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Ischemic stroke is a major cerebrovascular disease with high morbidity and mortality rates; however, effective treatments for ischemic stroke-related neurological dysfunction have yet to be developed. In this study, we generated neural progenitor cells from human leukocyte antigen major loci gene-homozygous-induced pluripotent stem cells (hiPSC-NPCs) and evaluated their therapeutic effects against ischemic stroke. hiPSC-NPCs were intracerebrally transplanted into rat ischemic brains produced by transient middle cerebral artery occlusion at either the subacute or acute stage, and their in vivo survival, differentiation, and efficacy for functional improvement in neurological dysfunction were evaluated. hiPSC-NPCs were histologically identified in host brain tissues and showed neuronal differentiation into vGLUT-positive glutamatergic neurons, extended neurites into both the ipsilateral infarct and contralateral healthy hemispheres, and synaptic structures formed 12 weeks after both acute and subacute stage transplantation. They also improved neurological function when transplanted at the subacute stage with γ-secretase inhibitor pretreatment. However, their effects were modest and not significant and showed a possible risk of cells remaining in their undifferentiated and immature status in acute-stage transplantation. These results suggest that hiPSC-NPCs show cell replacement effects in ischemic stroke-damaged neural tissues, but their efficacy is insufficient for neurological functional improvement after acute or subacute transplantation. Further optimization of cell preparation methods and the timing of transplantation is required to balance the efficacy and safety of hiPSC-NPC transplantation.

Background: The JCOG0804/WJOG4507L single-arm confirmatory trial indicated a satisfactory 10-year prognosis for patients who underwent limited resection for radiologically less-invasive lung cancer. However, only one prospective trial has reported a 10-year prognosis., Methods: We conducted a multicenter prospective study coordinated by the National Cancer Center Hospital East and Kanagawa Cancer Center. We analyzed the long-term prognosis of 100 patients who underwent limited resection of a radiologically less-invasive lung cancer in the peripheral lung field. We defined radiologically less-invasive lung cancer as lung adenocarcinoma with a maximum tumor diameter of ≤2 cm, tumor disappearance ratio of ≥0.5 and cN0. The primary endpoint was the 10-year local recurrence-free survival., Results: Our patients, with a median age of 62 years, included 39 males. A total of 58 patients were non-smokers; 87 had undergone wide wedge resection and 9 underwent segmentectomy. A total of four cases were converted to lobectomy because of the presence of poorly differentiated components in the frozen specimen or insufficient margin with segmentectomy. The median follow-up duration was 120.9 months. The 10-year recurrence-free survival and overall survival rates of patients with lung cancer were both 96.0%. Following the 10-year long-term follow-up, two patients experienced recurrences at resection ends after wedge resection., Conclusions: Limited resection imparted a satisfactory prognosis for patients with radiologically less-invasive lung cancer, except two cases of local recurrence >5 years after surgery. These findings suggest that patients with this condition who underwent limited resection may require continued follow-up >5 years after surgery., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although children with orofacial clefts have an increased risk for sleep-disordered breathing, no studies have examined the association of sleep duration. Thus, this study aimed to examine associations between orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age in Japan., A cohort study from the Japan Environment and Children's Study., This study consisted of 91 497 children, including ones with isolated cleft lip and palate (n = 69), isolated cleft lip only (n = 48), and isolated cleft palate only (n = 37), for which recruitment was undertaken during 2011 to 2014., Seep durations (hours per day) at 1 month, 6 months, 1 year, and 3 years of age, as reported by their mothers., In the control group, mean sleep durations and standard deviations at 1 month, 6 months, 1 year, and 3 years of age were 15.2 (2.5), 13.6 (1.9), 12.9 (1.6), and 11.6 (1.2) h, respectively. Compared to the control group, linear regression models reported effect sizes and 95% confidence intervals shorter than 1 h for sleep duration of each type of isolated orofacial cleft at each time point., This study suggested null associations between isolated orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age. Children with isolated orofacial clefts had sufficient mean sleep duration., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression., Methods: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center., Results: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001)., Conclusion: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images., Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status., Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory ( p  = .015, odds ratio = 2.44) and for the validation cohort ( p  = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort., Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: Low-grade adenosquamous carcinoma (LGASC) is a rare type of metaplastic carcinoma of the breast (MBC) with an indolent clinical course. A few LGASC cases with high-grade transformation have been reported; however, the genetics underlying malignant progression of LGASC remain unclear., Methods: We performed whole-genome sequencing analysis on five MBCs from four patients, including one case with matching primary LGASC and a lymph node metastatic tumor consisting of high-grade MBC with a predominant metaplastic squamous cell carcinoma component (MSC) that progressed from LGASC and three cases of independent de novo MSC., Results: Unlike de novo MSC, LGASC and its associated MSC showed no TP53 mutation and tended to contain fewer structural variants than de novo MSC. Both LGASC and its associated MSC harbored the common GNAS c.C2530T:p.Arg844Cys mutation, which was more frequently detected in the cancer cell fraction of MSC. MSC associated with LGASC showed additional pathogenic deletions of multiple tumor-suppressor genes, such as KMT2D and BTG1. Copy number analysis revealed potential 18q loss of heterozygosity in both LGASC and associated MSC. The frequency of SMAD4::DCC fusion due to deletions increased with progression to MSC; however, chimeric proteins were not detected. SMAD4 protein expression was already decreased at the LGASC stage due to unknown mechanisms., Conclusion: Not only LGASC but also its associated high-grade MBC may be genetically different from de novo high-grade MBC. Progression from LGASC to high-grade MBC may involve the concentration of driver mutations caused by clonal selection and inactivation of tumor-suppressor genes., (© 2023. The Author(s).)

