MANOCCA: a robust and computationally efficient test of covariance in high-dimension multivariate omics data.

Multivariate analysis is becoming central in studies investigating high-throughput molecular data, yet, some important features of these data are seldom explored. Here, we present MANOCCA (Multivariate Analysis of Conditional CovAriance), a powerful method to test for the effect of a predictor on the covariance matrix of a multivariate outcome. The proposed test is by construction orthogonal to tests based on the mean and variance and is able to capture effects that are missed by both approaches. We first compare the performances of MANOCCA with existing correlation-based methods and show that MANOCCA is the only test correctly calibrated in simulation mimicking omics data. We then investigate the impact of reducing the dimensionality of the data using principal component analysis when the sample size is smaller than the number of pairwise covariance terms analysed. We show that, in many realistic scenarios, the maximum power can be achieved with a limited number of components. Finally, we apply MANOCCA to 1000 healthy individuals from the Milieu Interieur cohort, to assess the effect of health, lifestyle and genetic factors on the covariance of two sets of phenotypes, blood biomarkers and flow cytometry-based immune phenotypes. Our analyses identify significant associations between multiple factors and the covariance of both omics data.

The Stability of Competitive Metacommunities Is Insensitive to Dispersal Connectivity in a Fluctuating Environment.

AbstractMaintaining the stability of ecological communities is critical for conservation, yet we lack a clear understanding of what attributes of metacommunity structure control stability. Some theories suggest that greater dispersal promotes metacommunity stability by stabilizing local populations, while others suggest that dispersal synchronizes fluctuations across patches and leads to global instability. These effects of dispersal on stability may be mediated by metacommunity structure: the number of patches, the pattern of connections across patches, and levels of spatiotemporal correlation in the environment. Thus, we need theory to investigate metacommunity dynamics under different spatial structures and ecological scenarios. Here, we use simulations to investigate whether stability is primarily affected by connectivity, including dispersal rate and topology of connectivity network, or by mechanisms related to the number of patches. We find that in competitive metacommunities with environmental stochasticity, network topology has little effect on stability on the metacommunity scale even while it could change spatial diversity patterns. In contrast, the number of connected patches is the dominant factor promoting stability through averaging stochastic fluctuations across more patches, rather than due to more habitat heterogeneity per se. These results broaden our understanding of how metacommunity structure changes metacommunity stability, which is relevant for designing effective conservation strategies.

Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Positive association between proinsulin and fatty liver index in people with type 2 diabetes.

The post-hoc study, derived from our previous prospective observational study, investigated the association between fasting serum proinsulin levels and hepatic steatosis in people with type 2 diabetes. The severity of hepatic steatosis was assessed using the fatty liver index. A total of 268 participants were divided into three groups: low (n = 110), moderate (n = 75), and high fatty liver index (n = 83). In both the crude and age/sex-adjusted analysis, logarithm-transformed proinsulin was significantly higher in the high fatty liver index group than in the low or moderate groups (all p < 0.01). The moderate fatty liver index group showed higher logarithm-transformed proinsulin than the low group (both p < 0.01). Positive associations between proinsulin and fatty liver index shown in this study would support an involvement of hepato-pancreatic crosstalk in the pathophysiology of type 2 diabetes.

Sequential N2 Adsorption by the Nanopore Entrance Filling Scheme in Nanopores of Carbon Nanotubes.

