatment of terminal dyspnea in cancer patients. Future randomized controlled trials should confirm the efficacy and safety of opioids other than morphine for terminal dyspnea.

Background Base pair mismatches in genomic DNA can result in mutagenesis, and consequently in tumorigenesis. To investigate how mismatch repair deficiency increases mutagenicity under oxidative stress, we examined the type and frequency of mutations arising in the mucosa of the small intestine of mice carrying a reporter gene encoding guanine phosphoribosyltransferase (gpt) and in which the Msh2 gene, which encodes a component of the mismatch repair system, was either intact (Msh2+/+::gpt/0; Msh2-bearing) or homozygously knockout (KO) (Msh2−/−::gpt/0; Msh2-KO). Results Gpt mutant frequency in the small intestine of Msh2-KO mice was about 10 times that in Msh2-bearing mice. Mutant frequency in the Msh2-KO mice was not further enhanced by administration of potassium bromate, an oxidative stress inducer, in the drinking water at a dose of 1.5 g/L for 28 days. Mutation analysis showed that the characteristic mutation in the small intestine of the Msh2-KO mice was G-to-A transition, irrespective of whether potassium bromate was administered. Furthermore, administration of potassium bromate induced mutations at specific sites in gpt in the Msh2-KO mice: G-to-A transition was frequently induced at two known sites of spontaneous mutation (nucleotides 110 and 115, CpG sites) and at nucleotides 92 and 113 (3′-side of 5′-GpG-3′), and these sites were confirmed to be mutation hotspots in potassium bromate-administered Msh2-KO mice. Administration of potassium bromate also induced characteristic mutations, mainly single-base deletion and insertion of an adenine residue, in sequences of three to five adenine nucleotides (A-runs) in Msh2-KO mice, and elevated the overall proportion of single-base deletions plus insertions in Msh2-KO mice. Conclusions Our previous study revealed that administration of potassium bromate enhanced tumorigenesis in the small intestine of Msh2-KO mice and induced G-to-A transition in the Ctnnb1 gene. Based on our present and previous observations, we propose that oxidative stress under conditions of mismatch repair deficiency accelerates the induction of single-adenine deletions at specific sites in oncogenes, which enhances tumorigenesis in a synergistic manner with G-to-A transition in other oncogenes (e.g., Ctnnb1).

The aim of this study was to evaluate the association between labral length and radiographic parameters of lateral and anterior acetabular coverage and the femoro-epiphyseal acetabular roof (FEAR) index in patients with developmental dysplasia of the hip (DDH).We retrospectively analyzed data from patients with DDH who visited our hip joint clinic for the first time due to hip symptoms. DDH presence was defined as a lateral center-edge angle (LCEA) of ≤25°. The labral lengths on the anterior and lateral sides were measured on central axial and central coronal slices of T1-weighted magnetic resonance imaging, respectively. The Pearson correlation coefficients (r) and simple linear regression analyses were performed to determine the association of the lateral and anterior labral lengths with the radiographic parameters, including the LCEA, acetabular roof obliquity, FEAR index, anterior wall index, and vertical center anterior angle.This study included 88 patients, with a mean age of 39.6 ± 11.8 years. There were 65 women and 23 men. The lateral and anterior labral lengths correlated with all parameters of dysplasia. Specifically, the lateral labral length had a strong positive correlation with the FEAR index (R = 0.65, P.001). The anterior labral length had a strong negative correlation with the anterior wall index (R = -0.66, P.001).The lateral labral length had a strong positive correlation with the FEAR index. Furthermore, the anterior labral length had a correlation with the anterior dysplasia.Level III, retrospective cross-sectional study.