Prostate cancer remains a significant global health challenge. Traditionally anchored by the Gleason score/Grade Group (GS/GG), the landscape of prostate cancer diagnosis is undergoing transformative steps, particularly in the domain of biopsy procedures. GS/GG continues to be pivotal in malignancy grading, but recent technological strides have augmented the diagnostic relevance of biopsies. Integral to this progression is the adoption of advanced imaging techniques, especially magnetic resonance imaging, which has refined biopsy accuracy and efficiency. A deep understanding of prostate cancer pathology reveals a cribriform pattern and intraductal carcinoma of the prostate as independent forms of malignancy, suggesting a potentially aggressive disease course. Furthermore, the distinct behaviour of ductal adenocarcinoma and small cell carcinoma of the prostate, compared with acinar adenocarcinoma, necessitates their accurate differentiation during biopsy. The genomic era ushers in a renewed emphasis on tissue samples obtained from prostate biopsies, especially as mutations in genes, such as BRCA1 / 2 , and paves the way for precision medicine. This review encapsulates the evolving dynamics of prostate biopsy, from technological advancements to the profound implications on prostate cancer management and therapy., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Background: Physicians in public health administration agencies (public health physicians: PHP) play important roles in public health; however, there are not enough such physicians in Japan. This study aimed to elucidate the factors related to the resignation and migration of PHPs using nationwide survey data., Methods: Data from the Survey of Physicians, Dentists, and Pharmacists (2010, 2012, 2014, and 2016) were analyzed. The outcome was the resignation of PHPs or migration to public health administration agencies. The explanatory variables in the resignation analysis were age, sex, workplace, and board certification status. The type of work was added as an explanatory variable in the migration analysis, and clinical specialty was added to the clinical doctor-restricted analysis. The odds ratios (ORs) of the explanatory variables were calculated using generalized estimation equations., Results: In the resignation analysis among PHPs, women had a significantly lower OR, whereas younger PHPs and those with board certifications had significantly higher ORs. In the migration to public health administration agencies analysis among medical doctors, women and those aged between 35 and 39 years had significantly higher ORs, but those with board certifications had significantly lower ORs. Hospital/clinic founders or directors had significantly lower ORs, but the clinic staff and 'others/not working' had significantly higher ORs. In the migration to public health administration agencies analysis among clinical physicians, those aged between 35 and 39 years had significantly higher ORs. Still, those with two or more board certifications had significantly lower ORs. Hospital/clinic founders or directors had significantly lower ORs, but the clinic staff had significantly higher ORs. Clinical doctors specializing in surgery and other specialties had significantly lower ORs, but those specializing in pediatrics and psychiatry/psychosomatic medicine had significantly higher ORs., Conclusions: Having board certifications were significantly related to the resignation of PHPs and migration to public health administration agencies. Women migrated to public health administration agencies more than men and younger PHPs were more likely to resign. However, medical doctors aged between 35 and 39 years were more likely to migrate to public health administration agencies. Similarly, clinic staff, non-clinical physicians, and those whose specialties were pediatrics and psychiatry/psychosomatic medicine were more likely to migrate to public health administration agencies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The government of Japan has spent a significant amount on dental healthcare, but it remains unknown how the spending varies across age, type of service, and time. This study describes trends in dental expenditures in Japan., Methods: This descriptive study used two national data sources: Estimates of National Medical Care Expenditure and Survey on Economic Conditions in Health Care. We obtained annual total and average per capita dental expenditures by age in Japan from 1984 to 2020 and estimated the proportions of types of service from 1996 to 2021. All costs were adjusted for the 2020 Consumer Price Index (1 US dollar ≈ 100 yen in 2020)., Results: Total dental expenditures increased from 1.96 trillion yen in 1984 to 3.00 trillion yen in 2020. In particular, total and average per capita dental spending for older persons showed a rapid increase (total: from 185 billion yen in 1984 to 1.18 trillion yen in 2020; average per capita: from 15,500 yen in 1984 to 32,800 yen in 2020), contributing to the total amount increase. The crown restoration and prosthesis category amounted to 50.3% of the total expenditure in 1996, and this proportion declined to 32.4% by 2021. In 0-14 years persons, expenses on the crown restoration and prosthesis category decreased while the medical management category (mainly including fees for a management plan for oral diseases or oral functions) increased. In persons aged 65 years or older, expenses on the crown restoration and prosthesis category decreased, with increasing expenses in the medical management and at-home treatment categories., Conclusion: The amount of dental spending in Japan substantially increased from 1.96 trillion yen in 1984 to 3.00 trillion yen in 2020), a 1.53-fold increase. The observed changes in annual dental spending varied across age groups and types of service., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sato 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.)

Aims: Lenvatinib is a multikinase inhibitor used for treating unresectable or metastatic cancers, including thyroid cancer. As total thyroidectomy followed by radioactive iodine therapy is a commonly recommended initial treatment for thyroid cancer, histological findings of the thyroid after lenvatinib therapy remain unclear. Therefore, the aim of this study was to analyse in-vivo changes in patients who underwent thyroidectomy after lenvatinib therapy., Methods and Results: We screened 167 patients with thyroid cancer [papillary thyroid cancer (PTC), n = 102; follicular thyroid cancer (FTC), n = 26; anaplastic thyroid cancer (ATC), n = 39] who underwent lenvatinib therapy. Among these patients, six underwent thyroidectomy (lenvatinib-treated group: PTC, n = 3; FTC, n = 1; ATC, n = 2), and the specimens were examined. Five patients with PTC who did not receive lenvatinib therapy were included for comparison (untreated group). Microvessel density (MVD) was evaluated in both groups. The PTC and FTC specimens showed relatively more ischaemic changes than ATC specimens. Coagulative necrosis and ischaemic changes in cancer cells were frequently observed. ATC specimens showed fibrosis and mild cell damage. As hypothyroidism is a common side effect of lenvatinib therapy, non-cancerous thyroid tissues were also examined. Histological findings included mild lymphocytic infiltration, lymphoid follicular formation, histiocytic reaction and follicular epithelial destruction. The MVD in lenvatinib-treated tissues was significantly lower than that in untreated tissues., Conclusions: Lenvatinib therapy probably induces relatively specific ischaemic changes in thyroid cancer cells. Moreover, inflammatory cell infiltration and decreased MVD occur to varying degrees in non-cancerous thyroid tissue and may be related to hypothyroidism, a side effect of lenvatinib., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Effective methods of preventing and identifying childhood wasting are required to achieve global child health goals. Family mid-upper arm circumference (MUAC) programs train caregivers to screen their child for wasting with MUAC tapes. We assessed the effectiveness of a two-way short message service (SMS) platform (referred to as the Maternally Administered Malnutrition Monitoring System [MAMMS]) in western Kenya., Methods: In this individual-level randomised controlled trial in two rural countries in western Kenya, children (aged 5-12 months) were randomly allocated (1:1) to receive either standard care (SOC) or MAMMS. Randomisation method was permuted-block randomisation with a block size of 10. Eligible participants were children attending maternal child health clinics in the two counties whom had a MUAC between 12.5 and 14.0 cm. The MAMMS group received two MUAC tapes and weekly SMS reminders to screen their child's MUAC. The SOC group received routine community health volunteer services and additional quarterly visits from the study team. The primary analysis used a cox proportional hazards model to compare SOC and MAMMS time-to-diagnosis of wasting (MUAC <12.5 cm) confirmed by a health professional during 6-months follow-up. Secondary outcomes were days from enrolment to treatment initiation among children with wasting, proportion of all children with wasting who were identified by the two approaches (treatment coverage), mean MUAC at treatment initiation, and duration of wasting treatment. This trial was registered on ClinicalTrials.gov, NCT03967015., Findings: Between August 1, 2019 and January 31, 2022, 1200 children were enrolled, among whom the incidence of confirmed wasting was 37% lower in the MAMMS group (hazard ratio: 0.63, 95% CI: 0.42-0.94, p = 0.022). Among children with wasting, the median number of days-to-diagnosis was similar between study groups (MAMMS: 63 days [interquartile range (IQR): 23-92], SOC: 58 days [IQR: 22-94]). Treatment coverage in the MAMMS group was 83.3% (95% CI: 39.9-100.0) while coverage in the SOC group was 55.6% (95% CI: 22.3-88.9%, p = 0.300). Treatment duration and mean MUAC at treatment initiation were similar between groups., Interpretation: Family MUAC supported by SMS was associated with a 37% reduction in wasting among young children. Empowering caregivers to monitor their child's nutritional status at home may prevent a substantial proportion of moderate wasting., Funding: Thrasher Research Foundation and Pamela and Evan Fowler., Competing Interests: KR reports payments to their institution for grants or contracts from the National Institutes of Health. KR also reports payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from University of California, San Francisco. All other authors declare no competing interests., (© 2023 The Authors.)

Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front that reflects the direct effects of stromal cells on cancer. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of the invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had a significantly increased cancer-associated fibroblast (CAF) marker-positive area and lower density of CD8 + lymphocytes compared to that with hemato-BM. RNA sequencing analysis of primary and bone metastasis cancer revealed that bone metastasized cancer cells acquired drug resistance-related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide a favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers through CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cribriform pattern and intraductal carcinoma of the prostate (IDC-P) are widely accepted as poor prognostic factors in prostate cancer. However, it remains unclear to what extent the presence of these morphological features in prostate biopsy specimens, as diagnosed by hematoxylin-eosin-stained specimens only, affects the clinicopathological impact. In this study, we summarized the characteristics of the cribriform pattern and IDC-P in 850 prostate biopsy cases. The results showed a statistically significant increase in the incidence of cribriform pattern and IDC-P as grade group (GG) increased (especially in cases ≥ GG4, Chi-square test P < 0.001). The independent risk factors for cribriform pattern and IDC-P in biopsy specimens in the multivariate logistic regression analysis were the former GG, presence of IDC-P, lesion length of the highest GG core, latter GG, presence of the cribriform pattern, number of biopsies obtained, and number of highest GG core. Overall, 125 cases in which radical prostatectomy was conducted after biopsy were selected for further analysis. Multivariate logistic regression analysis using biopsy and surgical specimens confirmed that the presence of the cribriform pattern and IDC-P in biopsy specimens were independent risk factors for lymph node metastasis (odds ratios [95% confidence interval] were 6.54 [1.15-37.05] for the cribriform pattern and 23.71 [1.74-322.42] for IDC-P). The presence of the cribriform pattern and/or IDC-P in a biopsy specimen was a significant factor, even if only partially present, indicating lymph node metastasis. However, further validation is required to predict poor prognostic factors more accurately., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Myxofibrosarcoma (MFS) and undifferentiated sarcoma (US) have been considered as tumors of the same lineage based on genetic/epigenetic profiling. Although MFS shows a notably better prognosis than US, there are no clear criteria for distinguishing between them. Here, we examined 85 patients with MFS/US and found that tumors with infiltrative growth patterns tended to have more myxoid areas and higher local recurrence rates but fewer distant metastases and better overall survival. Morphologically characteristic sickle-shaped blood vessels, which tended to have fewer αSMA-positive cells, were also observed in these tumors, compared with normal vessels. Based on the incidence of these sickle-shaped blood vessels, we subdivided conventionally diagnosed US into two groups. This stratification was significantly correlated with metastasis and prognosis. RNA sequencing of 24 tumors (9 MFS and 15 US tumors) demonstrated that the proteasome, NF-kB, and VEGF pathways were differentially regulated among these tumors. Expression levels of KDR and NFATC4, which encode a transcription factor responsible for the neuritin-insulin receptor angiogenic signaling, were elevated in the sickle-shaped blood vessel-rich US tumors. These findings indicate that further analyses may help elucidate the malignant potential of MFS/US tumors as well as the development of therapeutic strategies for such tumors., (© 2023. The Author(s).)

Objectives: Multimorbidity is defined as the coexistence of two or more chronic physical or psychological conditions within an individual. The association between maternal multimorbidity and adverse perinatal outcomes such as preterm delivery and low birth weight has not been well studied. Therefore, this study aimed to investigate this association., Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study of pregnant women between 2011 and 2014. Those with data on chronic maternal conditions were included in the study and categorised as having no chronic condition, one chronic condition or multimorbidities. The primary outcomes were the incidence of preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA). Adjusted logistic regression was performed to estimate ORs (aORs) and 95% CIs., Results: Of the 104 062 fetal records, 86 885 singleton pregnant women were analysed. The median maternal age and body mass index were 31 years and 20.5 kg/m 2 , respectively. The prevalence of pregnant women with one or more chronic conditions was 40.2%. The prevalence of maternal multimorbidity was 6.3%, and that of PTB, LBW, and SGA were 4.6%, 8.1%, and 7.5%, respectively. Pre-pregnancy underweight women were the most common, observed in 15.6% of multimorbidity cases, followed by domestic violence from intimate partner in 13.0%. Maternal multimorbidity was significantly associated with PTB (aOR 1.50; 95% CI 1.33-1.69), LBW (aOR 1.49; 95% CI 1.35-1.63) and SGA (aOR 1.33; 95% CI 1.20-1.46)., Conclusion: Maternal multimorbidity was associated with adverse perinatal outcomes, including PTB, LBW and SGA. The risk of adverse perinatal outcomes tends to increase with a rise in the number of chronic maternal conditions. Multimorbidity becomes more prevalent among pregnant women, making our findings important for preconception counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The association between oral diseases and work productivity loss remains unclear. This study examined whether dental caries, tooth loss, and poor periodontal status were associated with absenteeism and presenteeism. This cross-sectional study used two independent datasets: 184 employees at a medical university and 435 employees from among the registrants of an online research company. Absenteeism and presenteeism, according to the World Health Organization Health and Work Performance Questionnaire, were dependent variables. The independent variables were the number of decayed and filled teeth (DFT), missing teeth (MT), and self-reported periodontal status. Multivariable linear regression models were developed to estimate unstandardised coefficients with 95% confidence intervals (CIs) for absenteeism and presenteeism. After adjusting for covariates, among the 435 employees enrolled from among the registrants of an online research company, poor periodontal status was significantly associated with a 7.8% (95%CI = -14.5, -1.0) decline in presenteeism but not absenteeism. DFT and MT were not significantly associated with either absenteeism or presenteeism in both populations. Given that periodontal status was potentially associated with a 7.8% decline in work performance, occupational specialists, managers, and dental health professionals should be aware of the impact on work productivity.

Background: Uterine adenosarcoma is a rare malignant tumor that accounts for 8% of all uterine sarcomas, and less than 0.2% of all uterine malignancies. However, it is frequently misdiagnosed in clinical examinations, including pathological diagnosis, and imaging studies owing to its rare and non-specific nature, which is further compounded by the lack of specific diagnostic markers., Case Presentation: We report a case of uterine adenosarcoma for which a comprehensive genomic profiling (CGP) test provided a chance to reach the proper diagnosis. The patient, a woman in her 60s with a history of uterine leiomyoma was diagnosed with an intra-abdominal mass post presentation with abdominal distention and loss of appetite. She was suspected to have gastrointestinal stromal tumor (GIST); the laparotomically excised mass was found to comprise uniform spindle-shaped cells that grew in bundles with a herringbone architecture, and occasional myxomatous stroma. Immunostaining revealed no specific findings, and the tumor was diagnosed as a spindle cell tumor/suspicious adult fibrosarcoma. The tumor relapsed during postoperative follow-up, and showed size reduction with chemotherapy, prior to regrowth. CGP was performed to identify a possible treatment, which resulted in detection of a JAZF1-BCORL1 rearrangement. Since the rearrangement has been reported in uterine sarcomas, we reevaluated specimens of the preceding uterine leiomyoma, which revealed the presence of adenosarcoma components in the corpus uteri. Furthermore, both the uterine adenosarcoma and intra-abdominal mass were partially positive for CD10 and BCOR staining., Conclusion: These results led to the conclusive identification of the abdominal tumor as a metastasis of the uterine adenosarcoma. The JAZF1-BCORL1 rearrangement is predominantly associated with uterine stromal sarcomas; thus far, ours is the second report of the same in an adenosarcoma. Adenosarcomas are rare and difficult to diagnose, especially in atypical cases with scarce glandular epithelial components. Identification of rearrangements involving BCOR or BCORL1, will encourage BCOR staining analysis, thereby potentially resulting in better diagnostic outcomes. Given that platinum-based chemotherapy was proposed as the treatment choice for this patient post diagnosis with adenosarcoma, CGP also indirectly contributed to the designing of the best-suited treatment protocol., (© 2023. The Author(s).)