The adsorption dynamics and mechanism of nitrogen molecules in 1-7 nm carbon nanotubes (CNTs) at 77 K were investigated by experiments and molecular dynamics simulations. The adsorbed nitrogen amount rapidly increased in 7 nm CNTs, while it gradually increased in 1 and 3 nm CNTs. The gradual increase in 3 nm CNTs was unexpected because of the presence of sufficient adsorption sites and the weak adsorption potential of nitrogen. The molecular dynamics simulations indicated that molecules were condensed in the entrance of nanopores after monolayer adsorption in 3 nm CNTs and monolayer and bilayer adsorption in 5 nm CNTs, called nanopore entrance filling. The proposed adsorption mechanism of nitrogen molecules in CNT nanopores is as follows: first, layer-by-layer adsorption occurs on monolayer sites, followed by preferential adsorption at the nanopore entrance. Consequently, preadsorbed molecules form a fluidic pore neck similar to an ink-bottle pore. Then, newly adsorbed molecules are condensed on the fluidic pore neck, and condensed molecules in the nanopore entrance finally move into the inner part of the nanopore. The proposed sequential adsorption mechanism via nanopore entrance filling without pore blocking starkly differs from micropore filling in micropores and layer-by-layer adsorption associated with capillary condensation in mesopores.

Inverse association between glucose variability and body fat in type 2 diabetes with impaired endogenous insulin secretion assessed using continuous glucose monitoring: A prospective observational study.

AIM: To evaluate the contribution of body fat mass and serum adiponectin concentration to glucose variability (GV) stability in people with type 2 diabetes with impaired versus preserved endogenous insulin secretion. MATERIALS AND METHODS: This multicentre prospective observational study included 193 people with type 2 diabetes who underwent ambulatory continuous glucose monitoring, abdominal computed tomography and fasting blood sampling. A fasting C-peptide (FCP) concentration >2 ng/mL was defined as preserved endogenous insulin secretion. The participants were divided into high (FCP > 2 ng/mL) and low FCP subgroups (FCP ≤ 2 ng/mL). Multivariate regression analysis was performed in each subgroup. RESULTS: In the high FCP subgroup, the coefficient of variation (CV) in GV was unrelated to abdominal fat area. In the low FCP subgroup, a high CV was significantly related to small abdominal visceral fat area (ß = -0.11, standard error 0.03; P < 0.05) and to small subcutaneous fat area (ß = -0.09, standard error 0.04; P < 0.05). No significant relationship between serum adiponectin concentration and continuous glucose monitoring-related variables was found. CONCLUSIONS: The contribution of body fat mass to GV depends on the endogenous insulin secretion residue. A small body fat area has independent adverse effects on GV in people with type 2 diabetes and impaired endogenous insulin secretion.

Targeted Metabolomic Profiling of Plasma Samples in Gastric Cancer by Liquid Chromatography-Mass Spectrometry.

INTRODUCTION: As the high mortality rate of gastric cancer (GC) is due to delayed diagnosis, early detection is vital for improved patient outcomes. Metabolic deregulation plays an important role in GC. Although various metabolite-level biomarkers for early detection have been assessed, there is still no unified early detection method. We conducted a plasma metabolome study to assess metabolites that may distinguish GC samples from non-GC samples. METHODS: Blood samples were collected from 72 GC patients and 29 control participants (non-GC group) at the Tokyo Medical University Hospital between March 2020 and November 2020. Hydrophilic metabolites were identified and quantified using liquid chromatography-time-of-flight mass spectrometry. Differences in metabolite concentrations between the GC and non-GC groups were evaluated using the Mann-Whitney test. The discrimination ability of each metabolite was evaluated by the area under the receiver operating characteristic curve. A radial basis function (RBF) kernel-based support vector machine (SVM) model was developed to assess the discrimination ability of multiple metabolites. The selection of variables used for the SVM utilized a step-wise regression method. RESULTS: Of the 96 quantified metabolites, 8 were significantly different between the GC and non-GC groups. Of these, N1-acetylspermine, succinate, and histidine were used in the RBF-SVM model to discriminate GC samples from non-GC samples. The area under the curve (AUC) of the RBF-SVM model was higher (0.915; 95% CI: 0.865-0.965, p < 0.0001), indicating good performance of the RBF-SVM model. The application of this RBF-SVM to the validation dataset resulted from the AUC of the RBF-SVM model was (0.885; 95% CI: 0.797-0.973, p < 0.0001), indicating the good performance of the RBF-SVM model. The sensitivity of the RBF-SVM model was better (69.0%) than those of the common tumor markers carcinoembryonic antigen (CEA) (10.5%) and carbohydrate antigen 19-9 (CA19-9) (2.86%). The RBF-SVM showed a low correlation with CEA and CA19-9, indicating its independence. CONCLUSION: We analyzed plasma metabolomics, and a combination of the quantified metabolites showed high sensitivity for the detection of GC. The independence of the RBF-SVM from tumor markers suggested that their complementary use would be helpful for GC screening.

