Effectiveness of self-sampling human papillomavirus test on precancer detection and screening uptake in Japan: The ACCESS randomized controlled trial.

Japan is lagging in cervical cancer prevention. The effectiveness of a self-sampling human papillomavirus (HPV) test, a possible measure to overcome this situation, has not yet been evaluated. A randomized controlled trial was performed to evaluate the effectiveness of a self-sampling HPV test on detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and screening uptake. Women between 30 and 58 years old who did not participate in the cervical cancer screening program for ≥3 years were eligible and assigned to the intervention group (cytology or self-sampling HPV test) or control group (cytology). Participants assigned to the intervention group were sent a self-sampling kit according to their ordering (opt-in strategy). A total of 7337 and 7772 women were assigned to the intervention and control groups, respectively. Screening uptake in the intervention group was significantly higher than that in the control group (20.0% vs. 6.4%; risk ratio: 3.10; 95% confidence interval [CI]: 2.82, 3.42). The compliance rate with cytology triage for HPV-positive women was 46.8% (95% CI: 35.5%, 58.4%). CIN2+ was detected in five and four participants in the intervention and control groups, respectively; there was no difference for intention-to-screen analysis (risk ratio: 1.32; 95% CI: 0.36, 4.93). Self-sampling of HPV test increased screening uptake; however, no difference was observed in the detection of CIN2+, probably due to the low compliance rate for cytology triage in HPV-positive women. Efforts to increase cytology triage are essential to maximize precancer detections.

Impact of the COVID-19 pandemic on gastric surgery in Japan: A nationwide study using interrupted time-series analyses.

BACKGROUND AND AIM: Changes in the number of surgeries for gastric cancer during the coronavirus disease 2019 (COVID-19) pandemic have been reported, but data are insufficient to understand the impact at the national level. This study aimed to determine the impact of the COVID-19 pandemic on gastric surgery in Japan. METHODS: Insurance claims data registered from January 2015 to January 2021 were used. Changes in the number of endoscopic resections and gastrectomies for gastric cancer were estimated using an interrupted time-series analysis. RESULTS: The number of endoscopic resections significantly decreased in July 2020 (-1565; 95% confidence interval [CI]: -2022, -1108) and January 2021 (-539; 95% CI: -970, -109), and the number of laparoscopic surgeries significantly decreased in July 2020 (-795; 95% CI: -1097, -492), October 2020 (-313; 95% CI: -606, -19), and January 2021 (-507; 95% CI: -935, -78). Meanwhile, the number of open gastrectomies remained unchanged, and the number of robot-assisted gastrectomies steadily increased since their coverage by public health insurance in April 2018. CONCLUSIONS: The decreased number of endoscopic resections and laparoscopic surgeries in Japan suggests a decline in early-stage gastric cancer diagnosis, likely due to the suspension of gastric cancer screening and diagnostic testing during the pandemic. Meanwhile, the number of open and robot-assisted gastrectomies remained unchanged and increased, respectively, indicating that these applications were not affected by the pandemic-related medical crisis. These findings highlight that procedures for cancer diagnosis, including screening, should still be provided during pandemics.

Participant mothers' attitudes toward genetic analysis in a birth cohort study.

To conduct a long-term birth cohort study that includes genetic analysis, it is crucial to understand the attitudes of participants to genetic analysis and then take appropriate approaches for addressing their ambiguous and negative attitudes. This study aimed to explore participants' attitudes toward genetic analysis and associated background factors among mothers who were enrolled in a large Japanese birth cohort. A questionnaire was sent to participants' households, and the responses of 1762 mothers (34.0%) were used for the study. The majority of mothers recognized genetic analysis for themselves and their children and sharing of genetic data as beneficial. A low knowledge level of genomic terminology was associated with ambiguous attitudes toward genetic analysis and data sharing. Education level was positively associated with the recognition of the benefits of genetic analysis. Concern about handling genetic information was associated with the unacceptability of data sharing. Trust was associated with the approval of genetic analysis. Most mothers preferred that genetic analysis results be returned. These findings suggest the need for multiple efforts to maximize participants' acceptance of genetic analysis, such as utilizing an educational approach to encourage familiarity with genetics/genomics, optimizing explanations for different educational levels, and explicitly disclosing the handling policy for genetic information.

Association of an IGHV3-66 gene variant with Kawasaki disease.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).

Handheld flow meter improves COPD detectability regardless of using a conventional questionnaire: A split-sample validation study.

BACKGROUND AND OBJECTIVE: Improved detectability of chronic obstructive pulmonary disease (COPD) using a handheld flow meter (HFM) with symptom-based questionnaires has not been sufficiently evaluated. This study aimed to identify the benefit of using an HFM in COPD screening. METHODS: A total of 2008 participants, who were ≥ 40 years of age, from Isumi City, Japan, were recruited. We developed two novel point systems for detecting COPD, one incorporated score of HFM alone (sHFM) and the other incorporated the score of International Primary Care Airway Group questionnaire (IPAG) and HFM (sIPAG + HFM). Validation using random sample allocation (split-sample validation) was carried out to assess the predictive performance of these models. RESULTS: Participants were assigned to a data set for model creation (n = 1007) or a data set for model assessment (n = 1001) to perform split-sample validation. Decision curve analysis showed that the net benefits of sHFM and sIPAG + HFM were higher than that of the IPAG score (sIPAG) and specificity of the former two were also significantly higher than that of sIPAG. However, the curves of sHFM and sIPAG + HFM were crossing and practically the same with no significant difference in sensitivity and specificity. CONCLUSION: This study confirms that HFM is significantly advantageous in detecting COPD despite the use of a conventional questionnaire.

Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease.

ORAI1 encodes a calcium channel essential in the store-operated calcium entry mechanism. A previous genetic association study identified a rare in-frame insertion variant of ORAI1 conferring Kawasaki disease (KD). To deepen our understanding of the involvement of rare variants of ORAI1 in KD pathogenesis, we investigated 3812 patients with KD and 2644 healthy individuals for variations in the protein-coding region of ORAI1. By re-sequencing the study participants' DNA, 27 variants with minor allele frequencies (MAFs) < 0.01 that had not been examined in the previous study were identified. Although no significant association with KD was observed either in single-variant analyses or in a collapsing method analysis of the 27 variants, stratification by MAFs, variant types, and predicted deleteriousness revealed that six rare, deleterious, missense variants (MAF < 0.001, CADD C-score ≥ 20) were exclusively present in KD patients, including three refractory cases (OR = ∞, P = 0.046). The six missense variants include p.Gly98Asp, which has been demonstrated to result in gain of function leading to constitutive Ca2+ entry. Conversely, five types of frameshift variants, all identified near the N terminus and assumed to disrupt ORAI1 function, showed an opposite trend of association (OR = 0.35, P = 0.24). These findings support our hypothesis that genetic variations causing the upregulation of the Ca2+/NFAT pathway confer susceptibility to KD. Our findings also provide insights into the usefulness of stratifying the variants based on their MAFs and on the direction of the effects on protein function when conducting association studies using the gene-based collapsing method.

Correction to: Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Association between blood manganese level during pregnancy and birth size: The Japan environment and children's study (JECS).

BACKGROUND: Manganese (Mn) is both an essential element and a potential toxicant. Although a few studies have suggested a nonlinear relationship between the maternal whole blood Mn level at delivery and infant birth weight, little is known about the effects of Mn levels during pregnancy on fetal growth, particularly with regard to sex-specific differences. METHODS: In this nationwide birth cohort study, we examined the association of maternal blood Mn level during pregnancy with infant birth weight, length, and head circumference in 16,473 mother-infant pairs. Pregnant women living in 15 regions across Japan were recruited between January 2011 and March 2014. The analysis of birth size (8,484 males and 7,989 females) was conducted using a nonlinear spline, followed by the use of quadratic regression or linear regression models. The analysis of small-for-gestational-age (SGA) (6,962 males and 6,528 females born vaginally) was conducted using multivariate logistic regression. Additionally, subgroup analysis was conducted according to the timing of blood sampling. RESULTS: The median maternal blood Mn level during pregnancy (i.e., 2nd and 3rd trimesters) was 16.2 µg/L (range, 4.3-44.5 µg/L). A positive linear association between the log blood Mn level and head circumference was observed in both male and female infants. However, a nonlinear relationship between the log blood Mn level and birth weight was observed only in male infants, such that the birth weight increased up to a blood Mn level of 18.6 µg/L. In the subgroup analysis stratified by the timing of maternal blood sampling, this nonlinear relationship was obvious only when sampling was performed in the 3rd trimester. Male infants in the lowest blood Mn level quartile (≤ 13.2 µg/L) faced an increased risk of SGA (odds ratio [95% confidence interval] = 1.35 [1.04-1.74]), as did those in the highest blood Mn level quartile (≥ 21.0 µg/L) when sampling was performed during the 3rd trimester (odds ratio [95% confidence interval] = 1.62 [1.10 to 2.39]), compared to those in the third blood Mn level quartile (the category including 18.6 µg/L). No association of blood Mn level with birth weight was observed among female infants, and blood Mn level was not associated with birth length in either male or female infants. CONCLUSION: A low blood Mn level during pregnancy or a high blood Mn level during the 3rd trimester was associated with a lower birth weight and increased risk of SGA in male infants, but not in female infants. A low blood Mn level was found to correlate slightly with a small head circumference among infants of both sexes.

Inequality within a community at the neighborhood level and the incidence of mood disorders in Japan: a multilevel analysis.

PURPOSE: This study analyzes whether income inequality within a community at the neighborhood level is associated with incidence of mood disorder in Japan. METHODS: A retrospective cohort study was performed using the data of 116,658 National Health Insurance beneficiaries aged between 20 and 69 in Chiba City, Japan. To evaluate income inequality within a community, the Gini coefficient within a 30-min walking distance from an individual's residence was calculated using income distribution estimated by the National Census and the Housing and Land Survey 2013. Incidence of mood disorder was determined through insurance claims submitted from April 1, 2013, to March 31, 2016. A multilevel logistic analysis with three levels-the individual, household, and residential district-was performed to evaluate the association. RESULTS: Income inequality within a community at the neighborhood level was not associated with incidence of mood disorder in the models with and without equivalent household income (p for trend = 0.856 and 0.947, respectively). No difference was observed in the impact of the Gini coefficient among income levels, lower versus higher income groups (p for interaction between Gini coefficient and household income = 0.967). In contrast, lower equivalent income at the household level was significantly associated with higher incidence of mood disorder (p for trend < 0.001). CONCLUSIONS: While we confirmed that lower income at the household level itself had an adverse effect on mental health, income inequality within a community at the neighborhood level was not a significant factor for incidence of mood disorder in Japan.