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Background: Internal medicine (IM) doctors in Japan play the role of primary care physicians; however, the shortage of rural physicians continues. This study aims to elucidate the association of age, sex, board certification, type of work, and main clinical work with the retention or migration of IM doctors to rural areas., Methods: This retrospective cohort study included 82,363 IM doctors in 2010, extracted from the national census data of medical doctors. The explanatory variables were age, sex, type of work, primary clinical work, and changes in board certification status. The outcome was retention or migration to rural areas. The first tertile of population density (PD) of municipalities defined as rural area. After stratifying the baseline ruralities as rural or non-rural areas, the odds ratios (ORs) of the explanatory variables were calculated using generalized estimation equations. The analyses were also performed after age stratification (<39, 40-59, ≥60 years old)., Results: Among the rural areas, women had a significantly higher OR for retention, but obtaining board certification of IM subspecialties had a significantly lower OR. Among the non-rural areas, physicians who answered that their main work was IM without specific subspecialty and general had a significantly higher OR, but obtaining and maintaining board certification for IM subspecialties had a significantly lower OR for migration to rural areas. After age stratification, the higher OR of women for rural retention was significant only among those aged 40-59 years. Those aged under 40 and 40-59 years in the non-rural areas, who answered that their main work was IM without specific subspecialty had a significantly higher OR for migration to rural areas, and those aged 40-59 years in the rural areas who answered the same had a higher OR for rural retention., Conclusions: Obtaining and maintaining board certification of IM subspecialties are possible inhibiting factors for rural work, and IM doctors whose main work involves subspecialties tend to work in non-rural areas. Once rural work begins, more middle-aged female IM doctors continued rural work compared to male doctors.

This study aimed to document the complication status of infants with orofacial clefts born between 2011 and 2014 in Japan. This was a descriptive study using data from the Japan Environment and Children's Study. Among 103 060 pregnancies, 248 infants with orofacial clefts were included (livebirth, 239; stillbirth, 4; miscarriage, 5). The items of interest were complication status of orofacial clefts: isolated (typical orofacial clefts only); multi-malformed (orofacial clefts with unrelated major defects); syndromic (orofacial clefts with a syndrome or a chromosomal defect). Regarding the cleft subtypes, of 248 infants with orofacial clefts, 104 had cleft lip with cleft palate (CLP) (41.9%), 68 had cleft lip without cleft palate (CL) (27.4%), 58 had cleft palate without cleft lip (CP) (23.4%), and 18 were nonclassified (7.3%). In infants with CLP, the proportions of isolated, multi-malformed, and syndromic phenotypes were 73.1%, 15.4%, and 11.5%, respectively. In infants with CL, the proportions were 79.4%, 16.2%, and 4.4%, respectively. In infants with CP, the proportions were 69.0%, 13.8%, and 17.2%, respectively. The most frequently associated congenital anomaly was congenital heart disease. In infants with syndromic CLP, 41.7% had trisomy 13. In infants with syndromic CP, 80.0% had the Pierre Robin sequence. Congenital heart disease could be the most frequently associated congenital anomaly. The most frequently associated syndrome could be trisomy 13 in those with CLP and Pierre Robin sequence in those with CP., (© 2022 Japanese Teratology Society.)

Objective: This cross-sectional study aimed to examine factors potentially associated with psychological distress among undergraduate students during the coronavirus disease 2019 pandemic in Japan., Methods: We analyzed data of 958 undergraduates (median age 20 y; 56.8% women) from a Web-based, self-administered questionnaire survey conducted from August to September 2020. Prevalence ratios (PRs) for psychological distress defined as 5 points or over of the Kessler Psychological Distress Scale (K6) were calculated by Poisson regression models., Results: The proportion of psychological distress was 40.0%. In the mutually-adjusted model, the following were significantly associated with psychological distress: decreases in household income to 50-99% of the prepandemic amount compared with no change (PR = 1.48), newly experiencing unpaid wages compared with no experience (PR = 1.44), insufficient money to buy necessities compared with no shortage (PR = 1.45), receiving a student loan or scholarship compared with none (PR = 1.27), and communication 1 to 3 times a month compared with at least once a week (PR = 1.22). In contrast, school closure during the pandemic compared with no closure was inversely associated with psychological distress (PR = 0.78)., Conclusions: Among undergraduate students in Japan, economic difficulties significantly predicted psychological distress.

Prostate biopsy is essential in diagnosing prostate cancer. The Prostate Imaging-Reporting and Data System (PI-RADS) and magnetic resonance imaging (MRI)-transrectal ultrasound fusion-guided biopsy are also useful for diagnosis. However, the burden of implementing and maintaining these techniques should be considered. Therefore, we investigated the significance of non-standardized pre-biopsy MRI abnormalities (conditions not in accordance with PI-RADS) and subsequent targeted biopsy. We collected clinicopathological data, including the presence or absence of MRI abnormalities, through biopsies from January 2017 to February 2022 at the Kanagawa Cancer Center and performed statistical analyses. We enrolled in 1086 cases: MRI abnormalities were observed in 861 cases (79.3%). In these 861 cases, the adenocarcinoma detection rate, number of positive cores, and length of the highest Grade Group (GG) lesions were significantly higher. In the multivariate analysis, MRI abnormalities were the most significant factor for detecting adenocarcinoma of ≥GG 2 (odds ratio: 4.52, 95% confidence interval: 3.08-6.63). Targeted biopsy showed a higher percentage of positive cores with ≥GG2 and longer highest GG lesion lengths than systematic biopsy. Furthermore, the highest GG was upgraded in 109 of 788 cases by targeted biopsy. However, several adenocarcinomas (125/788; 15.9%) could not be detected using only targeted biopsy. Non-standardized MRI abnormalities are powerful predictors of cancer and grading. Targeted biopsies based on MRI abnormalities provide several benefits. Owing to the relatively low implementation hurdle, these biopsies may serve as a bridge until the ideal approaches are popularized if the limitations are well understood., Competing Interests: Declarations of interest None., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Urinary cotinine concentration (UCC) reflects smoking status. However, in pregnant women, its association with adverse birth outcomes related to fetal growth is not widely known. Thus, we aimed to explore this relationship by focusing on dose-response relationships. We investigated 86,638 pregnant women enrolled between 2011 and 2014 in a prospective cohort study in Japan and observed three birth outcomes (preterm birth, low birth weight, and small-for-gestational age). We measured UCC in the second or third trimester, and categorized the participants using cut-off values (negative cotinine concentration, passive cotinine concentration, and active cotinine concentration corresponding to non-smokers, passive smokers, and active smokers, respectively). Logistic regression analyses were conducted to evaluate the risks, and dose-response relationships were visualized using restricted cubic spline curves. Analyses based on self-reported smoking status were also performed. We found that in low active and highly active cotinine concentrations, the adjusted odds ratios (aORs) of birth outcomes were significantly increased (preterm birth, 1.24 [95% CI 1.06-1.46], 1.39 [95% CI 1.19-1.62]; low birth weight, 1.40 [95% CI 1.24-1.58], 2.27 [95% CI 2.05-2.53]; small-for-gestational age, 1.35 [95% CI 1.19-1.52], 2.39 [95% CI 2.16-2.65]). Restricted cubic spline curves demonstrated risk elevations in the active cotinine concentration range. Our research revealed dose-response relationships between UCC during pregnancy and the risks of preterm birth, low birth weight, and small-for-gestational age. Measurement of UCC to ascertain smoking status during pregnancy may be a useful approach for predicting the risks of these birth outcomes., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Bladder cancer is the most common urinary tract cancer. Patients diagnosed with advanced T-stage/muscle-invasive bladder cancer through transurethral resection of bladder tumors (TURBT) are treated with total radical cystectomy; however, there is a high chance of recurrence. Nevertheless, markers for predicting this recurrence are not currently available. Here, we evaluated the chronological change of ephrin type-A receptor 2 (EPHA2) expression, a molecule known for its role in cell adhesion, to predict bladder cancer recurrence after cystectomy, using TURBT and cystectomy specimens., Materials and Methods: An immunostaining evaluation method that combines whole-slide images and image analysis software was developed to quantify and evaluate stainability objectively. We assessed the correlation between EPHA2 expression and bladder cancer recurrence using this novel immunostaining method and chronological changes in target protein expression in TURBT and radical cystectomy samples., Results: In TURBT specimens, the number of cases with a high N-terminal/C-terminal EPHA2 ratio in the group with recurrence was significantly higher than in the non-recurrent group (p=0.019). The number of cases with a high level of C-terminal EPHA2 positivity in the radical cystectomy specimen when compared to the TURBT specimen obtained from the same patient was significantly higher in the recurrent group than in the non-recurrent group (p=0.0034)., Conclusion: EPHA2 appears to be a promising marker for bladder tumor recurrence after cystectomy and its evaluation may enable the selection of appropriate cases for adjuvant therapy among patients undergoing radical cystectomy. Further studies, including mass-scale analysis, are required to confirm these results., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 46-year-old woman presented with discomfort in her right lateral gaze, right-sided headache, and facial numbness 17 days after concurrent chemoradiotherapy(CCRT)for a Stage ⅢB cervical cancer. The initial imaging investigations, maxillofacial and otolaryngology reviews did not reveal a diagnosis. After 54 days of CCRT, her symptoms deteriorated. Magnetic resonance imaging(MRI)showed a tumor in the right infratemporal fossa and its biopsy confirmed a metastatic cervical cancer. In view of the rapid deterioration and the potential visual loss, palliative intensity-modulated radiotherapy(IMRT) was given. Although the symptoms improved temporarily, multiple metastases were subsequently found. Despite chemotherapy, the patient died 11 months after developing the symptoms of infratemporal fossa metastasis.