PURPOSE The purpose of the current study was to clarify the blood flow pattern in the left atrium (LA), potentially causing the formation of thrombosis after left upper lobectomy (LUL). The blood flow in the LA was evaluated and compared between LUL patients with and without thrombosis. For the evaluation, we applied highly accelerated 4D flow MRI with dual-velocity encoding (VENC) scheme, which was expected to be able to capture slow flow components in the LA accurately. METHODS Eight volunteers and 18 patients subjected to LUL underwent dual-VENC 4D Flow MRI. Eight patients had a history of thrombosis. We measured the blood flow velocity and stasis ratio (proportion in the volume that did not exceed 10 cm/s in any cardiac phase) in the LA and left superior pulmonary vein (LSPV) stump. For visual assessment, the presence of each collision of the blood flow from pulmonary veins and vortex flow in the LA were evaluated. Each acquired value was compared between healthy participants and LUL patients, and in LUL patients with and without thrombosis. RESULTS In LUL patients, blood flow velocity near the inflow part of the left superior pulmonary vein (Lt Upp) and mean velocity in the LA were lower, and stasis ratio in the LA was higher compared with healthy volunteers (Lt Upp 9.10 ± 3.09 vs.13.23 ± 14.19 cm/s, mean velocity in the LA 9.81 ± 2.49 vs. 11.40 ± 1.15 cm/s, and stasis ratio 25.28 ± 18.64 vs. 4.71 ± 3.03%, P = 0.008, 0.037, and < 0.001). There was no significant difference in any quantification values between LUL patients with and without thrombosis. For visual assessment, the thrombus formation was associated with no collision pattern (62.5% vs. 10%, P = 0.019) and not with vortex flow pattern (50% vs. 30%, P = 0.751). CONCLUSION The net blood flow velocity was not associated with the thrombus formation. In contrast, a specific blood flow pattern, the absence of blood flow collision from pulmonary veins, correlates to the thrombus formation in the LA.

Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta‐ and mega‐analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta‐analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega‐analysis. Furthermore, a schizophrenia‐specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega‐analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings., The Cognitive Genetics Collaborative Research Organization (COCORO), which is a Japanese consortium established to elucidate psychiatric disorders and brain functions, replicated the results of the ENIGMA consortium, such as subcortical volume abnormalities and white matter microstructural abnormalities in schizophrenia, using the mega‐analysis method. These replication studies strengthened the reliability and generalization of the results of the ENIGMA consortium based on common and different methods in both consortiums. Further replication and harmonization of large consortia will contribute to the generalization of their research findings.

This study aimed to evaluate the role of an objective physiologic biomarker, arterial blood pressure variability, for the early identification of adverse short-term electroencephalogram (EEG) outcomes in infants with hypoxic-ischemic encephalopathy (HIE).In this multicenter observational study, we analyzed blood pressure of infants meeting these criteria: (1) neonatal encephalopathy determined by modified Sarnat exam, (2) continuous mean arterial blood pressure (MABP) data between 18 and 27 hours after birth, and (3) continuous EEG performed for at least 48 hours. Adverse outcome was defined as moderate-severe grade EEG at 48 hours. Standardized signal preprocessing was used; the power spectral density was computed without interpolation. Multivariate binary logistic regression was used to identify which MABP time and frequency domain metrics provided improved predictive power for adverse outcomes compared with standard clinical predictors (5-minute Apgar score and cord pH) using receiver operator characteristic analysis.Ninety-one infants met inclusion criteria. The mean gestational age was 38.4 ± 1.8 weeks, the mean birth weight was 3,260 ± 591 g, 52/91 (57%) of infants were males, the mean cord pH was 6.95 ± 0.21, and 10/91 (11%) of infants died. At 48 hours, 58% of infants had normal or mildly abnormal EEG background and 42% had moderate or severe EEG backgrounds. Clinical predictor variables (10-minute Apgar score, Sarnat stage, and cord pH) were modestly predictive of 48 hours EEG outcome with area under curve (AUC) of 0.66 to 0.68. A composite model of clinical and optimal time- and frequency-domain blood pressure variability had a substantially improved AUC of 0.86.Time- and frequency-domain blood pressure variability biomarkers offer a substantial improvement in prediction of later adverse EEG outcomes over perinatal clinical variables in a two-center cohort of infants with HIE.· Early outcome prediction in HIE is suboptimal.. · Patterns in blood pressure physiology may be predictive of short-term outcomes.. · Early time- and frequency-domain measures of blood pressure variability predict short-term EEG outcomes in HIE infants better than perinatal factors alone..

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima’s scores evaluation. All patients who received nalfurafine exhibited improved Kawashima’s scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.

Background Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. Case report The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. Discussion The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.

Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female mice in vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.

