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Tumour genomic profiling (TGP), conducted in search of therapeutics, sometimes reveals potentially pathogenic germline variants as secondary findings (SFs). Physicians involved in TGP are often specialised in oncology and not in clinical genetics. To better utilise SFs, we explored issues physicians have during disclosure and the potential for collaborations with clinical genetics professionals. Semi-structured interviews were conducted with 14 physicians who had experience in handling outpatient TGP at designated core hospitals for cancer genomic medicine in Japan. The data were analysed thematically. The difficulties physicians experienced during informed consent (IC) included educating patients about SFs, providing detailed information on SFs, and explaining the impact of SFs on patients’ family members. When SFs were detected, physicians had reservations regarding the relevance of the disclosure criteria. Confirmatory germline tests were performed using peripheral blood when tumour-only tests detected suspected SFs. Some physicians had reservations about the necessity of confirmatory tests when they did not affect the patients’ treatment options. To encourage patients to receive confirmatory tests, improvements are necessary in the healthcare system, such as insurance reimbursements, education for physicians so that they can provide a better explanation to their patients, and genetic literacy of physicians and patients. The physicians offered insights into the challenges they experienced related to IC, disclosure of SFs, and expectations for active collaborations with clinical genetics professionals. Wider healthcare insurance coverage and better genetic literacy of the population may lead to more patients taking confirmatory tests when SFs are suspected.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer‐Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target‐capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third‐degree relatives), triple‐negative breast cancer patients under the age of 60, and ovarian cancer history (all P, Combination of major clinicopathological risk factors and predictive scores could help identify and characterize high‐risk population carrying BRCA1/2 PGVs among Japanese breast cancer patients. Significant associations were found between the presence of PGVs and early disease onset, number of familial cancer cases within third‐degree relatives, triple‐negative breast cancer patients under the age of 60, and ovarian cancer history (all P

Circulating levels of inflammatory proteins have to be prognostic markers of all-cause mortality. α1-Antitrypsin (AAT) is a major inflammatory plasma protein, but its association with all-cause mortality is unclear. We aimed to evaluate the prognostic significance of AAT levels for all-cause mortality. Study participants comprised 9682 community residents (53.5 ± 13.3 years old). During the 9.8-year follow-up period, 313 participants died from any cause. The mortality rate increased linearly with AAT quintiles (Q1, 18.2; Q2, 24.7; Q3, 23.8; Q4, 31.9; Q5, 64.6 per 10,000 person-years). There were significant correlations between AAT and high-sensitivity C-reactive protein (hsCRP) levels (correlation coefficient, 0.331; P P P P

Purpose To describe the distribution of ocular biometry and refraction in Japanese adults. Design Cross-sectional analysis of a prospective cohort study. Participants A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Participants were between 34 and 80 years of age. Methods All participants underwent axial length (AL; in millimeters), anterior chamber depth (ACD; in millimeters), corneal diameter (white to white; in millimeters), and central corneal thickness (CCT; in micrometers) measurement (IOL Master; Carl Zeiss Meditec, Dublin, CA) and refraction (spherical equivalent [SE]; in diopters [D]) and corneal curvature (CC; in millimeters) measurement (ARK-530A; Nidek, Aichi, Japan). Distribution of these ocular biometric parameters and prevalence of myopia, high myopia, and extreme myopia were summarized. Main Outcome Measures Distribution of ocular biometry and refraction. Results After standardization to the national population of 2015, estimates of mean AL and SE were 24.21 mm and –1.44 D, respectively. Estimates of mean CC, corneal diameter, CCT, and ACD were 7.69 mm, 12.01 mm, 543.96 μm, and 3.21 mm, respectively. After standardization of age and gender, the prevalence of myopia (SE, ≤–0.5 D) and high myopia (SE, ≤–6.0 D) were 49.97% and 7.89%, respectively. Approximately 70% of the younger participants (34–59 years of age) showed myopia, whereas high myopia was observed in approximately 10%. Although the number of individuals with myopia or high myopia was higher in the younger age groups, the prevalence of more extreme phenotypes remained stable across all ages, especially in women. Axial length of more than 30 mm was observed only in older women (n = 5 [0.05%]). Conclusions We showed detailed distributions of various ocular biometry and refraction parameters using a large general Japanese cohort. Prevalences of myopia and high myopia from 2013 through 2016 were higher than those in earlier studies, which reflects recent environmental change. However, constant prevalence of extreme myopia across all ages suggests high genetic predisposition of the extreme phenotype.

Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between “≤9 y of education” and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between “≤9 y of education” and “depressive symptoms” in the general Japanese population.

BACKGROUND High sleep blood pressure (BP) has been suggested to be an independent risk factor for cardiovascular outcomes. To assess the applicability of sleep BP measured using a timer-equipped home device, we investigated the association between home device-measured sleep BP and large artery stiffness. METHODS We performed a cross-sectional analysis of a dataset from the Nagahama study (N = 5916), a general population-based cohort study. Home morning BP and sleep BP were measured using a timer-equipped cuff-oscillometric device (HEM-7080IC). Office BP, carotid intima--media thickness (IMT), and brachial--ankle pulse wave velocity (baPWV) were measured at the follow-up investigation of the Nagahama study. RESULTS Sleep hypertension (SBP ≥120 mmHg and/or DBP ≥70 mmHg) was associated with the arterial parameters (IMT: β = 0.051, baPWV: β = 0.141, both P

Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa's Dementia Scale score (Q1: reference, Q2: β= -0.011, p = 0.537, Q3: β= -0.043, p = 0.016, Q4: β= -0.064, p < 0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy. Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.

OBJECTIVE An association between the Moyamoya disease susceptible gene ring finger protein 213 (RNF213) variant and ischemic stroke and coronary artery disease has been suggested in case-control studies. We aimed to investigate the possible association between the RNF213 variant and the incidence of cardiovascular disease in a general population. METHODS The study participants consisted of 9153 Japanese community residents without history of cardiovascular disease. The clinical parameters employed in this analysis were observed at baseline between 2008 and 2010. The RNF213 p.R4859K variant was determined by TaqMan probe assay and then confirmed by Sanger sequencing. RESULTS During 8.52 years follow-up period, we observed 214 incident cases of cardiovascular diseases (99 total stroke cases, 119 major adverse cardiac event cases, including 4 cases of both). The incidence rate was higher for the variant allele carriers (120 cases; incidence rate, 71.0 per 10 000 person-years) than for the homozygotes of the wild-type allele (26.9), and the group differences achieved statistical significance (P = 0.009). Although the RNF213 variant was also associated with systolic blood pressure (dominant model: coefficient of 8.19 mmHg; P

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G&gt, A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

Aim We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. Methods Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. Results Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. Conclusion The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Purpose: To report fundamental epidemiologic data for choroidal parameters such as choroidal thickness and index of choroidal vascularity in Japanese individuals and to evaluate their correlations with age, sex, systemic parameters, and other ocular parameters. Design: Population-based cohort study. Participants: A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Methods: All participants underwent standardized ophthalmic examinations, including OCT with enhanced depth imaging (EDI; RS-3000 Advance; Nidek). We manually segmented the choroidoscleral interface to measure subfoveal choroidal thickness (SFCT) and calculated the normalized choroidal intensity obtained with EDI (NCIEDI) and choroidal vascularity index (CVI). These are indices of choroidal brightness in OCT and reportedly represent the dilation of choroidal vessels. After summarizing the age-sex stratified distributions of SFCT, NCIEDI, and CVI, their associations with age, sex, axial length (AL), and spherical equivalent (SE) were evaluated using linear regression analysis with adjustments for possible confounders. Main Outcome Measures: Distribution of SFCT, NCIEDI, and CVI in the healthy Japanese population and their characteristics. Results: Age-sex standardized SFCT, NCIEDI, and CVI were 291.2 μm, 0.653, and 66.88%, respectively. In both men and women, SFCT was associated negatively with age (P < 0.001) and NCIEDI was associated positively with age (P < 0.001). Although both SFCT and NCIEDI did not differ significantly between men and women overall (P = 0.87 and P = 0.21, respectively), among younger participants (35–50 years of age), men showed significantly greater SFCT than women (P < 0.001). Only in men was CVI associated positively with age (P < 0.001). In the multivariable analysis, SFCT was associated significantly with age, sex, AL, SE, and the interaction term of age and sex (P < 0.001). Independent of SFCT, NCIEDI and CVI were associated significantly with age (P < 0.001). Conclusions: We report normative Japanese SFCT, NCIEDI, and CVI data using a large general Japanese cohort. The association analysis of SFCT with NCIEDI and CVI suggested that younger individuals have a more lumen-rich choroid for their choroidal thickness than older individuals.