Introduction : Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis ; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination . The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Njunge JM et al.)

A recurrent tumor is defined as a re-emerging subclone originating from an ancestorial clone of the primary neoplasm. Hence, it should be distinguished from de novo tumor emerging from other clones. Herein, we describe an exceptional case in which the locally re-emerging glioma did not share genetic alterations of the primary tumor. While the initial tumor harbored mutations in IDH1 and TERT genes as well as 1p/19q codeletion, the re-emerging tumor did not present any of these genetic abnormalities. Variant calling for tumor samples using whole-genome sequencing revealed that 1696 mutations within the primary tumor faded in the re-emerging tumor, and that 4591 mutations were newly detected in the re-emerging tumor. These results suggested that the initial and re-emerging tumors did not share same clonal origins, although the second tumor appeared adjacent to the old surgical cavity 5 years after the initial surgery. We finally speculated that the re-emerging tumor could be a "de novo glioma" or "radiation-induced glioblastoma following treatment of a diffuse glioma." This case highlights the importance of molecular re-evaluation of clinically diagnosed "recurrent" glioma lesions., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Objective: Previous studies have indicated that spatial variation in suicide mortality is associated with area-specific socioeconomic characteristics, such as socioeconomic deprivation and social fragmentation. However, most of these studies have been conducted in the West and findings from Asian countries are limited. This study aims to investigate associations between socioeconomic characteristics and suicide mortality rates across 1887 municipalities in Japan between 2009 and 2017. We also assessed these associations by gender and age group., Methods: Suicide data were obtained from the suicide statistics of the Ministry of Health, Labour and Welfare in Japan and included information on the number of suicides by gender, age and municipality location. Social fragmentation, socioeconomic deprivation and urbanicity were used as socioeconomic characteristics in this study and were created from survey data obtained from the 2010 census. Bayesian hierarchical models were used to examine associations between socioeconomic characteristics and suicide risk., Results: Suicide rates were significantly higher in municipalities with higher levels of deprivation, with a rate ratio of 1.13 (95% credible interval: 1.10 to 1.17) in the highest quartile compared with the lowest. Higher levels of urbanicity had significantly lower suicide rates, with a rate ratio of 0.79 (95% credible interval: 0.77 to 0.82) in the highest quartile compared with the lowest. However, associations between exposures and suicide varied considerably by gender and age. Among both men and women aged 0-39 years, fragmentation was significantly associated with suicide, with rate ratios of 1.07 and 1.15 for men and women, respectively, in the highest quartile compared with the lowest., Conclusion: Suicide prevention in Japan should particularly focus on areas with high levels of deprivation or low levels of urbanicity. Furthermore, young Japanese people residing in the most fragmented municipalities were also at high risk of suicide, and appropriate measures need to be taken., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psychological stress is a potential risk factor for oral diseases. However, evidence for the association between work stress and oral diseases is scarce. We aimed to examine the associations of work stress, according to the effort-reward imbalance model, with dental caries, periodontal status, and tooth loss., Methods: This cross-sectional study included 184 regular employees at a medical university and 435 registrants of a web research company. Work stress was assessed using the effort-reward imbalance (ERI) ratio. Dental caries and tooth loss were assessed according to the number of decayed, filled, and missing teeth (DMFT) among the set of 28 teeth. Periodontal status was assessed using a self-administered questionnaire. For the DMFT, a linear regression model was used to estimate the unstandardised coefficients. A Poisson regression model was used to estimate the prevalence ratios (PRs) of poor periodontal status., Results: Among medical university employees and employees enrolled from among the registrants of an online research company, a one-unit increase in the ERI ratio was associated with -2.81 (95% CI [-4.70 to -0.92]; p -value = 0.004) and -0.84 (95% CI [-1.80 to 0.12]; p -value = 0.085) changes in the DMFT from adjusted linear regression models, respectively. In employees enrolled from among the registrants of an online research company, a one-unit increase in the ERI ratio was also associated with 1.55 (95% CI [1.04-2.32]; p -value = 0.032) of the PR for poor periodontal status based on Poisson regression models., Conclusion: ERI at work was associated with an increased risk of poor periodontal status., Competing Interests: The authors declare that they have no competing interests., (© 2022 Sato et al.)

Despite recent signs of progress in diagnostic radiology, it is quite rare that a glioblastoma (GBM) is detected asymptomatically. We describe two patients with asymptomatic nonenhancing GBMs that were not diagnosed with neoplasia at first. The patients had brain scans as medical checkups, and incidentally lesions were detected. In both cases, surgical specimens histopathologically showed no evidence of neoplasia, whereas molecular genetic findings were isocitrate dehydrogenase (IDH)-wildtype, O 6 -methylguanine-DNA methyltransferase promoter ( pMGMT ) unmethylated, and telomerase reverse transcriptase ( TERT ) promoter mutated, which matched to GBM. One patient was observed without adjuvant therapy and the tumor recurred 7 months later. Reoperation was performed, and histopathologically GBM was confirmed with the same molecular diagnosis as the first surgical specimen. Another patient was carefully observed, and chemoradiotherapy was begun 6 months after the operation following the extension of the lesion. Eventually, because of disease progression, both patients deceased. We postulate that in each case, the tumor was not lower-grade glioma but corresponded to the early growth phase of GBM cells. Thus far, cases of malignant transformation from lower-grade glioma or asymptomatic GBM with typical histologic features are reported. Nevertheless, to the best of our knowledge, no such case of nonenhancing, nonhistologically confirmed GBM was reported. We conjecture these cases shed light on the yet unknown natural history of GBM. GBM can take the form of radiological nonenhancing and histological nonneoplastic fashion before typical morphology. Molecular genetic analysis can diagnose atypical preceding GBM, and we recommend early surgical removal and adjuvant treatment., Competing Interests: The authors report no conflicts of interest pertinent to this manuscript., (© 2022 The Japan Neurosurgical Society.)