Low energy availability in female athletes often causes hypothalamic amenorrhea and osteoporosis, in turn promoting stress fractures. Mechanisms underlying these conditions remain unclear. Here we show that model mice subjected to food restriction (FR) or FR-plus-voluntary running exercise exhibit significantly reduced bone mineral density, cortical bone parameters and uterine weight than do control mice, and that these parameters worsen in the FR-plus-exercise group. Relative to controls, FR and FR-plus-exercise groups showed significantly lower mineral apposition rate and osteoclast number and significantly reduced serum insulin-like growth factor-1 (IGF1) levels. Outcomes were rescued by ED71 or 1.25(OH)2D3 treatment. Thus, we conclude that administration of active vitamin D analogues represents a possible treatment to prevent these conditions.

The May-Hegglin anomaly is characterized by inherited thrombocytopenia, giant platelets, and leukocyte cytoplasmic inclusion bodies. The Fechtner, Sebastian, and Epstein syndromes are associated with mutations of the MYH9-coding nonmuscle myosin heavy chain ⅡA, similar to the May-Hegglin anomaly, and are together classified as MYH9 disorders. MYH9 disorders may include symptoms of Alport syndrome, including nephritis and auditory and ocular disorders. A 6-year-old boy was diagnosed with an MYH9 disorder after incidental discovery of hematuria and proteinuria. Focal segmental glomerulosclerosis was detected on renal biopsy. However, despite no prior bleeding diatheses, he developed a large post-biopsy hematoma despite a preprocedural platelet transfusion calculated to increase the platelet count from 54,000/μL to >150,000/μL. Idiopathic thrombocytopenic purpura is a major cause of pediatric thrombocytopenia following acute infection or vaccination, and patients with MYH9 disorders may be misdiagnosed with idiopathic thrombocytopenic purpura and inappropriately treated with corticosteroids. Careful differential diagnosis is important in thrombocytopenic patients with hematuria and proteinuria for the early detection of thrombocytopenia. Patients with MYH9 disorders require close follow-up and treatment with angiotensin Ⅱ receptor blockers to prevent the onset of progressive nephritis, which may necessitate hemodialysis or renal transplantation. The need for renal biopsy in patients with MYH9 disorders should be carefully considered because there could be adverse outcomes even after platelet transfusion.

Background Ventilator weaning protocols are commonly implemented for patients receiving mechanical ventilation. However, the rate of extubation failure remains high despite the protocols. This study investigated the usefulness and accuracy of ventilator weaning through machine learning to predict successful extubation. Methods We retrospectively evaluated the data of patients who underwent intubation for respiratory failure and received mechanical ventilation in the intensive care unit (ICU). Data on 57 factors including patient demographics, vital signs, laboratory data, and data from ventilator were extracted. Extubation failure was defined as re-intubation within 72 hours of extubation. For supervised learning, the data were labeled requirement of intubation or not. We used three learning algorithms (Random Forest, XGBoost, and LightGBM) to predict successful extubation. We also analyzed important features and evaluated the area under curve (AUC) and prediction metrics. Results Overall, 13 of the 117 included patients required re-intubation. LightGBM had the highest AUC (0.950), followed by XGBoost (0.946) and Random Forest (0.930). The accuracy, precision, and recall performance were 0.897, 0.910, and 0.909, for Random Forest; 0.910, 0.912, and 0.931 for XGBoost; and 0.927, 0.915, and 0.960 for LightGBM, respectively. The most important feature was the duration of mechanical ventilation followed by the fraction of inspired oxygen, positive end-expiratory pressure, maximum and mean airway pressures, and Glasgow Coma Scale. Conclusions Machine learning could predict successful extubation among patients on mechanical ventilation in the ICU. LightGBM has the highest overall performance. The duration of mechanical ventilation was the most important feature in all models.