Identification of Methylsulochrin as a Partial Agonist for Aryl Hydrocarbon Receptors and Its Antiviral and Anti-inflammatory Activities.

Although aryl hydrocarbon receptors (AhRs) are related to the metabolic pathway of xenobiotics, recent studies have revealed that this receptor is also associated with the life cycle of viruses and inflammatory reactions. For example, flutamide, used to treat prostate cancer, inhibits hepatitis C virus proliferation by acting as an AhR antagonist, and methylated-pelargonidin, an AhR agonist, suppresses pro-inflammatory cytokine production. To discover a novel class of AhR ligands, we screened 1000 compounds derived from fungal metabolites using a reporter assay and identified methylsulochrin as a partial agonist of the aryl hydrocarbon receptor. Methylsulochrin was found to inhibit the production of hepatitis C virus (HCV) in Huh-7.5.1 cells. Methylsulochrin also suppressed the production of interleukin-6 in RAW264.7 cells. Furthermore, a preliminary structure-activity relationship study using sulochrin derivatives was performed. Our findings suggest the use of methylsulochrin derivatives as anti-HCV compounds with anti-inflammatory activity.

The Association Between Informal Caregiving and Poor Self-rated Health Among Ever-married Women in Japan: A Nationally Representative Survey.

BACKGROUND: The number of people providing informal caregiving, including dual care, which is the combination of child and nursing care, is increasing. Due to the burden of multiple responsibility, dual care could negatively affect the health of informal caregivers. Previous research has not studied the effects of combining different types of informal caregiving. Therefore, we examined, among Japanese women, 1) the association between types of informal caregiving and self-rated health (SRH), and 2) difference in this association according to caregivers' socio-economic conditions. METHODS: We analyzed the nationally representative 2013 Comprehensive Survey of Living Conditions data of 104,171 women aged 20-59 years. The odds ratios (ORs) for poor SRH by type of informal caregiving (no care, childcare, nursing care, and dual care) were estimated using logistic regression. We also conducted sub-group analyses by socio-economic conditions (equivalent monthly household expenditure and educational attainment). RESULTS: Compared to the no care group, the adjusted ORs for poor SRH of the childcare, nursing-care, and dual care groups were 0.92 (95% confidence interval [CI], 0.88-0.97), 1.33 (95% CI, 1.21-1.47), and 1.42 (95% CI, 1.23-1.64), respectively. There was no extra risk arisen from combining childcare and nursing care. The sub-group analyses indicated that neither household expenditure nor educational attainment affected the association between caregiving type and poor SRH. CONCLUSION: Our study found that informal nursing care and dual care impose a health burden on female caregivers, regardless of their socio-economic conditions. This highlights the importance of addressing the effects of informal caregiving on the health of women.

Impaired psychomotor vigilance associated with sleep-disordered breathing in women working in the care of older adults in Japan.