Background: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs., Methods: This prospective cohort study used data from the Japan Environment and Children's Study, for which baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as a potential mediator., Results: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP, 2.38; 95% confidence interval [CI], 1.30-4.36 and IRR of CL, 2.73; 95% CI, 1.40-5.33), but not ones with CP (IRR 1.08; 95% CI, 0.28-4.15). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP, 2.16; 95% CI, 1.19-3.93)., Conclusion: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

This study examined the prevalence of intimate partner violence (Intimate Partner Violence) and its associations with sexual agency among women and adolescent girls in the Philippines. Data came from the 2017 Philippines National Demographic and Health Survey (DHS), a nationally representative, cross-sectional survey of women and girls ages 15-49. Participants included 11,727 women and girls who reported having a current male partner. Survey measures included three indicators of Intimate Partner Violence (physical, sexual, emotional), ability to refuse sex, ability to insist on condom use, perception that a husband/boyfriend can be justified in hitting or beating his wife/girlfriend, and sociodemographic characteristics. Descriptive and multivariable statistical analyses were conducted, with survey weightings used to account for the complex survey design. Overall, 23.9% reported Intimate Partner Violence in their current partnership (10.1% physical violence, 3.4% sexual violence, 19.0% emotional violence), 11.2% believed a husband or partner could be justified in hitting or beating their wife, 10.5% reported being unable to refuse sex with their partner, and 20.4% were unable to ask their partner to use a condom. In multivariable analyses, experiences of sexual (OR .68; 95% CI .50, .92), physical (OR .83; 95% CI .68, 1.02), and emotional violence (OR .69; 95% CI .58, .81) were associated with lower adjusted odds of being able to ask a partner to use a condom. When placed in the same model, emotional violence had the strongest association with lower odds of negotiating condom use with partner (OR .70; 95% CI .57, .85). Perception that a husband/boyfriend can be justified in hitting or beating his wife/girlfriend was associated with lower ability to refuse sex and ask a partner to use a condom. Findings indicate a need for further investment in interventions to prevent Intimate Partner Violence and support the sexual health and agency of women and girls who have experienced Intimate Partner Violence in the Philippines.

Background: The COVID-19 pandemic is negatively impacting mental health globally. While increased social cohesion may have initially decreased suicide risk, there are few reports on the long-term impact. We examined the impact of the pandemic on suicide by gender and age through December 2021 in Japan., Methods: We analyzed trends in monthly suicide rates by age and gender from January 2016 to December 2021 using provisional mortality data in an interrupted time series analysis. We also considered linear trends in the pre-pandemic period and seasonal variations. Pandemic onset was defined as from April 2020. Estimated excess deaths by suicide that occurred during the pandemic were calculated., Findings: Excess number of suicide deaths during the pandemic period was estimated to be 1208 for men and 1825 for women. While there was no statistically significant increase in suicide rates overall for both men and women during the pandemic compared to the pre-pandemic, age-specific analyses showed a statistically significant increase in men 20-29 and 40-49 years, and in women of all age groups, except those under 20, 40-49 and over 80 years., Interpretation: The COVID-19 pandemic has had a negative impact on suicide rates in Japan and the impact is most pronounced in women and younger age groups. Subgroup analyses are needed, with a particular focus on those considered to be vulnerable and at increased suicide risk., Funding: A Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Award Number 21K10462)., Competing Interests: We declare no competing interests., (© 2022 The Authors.)

In prostate cancer, accurate diagnosis and grade group (GG) decision based on biopsy findings are essential for determining treatment strategies. Diagnosis by experienced urological pathologists is recommended; however, their contribution to patient benefits remains unknown. Therefore, we analyzed clinicopathological information to determine the significance of reassessment by experienced urological pathologists at a high-volume institution to identify factors involved in the agreement or disagreement of biopsy and surgical GGs. In total, 1325 prostate adenocarcinomas were analyzed, and the GG was changed in 452/1325 (34.1%) cases (359 cases were upgraded, and 93 cases were downgraded). We compared the highest GG based on biopsy specimens, with the final GG based on surgical specimens of 210 cases. The agreement rate between the surgical GG performed and assessed in our institute and the highest biopsy GG assessed by an outside pathologist was 34.8% (73/210); the agreement rate increased significantly to 50% (105/210) when biopsy specimens were reevaluated in our institute (chi-square test, P < 0.01). Multivariate logistic regression analysis showed that only the length of the lesion in the positive core with the highest GG in the biopsy was a significant factor for determining the agreement between biopsy GG and surgical GG, with an odds ratio of 1.136 (95% confidence interval: 1.057-1.221; P < 0.01). Thus, reassessment by experienced urological pathologists at high-volume institutions improved the agreement rate. However, it should be noted there is a high probability of discordance between a small number of lesions or short lesions and surgical GG., (© 2022. The Author(s).)

Objective: X-linked hydrocephalus (XLH), the most common genetic hydrocephalus, is caused by mutation of the L1 cell adhesion molecule (L1CAM). A fetus/neonate with this disorder frequently shows an adducted thumb, which has been employed as a helpful finding in the prenatal diagnosis of XLH., Materials and Methods: We describe a male fetus with hydrocephalus without an adducted thumb: the pregnancy was terminated at 21 weeks' gestation on the parents' request. Direct sequencing of the umbilical cord revealed L1CAM mutation, which confirmed the diagnosis of XLH., Results: Our literature review demonstrated that while an adducted thumb was observed in almost all fetuses with this disorder after 24 weeks' gestation, it was noted in only 57% (8/14) of fetuses/neonates at less than 24 weeks: it was absent in 43%., Conclusion: Even if an adducted thumb is not observed, XLH should not be ruled out, especially in early gestation., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: The extremes of maternal pre-pregnancy body mass index (BMI) are known to be risk factors associated with obstetric and adverse perinatal outcomes. Among Japanese women aged 20 years or older, the prevalence of underweight (BMI < 18.5 kg/m 2 ) was 11.5% in 2019. Maternal thinness is a health problem caused by the desire to become slim. This study aimed to investigate the association between the severity of maternal low pre-pregnancy BMI and adverse perinatal outcomes, including preterm birth (PTB), low birth weight (LBW), and small-for-gestational age (SGA)., Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant individuals between 2011 and 2014. Pre-pregnancy BMI was categorized as severe-moderate underweight (BMI < 16.9 kg/m 2 ), mild underweight (BMI, 17.0-18.4 kg/m 2 ), low-normal weight (BMI, 18.5-19.9 kg/m 2 ), high-normal weight (BMI, 20.0-22.9 kg/m 2 ), overweight (BMI, 23.0-24.9 kg/m 2 ), and obese (BMI ≥ 25.0 kg/m 2 ). The high-normal weight group was used as the reference for statistical analyses. Adjusted logistic regression was performed to evaluate the association between pre-pregnancy BMI and PTB, LBW, and SGA., Results: Of 92,260 singleton pregnant individuals, the prevalence was 2.7% for severe-moderate underweight, 12.9% for mild underweight, and 24.5% for low-normal weight. The prevalence of adverse outcomes was 4.6% for PTB, 8.1% for LBW, and 7.6% for SGA. The adjusted odds ratios (aORs) for PTB were 1.72 (95% confidence interval [CI], 1.46-2.03) for severe-moderate underweight and 1.26 (95% CI, 1.14-1.39) for mild underweight. The aORs of LBW were 2.55 (95% CI, 2.27-2.86) for severe-moderate underweight, 1.64 (95% CI, 1.53-1.76) for mild underweight, and 1.23 (95% CI, 1.16-1.31) for low-normal weight. The aORs of SGA were 2.53 (95% CI, 2.25-2.84) for severe-moderate underweight, 1.66 (95% CI, 1.55-1.79) for mild underweight, and 1.29 (95% CI, 1.21-1.38) for low-normal weight., Conclusions: A dose-response relationship was found between the severity of low pre-pregnancy BMI and PTB, LBW, and SGA. Even low-normal BMI (18.5-19.9 kg/m 2 ) increased the risk of LBW and SGA. This study provides useful information for pre-conception counseling in lean individuals., (© 2022. The Author(s).)