β-catenin is a multi-functional protein with a central role in regulating embryonic development and tissue homeostasis. The abnormal accumulation of β-catenin, due to disrupted β-catenin degradation or unregulated β-catenin synthesis, causes the development of cancer. A recent study showed that the overexpression of proto-oncogene serine/arginine-rich splicing factor 9 (SRSF9) promotes β-catenin accumulation via binding β-catenin mRNA and enhancing its translation in a manner that is dependent on the mechanistic target of rapamycin (mTOR). However, the regulation of the interaction between SRSF9 and mRNA of β-catenin remains unclear. Here, we show that AMP-activated protein kinase (AMPK) phosphorylates SRSF9 at the RNA-interacting SWQDLKD motif that plays a major role in determining substrate specificity. The phosphorylation by AMPK inhibits the binding of SRSF9 to β-catenin mRNA and suppresses β-catenin protein synthesis caused by SRSF9 overexpression without changing the β-catenin mRNA levels. Our findings suggest that AMPK activators are potential therapeutic targets for SRSF9-derived overproduction of β-catenin in cancer cells.

[Background] Maintaining physical activity is important for older adults. “Self-care agency” is the ability to perform self-care, which is defined as people following their own will, managing themselves, and maintaining activities. We investigated the relationship among physical activity and self-care agency, demographic factors and physical condition in older adults. [Methods] Self-care agency was assessed by using the Self-Care Agency Questionnaire developed for Japanese patients with chronic diseases. Among 175 older adults aged 65 years or older living in a rural area, responses from 83 who performed physical activities were analyzed. Correspondence analysis was conducted to characterize demographic factors and self-care agency. [Results] A higher proportion of women than men were engaged in physical activity. Irrespective of age and sex, many of the participants performed stretching exercises, walking, radio exercises, TV exercises, and participated in community circles. Participants who engaged in physical activities had significantly higher self-care agency scores than inactive participants. Among the active participants, the self-care agency score was significantly higher for women than men (P = .04) and was also significantly higher for participants aged ≥ 75 years compared to those aged < 75 years. Individuals with a high self-care agency tended to participate in local programs and perform brief physical activities at home. [Conclusion] Physically active older adults demonstrated high self-care agency. Their activities were easily carried out in their daily lives, with activities varying by age and sex. Support from community health experts is needed to promote suitable physical activity among older adults tailored for age and sex, especially among older adults who have low self-care agency.

An 81-year-old woman was diagnosed with corticobasal degeneration (cognitive decline and left hand posturing). Hyponatremia and bilateral faciobrachial dystonic seizures (FBDS) ensued. Neurologic examination (figure, A; video) revealed persistent involuntary continuous left 3rd and 4th finger flexor activation and delayed relaxation. EMG revealed high-frequency spontaneous discharges, including neuromyotonia and fast myokymia of the left flexor digitorum superficialis and pronator teres (figure, B). LGI1 immunoglobulin G (IgG)1 was detected, but not CASPR2-IgG (figure, C–E). Oncologic evaluation revealed breast ductal carcinoma in situ. Encephalopathy and FBDS resolved after IV immunoglobulin. Encephalopathy coexisting with peripheral nerve hyperexcitability can mimic neurodegeneration, and should prompt exclusion of LGI1/CASPR2 autoimmunity.2

Purpose The Scored Patient-Generated Subjective Global Assessment (PG-SGA(C)) is a globally recognized and used nutritional screening, assessment, monitoring, and triaging tool. The aim of this study was to translate and culturally adapt the original English PG-SGA for the Japanese speaking populations and to assess its linguistic validity (i.e., comprehensibility, difficulty) and content validity, as perceived by Japanese patients and healthcare professionals. Methods In accordance with methodology used in previous Dutch, Thai, German, and Norwegian PG-SGA studies, we followed the ten steps of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Principles of Good Practice for Translation and Cultural Adaptation for Patient-Reported Outcome Measures. The study enrolled 50 patients and 50 healthcare professionals (HCPs) to evaluate the comprehensibility and difficulty of the translated and culturally adapted PG-SGA. The HCPs also evaluated the content validity of the translation. We evaluated each item and quantified scale indices for content validity (item content validity index (I-CVI), scale content validity index (S-CVI)), comprehensibility (item comprehensibility index (I-CI), scale comprehensibility index (S-CI)), and difficulty (item difficulty index (I-DI), scale difficulty index (S-DI)). Results Patients evaluated the comprehensibility and difficulty of the patient component as excellent (S-CI = 0.97, S-DI = 0.96). The professionals rated the Japanese version of both components of the PG-SGA as very relevant (S-CVI = 0.94). The professionals evaluated the comprehensibility of the professional component as being acceptable (S-CI = 0.88) but difficult (S-DI = 0.69), based predominantly on items related to physical examination (I-DI = 0.33-0.67). Conclusion The PG-SGA was systematically translated and culturally adapted for the Japanese setting according to the ISPOR process. The Japanese version of the PG-SGA was perceived as comprehensive, easy to use, and relevant. Perceived difficulty in professional components, specifically in the context of metabolic demand and physical examination, will require appropriate training for professionals in order to optimize implementation.