PURPOSE: With a rapidly aging society, there is increasing interest in the health of female workers in the field of care services for older adults due to increasing demands to maintain 24-h care and to support older adults without errors or accidents. Therefore, the purpose of this cross-sectional study was to examine the association between sleep-disordered breathing (SDB) and sustained attention in women caring for older adults in Japan. METHODS: The study was conducted in women aged 18-67 years old working in care service facilities for older adults in Japan. The sustained attention of participants was measured by the 10-min psychomotor vigilance task (PVT). SDB was assessed based on the respiratory disturbance index (RDI), which was measured using an ambulatory airflow monitor with a polyvinylidene fluoride (PVDF) film sensor to monitor the respiratory airflow of nasal and oral breathing. The participants wore the monitor to record the breathing status while asleep at home. The severity of SDB was categorized as follows: normal, RDI < 5 events/h; mild SDB, RDI 5-10 events/h; and moderate-to-severe SDB, RDI ≥ 10 events/h. RESULTS: Of 688 women enrolled, medians of age, body mass index (BMI), sleep duration, and prevalence of hypertension tended to be higher with increasing RDI. No significant association was found between RDI and PVT parameters. However, when we limited the analysis to women with BMI ≥ 22 kg/m2, those with moderate-to-severe SDB had significantly higher odds of having the slowest 10% reaction times compared to those without SDB (OR = 2.03; 95% CI = 1.17-3.53). The association did not decrease after adjusting to account for sleep duration, alcohol drinking habits, and history of hypertension (OR = 1.97; 95% CI = 1.10-3.52). A significant increasing trend was also found between RDI and the slowest 10% of reaction times (p for trend = 0.03). CONCLUSIONS: Our findings suggest that SDB is associated with reduced sustained attention in participants with BMI ≥ 22 kg/m2, although the number of assessments of SDB and PVT was only once per participant due to the nature of the cross-sectional study.

Metagenomic Shotgun Sequencing Analysis of Canalicular Concretions in Lacrimal Canaliculitis Cases.

Lacrimal canaliculitis is a rare infection of the lacrimal canaliculi with canalicular concretions formed by aggregation of organisms. Metagenomic shotgun sequencing analysis using next-generation sequencing has been used to detect pathogens directly from clinical samples. Using this technology, we report cases of successful pathogen detection of canalicular concretions in lacrimal canaliculitis cases. We investigated patients with primary lacrimal canaliculitis examined in the eye clinics of four hospitals from February 2015 to July 2017. Eighteen canalicular concretion specimens collected from 18 eyes of 17 patients were analyzed by shotgun metagenomics sequencing using the MiSeq platform (Illumina). Taxonomic classification was performed using the GenBank NT database. The canalicular concretion diversity was characterized using the Shannon diversity index. This study included 18 eyes (17 patients, 77.1 ± 6.1 years): 82.4% were women with lacrimal canaliculitis; canalicular concretions were obtained from 12 eyes using lacrimal endoscopy and six eyes using canaliculotomy with curettage. Sequencing analysis detected bacteria in all samples (Shannon diversity index, 0.05-1.47). The following genera of anaerobic bacteria (>1% abundance) were identified: Actinomyces spp. in 15 eyes, Propionibacterium spp., Parvimonas spp. in 11 eyes, Prevotella spp. in 9 eyes, Fusobacterium spp. in 6 eyes, Selenomonas spp. in 5 eyes, Aggregatibacter spp. in 3 eyes, facultative and aerobic bacteria such as Streptococcus spp. in 13 eyes, Campylobacter spp. in 6 eyes, and Haemophilus spp. in 3 eyes. The most common combinations were Actinomyces spp. and Streptococcus spp. and Parvinomonas spp. and Streptococcus spp., found in 10 cases. Pathogens were identified successfully using metagenomic shotgun sequencing analysis in patients with canalicular concretions. Canalicular concretions are polymicrobial with anaerobic and facultative, aerobic bacteria.

Overproduction of Chloroplast Glyceraldehyde-3-Phosphate Dehydrogenase Improves Photosynthesis Slightly under Elevated [CO2] Conditions in Rice.