This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 71-year-old woman became aware of a 25-mm mass in her right breast as identified by her previous doctor. Needle biopsy findings suggested malignant lymphoma, and she was referred to our hospital for further evaluation. She was diagnosed with diffuse large B-cell lymphoma (DLBCL) at our hospital. Positron emission tomography-computed tomography (PET-CT) revealed an elevated SUVmax (maximum standardized uptake value; 10.3), with the mass localized in the right breast, but magnetic resonance imaging findings revealed that the mass had shrunk to 10 mm. Needle biopsy was repeated in our hospital, and lymphoma cells were absent. Two months later, CT scan revealed complete disappearance of the mass, and, since then, the patient has been free of recurrence. Although there are reports of spontaneous remission of nonHodgkin's lymphoma, it is rare in the case of high-grade B-cell lymphoma. The mechanism of spontaneous remission is unclear; however, advancing age, localized stage, activated B-cell (ABC) or nongerminal center B-cell (GCB) type, and a history of infection are the associated factors. The findings from this case suggest that DLBCL can be cured without therapeutic intervention; however, careful followup may be needed.

Differentiating small cell neuroendocrine (NE) carcinoma (SCNC) of the prostate from adenocarcinoma with NE differentiation based on morphological features alone sometimes can be challenging. Given that treatment strategies vary depending on histological type, an accurate diagnosis is critical. This study aimed to identify the accurate diagnostic factors for SCNC of the prostate. Furthermore, the possibility of novel treatment strategies through genetic analysis was also investigated. Prostate biopsies conducted in our hospital between January 2017 and May 2020 were included. Consequently, seven cases of SCNC and four cases of adenocarcinoma with NE differentiation were identified. No significant differences in the serum neuron-specific enolase, pro-gastrin-releasing peptide, and prostate-specific antigen (PSA) levels were observed between both tumors. The Ki-67 labeling index was significantly higher, and PSA immunoreactivity tended to be lower in SCNC. Although the morphology was undetectable, genetic analysis confirmed several mutations, including those of PIK3CA and TP53. The fact that morphological findings are not apparent indicates that genetic investigation rather than only morphological findings would be important in the future. In conclusion, given the heterogeneity of serum NE markers in SCNC, diagnosis based on these markers alone is challenging. A high Ki-67 labeling index and low PSA immunoreactivity may be useful for diagnosis, but p53 immunoreactivity is insufficient in distinguishing. Although further studies are required to interpret the results of the genetic analysis involving ALK, PIK3CA, and TP53 mutations, the results of our genetic analysis suggest that PIK3CA mutations in SCNC of the prostate may provide a novel therapeutic strategy., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Study Objectives: Patients with sleep-disordered breathing have cyclic variation of heart rate (CVHR) in response to respiratory events. However, limited data are available regarding the utility of CVHR as a screening tool for sleep-disordered breathing in patients with mixed heart failure (HF) and those without HF., Methods: We enrolled consecutive patients with and without HF who underwent full polysomnographies with simultaneous Holter electrocardiogram monitoring. We determined the temporal position of the individual dips comprising the CVHR score using time-domain methods., Results: The data of 101 patients, including 70 with and 31 without HF, were analyzed. The CVHR score was significantly correlated with the apnea-hypopnea index ( r = .667, P < .001) and limits of agreement between the apnea-hypopnea index and CVHR score were -21.8 to 35.2. The receiver operating characteristic analysis demonstrated that the CVHR score (best cut-off of 23.5 events/h) identified severe sleep-disordered breathing with a sensitivity of 83.3%, specificity of 79.5%, and the area under the curve of 0.856. In addition, there was no interaction between the presence or absence of HF and the apnea-hypopnea index-CVHR score relationship ( P = .323)., Conclusions: The CVHR score, determined by Holter electrocardiogram monitoring, is a useful tool for evaluating sleep-disordered breathing even in patients with mixed HF and patients without HF., Citation: Yatsu S, Kasai T, Naito R, et al. Utility of cyclic variation of heart rate score as a screening tool for sleep-disordered breathing in patients with heart failure. J Clin Sleep Med . 2021;17(11):2187-2196., (© 2021 American Academy of Sleep Medicine.)

Background: Analytical information obtained from clinical tissue samples has recently become more important due to recent advancements in the clinical practice of medicine, for example, gene panel testing. However, acquiring and managing the sample quality, which greatly influences the analyses, are not sufficient and hence requires immediate attention. We introduced time stamp (TS) recording and documentation using the Standard PREanalytical Code (SPREC) for breast cancer surgery samples to monitor and control their quality. Materials and Methods: The TS recording used SPREC for quality control of each sample by recording seven factors: type of sample, type of collection, warm ischemia time (WIT), cold ischemia time (CIT), fixation type, fixation time (FT), and long-term storage. The responsibilities to record each factor were assigned among group members (breast surgeons, anesthesiologists, pathologists, operating room nurses, and medical technologists in pathology). Results: Records based on SPREC were recorded for 393 surgical cases of first-time breast cancer patients performed at the Kanagawa Cancer Center from May 2018 to April 2019. The vascular clamp time was defined as when skin flap formation was completed, regardless of the surgical procedure. An anesthesiologist recorded the vascular clamp time and sample collection time, and the pathologist recorded the fixation start time and fixation end time. WIT was 23 (3-116) minutes (breast-conserving surgery, 11 [3-38] minutes; mastectomy, 26 [5-116] minutes; and nipple-sparing mastectomy, 39 [31-43] minutes), CIT was 37 (3-1052) minutes, and FT was 43 (17-115) hours. The median CIT and FT were significantly shortened after introducing the TS system, and the variabilities were reduced. Conclusion: A TS system for quality control of breast cancer surgical sample functions well due to the establishment of highly versatile WIT and a working group consisting of multiple members of different occupations who shared roles.

Background: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas., Methods: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis., Results: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology., Conclusion: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma., (© 2021. The Author(s).)

Background: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD., Methods: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude- and confounder-adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD., Results: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the P for trend was statistically significant in the crude and multivariate model excluding anti-depressant medication, but the significance disappeared in the full model (P = 0.050)., Conclusions: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD., (© 2021. The Author(s).)

Purpose: Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis., Methods: Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images., Results: The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS., Conclusions: These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Prostate cancer has become increasingly common worldwide. Although Grade group (GG) is widely accepted as an indicator of prostate cancer grade, there are malignancies that cannot be defined by GG alone. Moreover, the relationship between GG and other parameters remains unclear. Herein, we aimed to explore the biological characteristics of prostate cancer., Methods: This study included 299 radical prostatectomy cases. The Chi-square test and analysis of variance were used to analyze the association of GG with binary and continuous variables. We then conducted morphological analyses. Multivariate analyses were performed to extract the data on risk factors for biochemical recurrence (BCR) and lymph node metastasis., Results: The lymphatic, venous, perineural, and seminal vesicle invasion rates were 37/299 (12.4%), 25/299 (8.4%), 280/299 (93.6%), and 23/299 (7.7%), respectively. The extraprostatic extension (EPE), positive surgical margin, tertiary Gleason pattern 5, intraductal carcinoma of the prostate gland, and lymph node metastasis rates were 89/299 (29.8%), 106/299 (35.5%), 33/260 (12.7%), 56/299 (18.7%), and 23/299 (7.7%), respectively. As GG increased, various parameters became easier to visualize; however, there were differences between the parameters. Postoperative BCR was observed in 31/242 (12.8%) cases without preoperative hormone therapy; GG2, GG3, GG4, and GG5 accounted for 4, 7, 7, and 13 cases, respectively. Multivariate analyses revealed that GG and tumor diameter were significant risk factors for early BCR, whereas lymphatic invasion, EPE, and seminal vesicle invasion were significant risk factors for lymph node metastasis. For BCR, the odds ratios (ORs) for GG and tumor diameter were 2.253 (95% confidence interval (CI]): 1.297-3.912; P=0.004) and 1.074 (95% CI: 1.011-1.142; P=0.022), respectively. For lymph node metastasis, ORs for the presence of lymphatic invasion, EPE, and seminal vesicle invasion were 7.425 (95% CI: 1.688-22.583; P=0.004), 4.391 (95% CI: 1.037-18.589; P=0.044), and 5.755 (95% CI: 1.308-25.316; P=0.021), respectively., Conclusions: We summarized various parameters correlating with each GG. Through multivariate analyses, we established the independent risk factors for early BCR and lymph node metastasis. In addition to GG, other important indices of malignancy were determined and weighted to provide a basis for future investigations., 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 © 2021 Okubo, Sato, Osaka, Yamamoto, Suzuki, Ida, Yoshioka, Suzuki, Washimi, Yokose, Kishida and Miyagi.)