Background Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. Methods Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. Results Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. Conclusions We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

Pluripotent stem cells underpin a growing sector that leverages their differentiation potential for research, industry, and clinical applications. This review evaluates the landscape of methods in single-cell transcriptomics that are enabling accelerated discovery in stem cell science. We focus on strategies for scaling stem cell differentiation through multiplexed single-cell analyses, for evaluating molecular regulation of cell differentiation using new analysis algorithms, and methods for integration and projection analysis to classify and benchmark stem cell derivatives against in vivo cell types. By discussing the available methods, comparing their strengths, and illustrating strategies for developing integrated analysis pipelines, we provide user considerations to inform their implementation and interpretation.

How physicians use opioids for dyspnea in imminently dying cancer patients (terminal dyspnea) varies markedly, which could hamper quality care.To examine the adherence to an algorithm-based treatment for terminal dyspnea, and explore its outcomes over 24 hours.This was a pre-planned subgroup analysis of a multicenter prospective observational study. Inclusion criteria were: advanced cancer patients admitted to palliative care units, ECOG performance status = 3-4, and a dyspnea intensity ≥2 on the Integrated Palliative care Outcome Scale (IPOS). We developed an algorithm to visualize how palliative care physicians would use parenteral opioids. Participating physicians (palliative care specialists) initiated parenteral opioids, choosing whether to use the algorithm based on their preference. We measured the adherence rate to the algorithm over 24 hours (predefined goal = 70%), and compared dyspnea IPOS scores and adverse events between patients with and without algorithm-based treatment.Of 164 patients (median survival = 5 days), 71 (43%) received algorithm-based treatment, and 70 (99%; 95% confidence interval = 92%-100%) adhered to it over 24 hours. In a complete case analysis, mean dyspnea IPOS scores significantly decreased from 2.9 (standard error = 0.1) to 1.5 (0.1) in the algorithm group (n = 54; P0.001), and 2.9 (0.1) to 1.6 (0.1) in the non-algorithm group (n = 72; P0.001). There was no significant between-group difference in changes in dyspnea IPOS scores (P = 0.65). Adverse events were rare (n = 5).The algorithm-based treatment was feasible, and might be as effective and safe as the usual care by palliative care specialists. Its implementation may help physicians provide quality care for terminal dyspnea.

Background Cryobiopsy enables specialists to perform high-quality, large, entirely circumferential biopsies; therefore, it may improve the diagnostic yield of peripheral pulmonary lesions (PPLs), as has been previously observed with regard to endobronchial tumors and interstitial lung diseases. Research Question How do the diagnostic accuracy and safety change by cryobiopsy when performed alongside conventional biopsy for PPLs? Study Design and Methods Consecutive patients who underwent cryobiopsy in addition to conventional biopsies for PPL diagnosis at our institution between June 2017 and May 2018 were reviewed retrospectively. The target location was estimated and sampling was performed using conventional devices (i.e., forceps, brush, and/or aspiration needle), and cryobiopsy was performed at the same location. Diagnostic outcomes and cryobiopsy safety when performed in addition to conventional sampling methods were analyzed in this observational study. Results In total, 257 patients were analyzed, and the overall diagnostic yield was 89.9%. Among them, 22 lesions were diagnosable by cryobiopsy exclusively, which improved the rate of diagnosis by 8.6%. Advantages of the use of cryobiopsy were the most apparent when lesions were adjacent to areas assessed via radial endobronchial ultrasound (69.4% vs. 84.3%). Multivariable analysis identified bronchus sign (positive/negative, P=0.001), lobe (other lobes/right upper lobe + left upper segment, P=0.028), and visibility on X-ray (visible/invisible, P=0.047) as factors that significantly affected diagnostic yield. On the other hand, three instances of severe hemorrhage (1.2%), and two of pneumothorax (0.8%) occurred. Although most complications were minor, two patients required hospitalization due to cerebral infarction and lung abscess. Interpretation Cryobiopsy improves the diagnostic yield of PPLs when combined with other conventional sampling methods; however, caution is required due to the possibility of complications.