Chloroplast glyceraldehyde-3-phosphate dehydrogenase (GAPDH) limits the regeneration of ribulose 1,5-bisphosphate (RuBP) in the Calvin-Benson cycle. However, it does not always limit the rate of CO2 assimilation. In the present study, the effects of overproduction of GAPDH on the rate of CO2 assimilation under elevated [CO2] conditions, where the capacity for RuBP regeneration limits photosynthesis, were examined in transgenic rice (Oryza sativa). GAPDH activity was increased to 3.2- and 4.5-fold of the wild-type levels by co-overexpression of the GAPDH genes, GAPA and GAPB, respectively. In the transgenic rice plants, the rate of CO2 assimilation under elevated [CO2] conditions increased by approximately 10%, whereas that under normal and low [CO2] conditions was not affected. These results indicate that overproduction of GAPDH is effective in improving photosynthesis under elevated [CO2] conditions, although its magnitude is relatively small. By contrast, biomass production of the transgenic rice plants was not greater than that of wild-type plants under elevated [CO2] conditions, although starch content tended to increase marginally.

An Individual-Level Meta-Analysis Using Real-World and Pivotal Studies on Mortality From the Use of Paclitaxel-Containing Devices in Japanese Femoropopliteal Disease Patients.

BACKGROUND: The effect of treatment with paclitaxel-containing devices (PTXD) on mortality in patients with peripheral artery disease remains controversial.Methods and Results:An independent patient-level meta-analysis of 12 clinical trials (1,389 PTXD patients and 1,192 non-PTXD patients) was conducted. This study included 7 pivotal trials and 5 post-marketing surveillance studies on endovascular treatment for femoropopliteal artery by 6 companies. The primary endpoint was all-cause death, and 5-year cumulative mortality was estimated by a Kaplan-Meier curve. Cox proportional hazard model was used to calculate the hazard ratio (HR) and confidential interval (CI). During the median follow up of 3.0 years, 459 patients died. The cumulative 5-year mortality for the entire cohort was significantly lower in the PTXD than in the non-PTXD group (24.4% vs. 27.4%, respectively; HR, 0.81; 95% CI, 0.67-0.97; P=0.023), but this difference was no longer significant after adjustment for relevant covariates (HR, 1.01; 95% CI, 0.39-2.58; P=0.987). The Cox proportional hazard model revealed that sex, hyperlipidemia, Type 2 diabetes, hemodialysis, Rutherford category, and age above 75 years were significantly associated with 5-year mortality, but treatment with PTXD was not. CONCLUSIONS: This large individual meta-analysis of patients with femoropopliteal artery disease found that the use of PTXD does not have a negative effect on 5-year mortality.

Histiocytic and dendritic cell neoplasms: Reappraisal of a Japanese series based on t(14;18) and neoplastic PD-L1 expression.

Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.

Hyaluronidase and degranulation inhibitors from the edible roots of Oenanthe javanica including seric acids F and G that were obtained by heating.

Oenanthe javanica is a vegetable grown in East Asia and Australia in which the roots and aerial parts are boiled together to make certain traditional dishes. Nineteen compounds (1-19) were isolated from O. javanica roots and the chemical structures of 2 new norlignans were determined. The inhibitory effects of the compounds on hyaluronidase and degranulation in RBL-2H3 cells were evaluated to determine antiallergic and antiinflammation activities. Saponins (2-4) and the new norlignan seric acid G (12) were among the active compounds identified. Seric acid G (12), a methoxy derivative of seric acid F (11), was obtained as an interconverting mixture of 3:1 trans-cis isomers. Seric acids F and G (11, 12) were derived from seric acids C (10) and E, respectively, by decarboxylation and dehydration reactions that occurred during heating. It was confirmed by HPLC analysis that all eleven of the O. javanica cultivars contained seric acid C (10).

Expression of programmed cell death ligand-1 by immune cells in the microenvironment is a favorable prognostic factor for primary diffuse large B-cell lymphoma of the central nervous system.

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.

Effects of Sex and Seasonal Climatic Changes on the Risk of Incidence of Anti-EGFR Therapy-Induced Rash in Cancer Patients: A Retrospective Study.