The characteristics of IDH-wild-type lower-grade astrocytoma remain unclear. According to cIMPACT-NOW update 3, IDH-wild-type astrocytomas with any of the following factors show poor prognosis: combination of chromosome 7 gain and 10 loss (+ 7/- 10), and/or EGFR amplification, and/or TERT promoter (TERTp) mutation. Multiplex ligation-dependent probe amplification (MLPA) can detect copy number alterations at reasonable cost. The purpose of this study was to identify a precise, cost-effective method for stratifying the prognosis of IDH-wild-type astrocytoma. Sanger sequencing, MLPA, and quantitative methylation-specific PCR were performed for 42 IDH-wild-type lower-grade astrocytomas surgically treated at Kyoto University Hospital, and overall survival was analysed for 40 patients who underwent first surgery. Of the 42 IDH-wild-type astrocytomas, 21 were classified as grade 4 using cIMPACT-NOW update 3 criteria and all had either TERTp mutation or EGFR amplification. Kaplan-Meier analysis confirmed the prognostic significance of cIMPACT-NOW criteria, and World Health Organization grade was also prognostic. Cox regression hazard model identified independent significant prognostic indicators of PTEN loss (risk ratio, 9.75; p < 0.001) and PDGFRA amplification (risk ratio, 13.9; p = 0.002). The classification recommended by cIMPACT-NOW update 3 could be completed using Sanger sequencing and MLPA. Survival analysis revealed PTEN and PDGFRA were significant prognostic factors for IDH-wild-type lower-grade astrocytoma., (© 2021. The Author(s).)

In the United States, nursing is the largest healthcare profession, with over 3.2 million registered nurses (RNs) nationwide and comprised of mostly women. Foreign-trained RNs make up 15 percent of the RN workforce. For over half a century, the U.S. healthcare industry has recruited these RNs in response to nurse shortages in hospitals and nursing homes. Philippines-trained RNs make up 1 out of 20 RNs in this country and continue to be the largest group of foreign-trained nurses today. Recently, the news media has publicized the many deaths of Filipino RNs as a result of the COVID-19 pandemic in the United States. Given the imperial historical ties between these two countries in the context of the nursing profession and the enduring labor inequities that persist, this nationally representative study is one of the few to our knowledge to not only quantitatively examine the current work differences in characteristics and experiences of Philippines-trained RNs and U.S.-trained white RNs practicing in the United States today, but to also do so from an intersectionality lens. The overall aim of this paper is to illuminate how these differences may serve as potential factors contributing to the disproportionate number of Filipino nurses' COVID-19 related vulnerability and deaths in the workplace., (© 2021 John Wiley & Sons Ltd.)

Objectives: Although psychological stress is a risk factor for oral diseases, there seems to be no review on work stress. This study aimed to review the evidence on the association between work stress and oral conditions, including dental caries, periodontal status and tooth loss., Design: A systematic review of published observational studies., Data Sources: A systematic literature search was conducted in PubMed and Scopus databases on 12 August 2020., Study Selection: Articles were screened based on the following inclusion criteria: published after 1966; in English only; epidemiological studies on humans (except case studies, reviews, letters, commentaries and editorials); and examined the association of work stress with dental caries, periodontal status and tooth loss., Data Extraction: Data were extracted from eligible studies. A quality assessment was conducted using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies., Results: Of 402 articles identified, 11 met the inclusion criteria, and 1 study assessed the association of work stress with dental caries and periodontal status. Of 11 studies, 1 reported a non-significant association between work stress and dental caries; 8 of 9 studies reported a significant association between work stress and worse periodontal status; and 1 of 2 studies reported a significant association between work stress and tooth loss. Nine of 11 studies were cross-sectional, while the remaining 2 studies had unclear methodology. Only two studies were sufficiently adjusted for potential confounders. Eight studies assessed work stress but did not use the current major measures. Three studies were rated as fair, while eight studies had poor quality., Conclusions: There is a lack of evidence on the association of work stress with dental caries and tooth loss. Eight studies suggested potential associations between periodontal status and work stress. Cohort studies using the major work stress measures and adjusting for the potential confounders are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: There are notable geographic variations in incidence rates of suicide both in Japan and globally. Previous studies have found that rurality/urbanity shapes intra-regional differences in suicide mortality, and suicide risk associated with rurality can vary significantly by gender and age. This study aimed to examine spatial patterning of and rural-urban differences in suicide mortality by gender and age group across 1887 municipalities in Japan between 2009 and 2017., Methods: Suicide data were obtained from suicide statistics of the Ministry of Health, Labour and Welfare in Japan. We estimated smoothed standardized mortality ratios for suicide for each of the municipalities and investigated associations with level of rurality/urbanity using Bayesian hierarchical models before and after adjusting for socioeconomic characteristics., Results: The results of the multivariate analyses showed that, for males aged 0-39 and 40-59 years, rural residents tended to have a higher suicide risk compared to urban ones. For males aged 60+ years, a distinct rural-urban gradient in suicide risk was not observed. For females aged 0-39 years, a significant association between suicide risk and rurality was not observed, while for females aged 40-59 years and females aged 60 years or above, the association was a U-shaped curve., Conclusion: Our results showed that geographical distribution of and rural-urban differences in suicide mortality in Japan differed substantially by gender and age. These findings suggest that it is important to take demographic factors into consideration when municipalities allocate resources for suicide prevention.

Objectives: Molecular profiling of marker mutations has become an essential aspect in the treatment planning for colorectal cancer (CRC). Anaplastic lymphoma kinase ( ALK ) mutations could be used as markers in CRC molecular profiling. However, the extremely low frequency of these mutations makes their confirmation in all patients inefficient. Thus, to determine whether ALK positivity could be indicated by morphological features, we have analyzed ALK positivity in CRC tissues with a signet-ring cell carcinoma (SRCC) component., Methods: We screened cases of patients who underwent CRC surgical resection at the Department of Gastrointestinal Surgery of the Kanagawa Cancer Center between January 2015 and December 2019. The selected samples were then assessed immunohistochemically using an antibody against p80 ALK., Results: In total, we were able to retrieve 29 cases of CRC with the SRCC component from the database; however, 5 cases were excluded owing to the absence of formalin-fixed paraffin-embedded tissue sections or the absence of the SRCC component when the tissues were observed. In the immunohistochemical analysis, two cases showed diffused positive immunoreactivity for ALK and were defined as ALK-positive CRC. Thus, the ALK positivity rate in CRC with SRCC was determined to be 8.3%., Conclusions: This present study sheds light on the morphological features of ALK-positive CRC. Our findings could contribute to the effective screening and improvement of front-line therapy for CRC., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2021 by The Japan Society of Coloproctology.)