An 80-year-old woman was admitted to our hospital due to appetite loss and vomiting. A blood examination showed liver disorder with disseminated intravascular coagulation. All tumor markers and hepatitis virus markers were negative. Contrast-enhanced computed tomography did not show tumor lesions, bone lesions, lymphadenopathies, or thrombosis. A bone marrow biopsy revealed large, atypical cells with brown pigmentation and positive immunostaining for HMB-45, S100 proteins, and CD79a without myeloid or lymphoid markers. We experienced a case of disseminated carcinomatosis of the bone marrow due to malignant melanoma of unknown primary origin.

Purpose Primary tumor location of colon cancer has been reported to affect the prognosis after curative resection. However, some reports suggested the impact was varied by tumor stage. This study analyzed the prognostic impact of the sidedness of colon cancer in Stages II, III, and liver metastasis after curative resection using propensity matched analysis. Methods Right-sided colon cancer was defined as a tumor located from cecum to splenic flexure, while any more distal colon cancer was defined as a left-sided colon cancer. Patients who underwent curative resection at Nara Medical University hospital between 2000 and 2016 were analyzed. Results There were 110 patients with Stage II, 100 patients with Stage III, and 106 patients with liver metastasis. After propensity matching, 28 pairs with Stage II and 32 pairs with Stage III were identified. In the patients with Stage II, overall survival and recurrence-free survival were not significantly different for right- and left-sided colon cancers. In the patients with Stage III, overall survival and recurrence-free survival were significantly worse in right-sided colon cancer. In those with liver metastasis, overall survival of right-sided colon cancer was significantly worse than left-sided disease, while recurrence-free survival was similar. Regarding metachronous liver metastasis, the difference was observed only in the patients whose primary colon cancer was stage III. In each stage, significantly higher rate of peritoneal recurrence was found in those with right-sided colon cancer. Conclusion Sidedness of colon cancer had a significant and varied prognostic impact in patients with Stage II, III, and liver metastasis after curative resection.

Introduction According to the Japanese guidelines for the management of Clostridioides difficile infection (CDI), the first choice is metronidazole (MNZ) for non-severe cases and vancomycin (VCM) for severe cases. However, the appropriateness of this first choice in Japanese patients is unclear. We therefore evaluated the appropriateness of the CDI management guidelines and the incidence of adverse drug reactions. Methods The electronic chart data at Keio University Hospital between January 2012 and June 2019 were retrospectively reviewed. The response rate, the relapse rate, and the adverse reaction rate of treatment for CDI using MNZ or VCM were investigated according to the disease severity. Factorial analysis associated with the response, relapse, and adverse reaction was also performed. Results In the 352 patients surveyed, no significant difference was observed in the response rate between MNZ and VCM regardless of the severity of CDI. The presence of cancer was a factor related to the persistence of diarrheal symptoms and older age was a risk factor for relapse. MNZ induced nausea significantly more frequently than VCM, and young age and female sex were risk factors for nausea. Conclusion As no significant difference was observed in the response rate of CDI between MNZ and VCM, the Japanese CDI management guidelines, which recommend MNZ as the first choice, were demonstrated to be appropriate. Attention to nausea was also suggested to be necessary when administering MNZ to young females.