Background and Objectives: Seasonal climatic changes may affect the development of the rash that is characteristic of treatment with anti-epidermal growth factor receptor (EGFR) antibodies. We evaluated the association between seasons and rash incidence among patients with cancer. Materials and Methods: Data from patients with colorectal or head and neck cancer treated with cetuximab or panitumumab during summer (S group; n = 34) or winter (W group; n = 37) between June 2014 and February 2019 were collected to retrospectively examine patient characteristics and rash incidence ≤ 8 weeks after treatment initiation. Results: Rashes were observed in 73.5% (n = 25) and 78.4% (n = 29) and grade 3 rashes were observed in 17.6% (n = 6) and 2.7% (n = 1) of the patients in the S and W groups, respectively. The incidence of grade ≥ 2 rashes in males in the S group was higher than that in the rest of the patient groups (p < 0.01). Conclusions: The higher incidence of skin rashes in males during summer might be attributed to the effects of ultraviolet light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies in sweat. These findings highlight the need for research on preventive measures for such rashes.

[Maternal occupation and infant mortality in Japan: Insights from the Vital Statistics (Occupational and Industrial Aspects)].

Objectives　The proportion of Japanese women who maintain their employment during pregnancy and after delivery has been increasing. Previous studies from Western countries showed an association between the mother's occupation and birth outcomes; however, to the best of our knowledge, no epidemiological study has analyzed this association in Japan. Therefore, data from the national Vital Statistics: Occupational and Industrial Aspects were used to examine the association between the mother's occupation and (1) the risk of stillbirth at or after 12 weeks of gestation, and (2) the risk of infant death under 1 year of age after livebirth.Methods　Data from the Vital Statistics: Occupational and Industrial Aspects (Live Birth Form, and Foetal Death Form) for fiscal years (FYs) 1995, 2000, 2005, 2010, and 2015 and Vital Statistics data files (Death Form) from FYs 1995-96, 2000-01, 2005-06, 2010-11, and 2015-16 were analyzed. The study population consisted of (1) 5,355,881 infants who were born during the survey period, with (2) 5,290,808 live birth excluding still birth during the same period. The odds ratios (ORs) were estimated for (1) stillbirth (without stillbirth = livebirth) and (2) infant death (without infant death = alive at 1 year of age) by mother's occupation (managers/specialist/technical workers, clerical workers, sales workers, service workers, blue collar workers, and not employed) using logistic regression. Blue collar workers included workers in security, agriculture/forestry/fishing, manufacturing process, transport, and machine operation. The population attributable risk (PAR) for stillbirth attributed to mother's occupation among employed mothers was also calculated.Results　There were 61,179 (1.1%) stillbirths in the study population and 12,789 (0.2%) infant deaths among 5,290,808 live birth. Compared to managers/specialist/technical workers, the adjusted ORs (95% confidence interval) for stillbirth among clerical workers, sales workers, service workers, blue collar workers and not employed women were 1.24 (1.20-1.29), 1.48 (1.41-1.56), 1.76 (1.69-1.83), 1.54 (1.46-1.61), and 0.95 (0.92-0.98), respectively. There was no association between the mother's occupation and infant deaths. The PAR values for stillbirth among mothers employed as clerical workers and service workers were 7.4% and 12.3%.Conclusion　The risk of stillbirth differed according to the mother's occupation in our study. The OR and PAR of stillbirth were the highest for service workers. Mother's occupation was not associated with the risk of infant death; therefore, the mothers' occupation is likely to affect the children's condition only during pregnancy. Our study suggests the importance of understanding the causal linkage between pregnant women's occupation and birth outcomes.

PD-L1 expression on tumor or stromal cells of nodal cytotoxic T-cell lymphoma: A clinicopathological study of 50 cases.

Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαß type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1- ), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1- ). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.

Age-related EBV-associated B-cell lymphoproliferative disorders and other EBV + lymphoproliferative diseases: New insights into immune escape and immunodeficiency through staining with anti-PD-L1 antibody clone SP142.

Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.