Background Oral allergy syndrome (OAS) is an IgE-mediated food allergy. Ingestion of causative antigens leads to the development of local symptoms such as numbness of the oral mucosa in most cases and anaphylaxis in a few cases. The prevalence of OAS including in healthy people has not been investigated. Thus, we conducted a questionnaire survey of Japanese university students. Methods We conducted a cross-sectional study of 2688 first-year students using a questionnaire survey in marksheet format and examined the epidemiological characteristics of OAS. Results Only 2.7% of students were aware of the term “oral allergy syndrome”. A total of 143 (5.3%) students had OAS. There were significant associations between OAS and other allergic diseases including allergic rhinitis (AR) (OR: 3.8, 95% CI: 2.7–5.5), atopic dermatitis (AD) (OR: 4.6, 95%CI: 3.3–6.6), and bronchial asthma (BA) (OR: 3.0, 95%CI: 2.0–4.5). The onset age of OAS showed bimodal peaks at 0 and 10 years, and the latter peak coincided with the peak onset age of AR. Conclusions Awareness of OAS was low in our study, which will make it difficult to treat properly and prevent its development. This survey confirmed the association between OAS and other allergic diseases, especially AR, which suggests that OAS is involved in the allergic march. A novel finding was that sensitization to antigens for OAS occurred around the same time as sensitization to antigens for AR. These results will help medical professionals diagnose OAS and develop lifestyle guidelines to prevent OAS-related symptoms such as anaphylaxis.

Background Visceral fat obesity can be defined quantitatively by abdominal computed tomography, however, the usefulness of measuring visceral fat area to assess the etiology of gastrointestinal reflux disease has not been fully elucidated. Methods A total of 433 healthy subjects aged 40–69 years (234 men, 199 women) were included in the study. The relationship between obesity-related factors (total fat area, visceral fat area, subcutaneous fat area, waist circumference, and body mass index) and the incidence of reflux erosive esophagitis was investigated. Lifestyle factors and stomach conditions relevant to the onset of erosive esophagitis were also analyzed. Results The prevalence of reflux erosive esophagitis was 27.2% (118/433; 106 men, 12 women). Visceral fat area was higher in subjects with erosive esophagitis than in those without (116.6 cm2 vs. 64.9 cm2, respectively). The incidence of erosive esophagitis was higher in subjects with visceral fat obesity (visceral fat area ≥ 100 cm2) than in those without (61.2% vs. 12.8%, respectively). Visceral fat obesity had the highest odds ratio (OR) among obesity-related factors. Multivariate analysis showed that visceral fat area was associated with the incidence of erosive esophagitis (OR = 2.18), indicating that it is an independent risk factor for erosive esophagitis. In addition, daily alcohol intake (OR = 1.54), gastric atrophy open type (OR = 0.29), and never-smoking history (OR = 0.49) were also independently associated with the development of erosive esophagitis. Conclusions Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in subjects aged 40–69 years.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

Purposes The closure of atrial septal defect (ASD) is associated with a significant reduction in right ventricular (RV) overload and an improvement in functional capacity in most adults with ASD. However, a subset of patients remains symptomatic even after closure due to therapeutic delay. To date, no clinically robust preoperative predictor of postoperative residual symptoms has been clearly identified. Methods In this study, 120 adult patients with ASD and 39 controls were investigated. As an index of RV myocardial deformation, RV global longitudinal strain (RV-GLS) was evaluated. The degree of coupling between RV and pulmonary artery (PA) was quantified by the tricuspid annular plane systolic excursion (TAPSE) divided by the PA systolic pressure (PASP). Results Compared to controls, baseline RV-GLS was significantly greater (- 27 ± 7 vs. - 23 ± 5%, P = 0.02) and TAPSE/PASP ratio was severely impaired (0.8 ± 0.3 vs. 2.1 ± 1.6 mm/mmHg, P < 0.01) in ASD patients. At 6 months after closure, 15 patients (12.5%) remained symptomatic. In patients without residual symptoms, TAPSE/PASP ratio significantly improved from 0.9 ± 0.3 to 1.0 ± 0.6 mm/mmHg (P = 0.02), and RV-GLS normalized (from - 28 ± 11 to - 24 ± 7%, P < 0.01) after closure. However, RV-GLS and TAPSE/PASP ratio showed no significant change in ASD patients with residual symptoms. On multivariate analysis, preoperative TAPSE/PASP ratio (odds ratio [OR] 0.034, 95% confidence interval [CI] 0.000-0.604, P = 0.03) and pulmonary vascular resistance index ([PVRI], OR 1.011, 95% CI 1.000-1.021, P < 0.05) were associated with the postoperative symptomatic status. Conclusion In terms of integrated assessment of the RV-PA unit, preoperative TAPSE/PASP ratio and PVRI were important determinants of residual symptoms after ASD closure.

Acquired coarctation of the aorta (CoA) following total aortic arch replacement (TAR) is a rare complication inducing left ventricular (LV) dysfunction probably due to increased LV afterload and secondary hypertension caused by increased upper body and decreased renal blood flow. We describe a case of a 35-year-old male who developed atypical CoA with severe LV dysfunction with LV ejection fraction of 10%, but without secondary hypertension after TAR using conventional elephant trunk (ET) technique for acute aortic dissection. Computed tomography revealed near-occlusive CoA due to narrowed distal ET. Because the myocardial histological findings were mild, and he had no cardiac failure history, we determined that LV function might be reversible. He underwent thoracic endovascular aortic repair (TEVAR), resulting in restored LV function. However, as the descending aortic false lumen distally to the end of ET was rapidly dilated, probably due to increased cardiac output and lower body blood flow, he underwent descending aortic replacement 3 months after TEVAR. In conclusion, a narrowed distal ET may cause LV dysfunction early after TAR, even without secondary hypertension. TEVAR may be a useful therapeutic option for a narrowed distant ET but can induce distal aortic dilatation.

Background Radiofrequency (RF) ablation of typical atrioventricular nodal reentrant tachycardia (tAVNRT) is performed without revealing out the location of antegrade slow pathway (ASp). In this study, we studied a new electrophysiological method of identifying the site of ASp. Methods This study included 19 patients. Repeated series of very high‐output single extrastimulations (VhoSESts) were delivered at the anatomical slow pathway region during tAVNRT. Tachycardia cycle length (TCL), coupling interval (CI), and return cycle (RC) were measured and the prematurity of VhoSESts [ΔPM (= TCL – CI)] and the prolongation of RCs [ΔPL (= RC – TCL)] were calculated. Pacing sites were classified into two categories: (i) ASp capture sites [DSPC(+) sites], where two different RCs were shown, and ASp non‐capture sites [DSPC(‐) sites], where only one RC was shown. RF ablation was performed at DSPC(+) sites and/or sites with catheter‐induced mechanical trauma (CIMT) to ASp. Results DSPC(+) sites were shown in 13 patients (68%). RF ablation was successful in all patients without any degree of atrioventricular block nor recurrence. Total number of RF applications was 1.8 ± 1.1. Minimal distance between successful ablation sites and DSPC(+)/CIMT sites and His bundle (HB) electrogram recording sites was 1.9 ± 0.8 mm and 19.8 ± 6.1 mm, respectively. ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 could identify ASp with sensitivity of 100%, 91.1%, and 88.9% and specificity of 92.9%, 97.0%, and 97.6%, respectively. Conclusions Sites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation., A case of Direct Slow Pathway Capture (DSPC) during typical atrioventricular nodal reentrant tachycardia.

International audience; Clinical manifestations of COVID-19 caused by the new coronavirus SARS-CoV-2 are associated with age1,2. Adults develop respiratory symptoms, which can progress to acute respiratory distress syndrome (ARDS) in the most severe form, while children are largely spared from respiratory illness but can develop a life-threatening multisystem inflammatory syndrome (MIS-C)3-5. Here, we show distinct antibody responses in children and adults after SARS-CoV-2 infection. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection course and immune response in children independent of whether they develop MIS-C, with implications for developing age-targeted strategies for testing and protecting the population.

A 20-year-old male without any symptoms was referred for heart murmur on a medical examination. A thrill was palpable at the upper left sternal border. His cardiac murmur showed respiratory variation. The systolic murmur was louder (Levine grade IV/VI) during expiration and diminished during inspiration (Levine grade I/VI). He was thin and had a narrow thoracic cage in the anteroposterior direction due to straight back syndrome (SBS). An echocardiogram and a right ventriculogram showed changes in the diameter of the right ventricular outflow tract (RVOT) on respiration. During expiration, the RVOT was compressed and narrow, while it was expanded during inspiration. Cardiac catheterization demonstrated a 10-mmHg of pressure gradient across the RVOT during expiration but no pressure gradient during inspiration. Thus, respiratory compression to the RVOT by a narrow thoracic cage due to SBS was the cause of the cardiac murmur with respiratory alterations. Our case highlights the importance of physical examination, including an inspection of the patient’s physique.