BACKGROUND Nocturia is a risk factor for poor quality of life and increased mortality. This study was aimed to clarifying dietary habits, eating behaviors, and sleep characteristics associated with nocturia to identify modifiable lifestyle factors for nocturia. METHODS This cross-sectional study included 5683 community residents (64.5 ± 7.7 years old). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. The frequency of food intake, unfavorable eating behaviors, and sleep characteristics that may have influence on salt intake and wasting were obtained using a structured questionnaire. RESULTS The frequency of nocturnal urination was increased with age (β = .312, P

Background Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68–8.3 per 100 000 births, but statistical data on the estimated number of TD patients across Japan are not available. The aim of this study was therefore to investigate the prevalence and prognosis of TD in Japan. Methods A nationwide primary questionnaire survey was conducted. Results A total of 127 obstetric, 186 pediatric, and 115 orthopedic facilities provided responses. Excluding duplications, we identified 73 patients with TD. Of the 73 cases, 15 were abortions, four were stillbirths, 51 were live births, and three had unknown details. Of the 51 live newborns, 27 died ≤7 days after birth, with an early neonatal mortality rate of 56%. Of the 24 newborns who survived the early neonatal period, 16 survived for ≥1 year. All of the 24 newborns received respiratory management and survived during the early neonatal period. Of the 51 live newborns, 25 did not receive respiratory management and died ≤2 days after birth. Conclusions The prevalence of TD in Japan is estimated to be at 1.1 (95%CI: 0.84–1.37) per 100 000 births, but the actual incidence is expected to be higher. To our knowledge, we have confirmed for the first time that newborns with TD may not always die during the early neonatal period but can survive the early neonatal period with appropriate respiratory management. Therefore, the term “thanatophoric dysplasia” does not accurately reflect the nature of the disease.

Germline mutations in CDH1, encoding E-cadherin, are known to be the causative mechanism of hereditary diffuse gastric cancer (HDGC). We encountered two cases of gastric cancer in a Japanese family with HDGC. A 28-year-old man (Case 1) died of advanced gastric cancer. His younger sister aged 27 (Case 2) was diagnosed with intramucosal signet ring cell carcinoma (SRCC). Both had identical germline CDH1 mutations, but Case 1 was positive for Helicobacter pylori infection, whereas Case 2 was negative. Case 2 underwent total gastrectomy. Whole-exome sequencing of an intramucosal SRCC in Case 2 revealed seven somatic mutations including one in CDH1. The six non-CDH1 mutations were classified as non-driver mutations. Decreased expression of E-cadherin in intramucosal SRCC was confirmed by immunohistochemistry. Our report demonstrated that CDH1 mutation was the only active driver mutation in Helicobacter pylori-uninfected intramucosal SRCC.

Abnormalities in circadian blood pressure (BP) variation, particularly increase in nocturnal BP, have been reported to be risk factors for cardiovascular disease, although the factors associated with BP abnormalities are not fully understood. This study aimed to clarify possible associations of sleep characteristics, including sleep fragmentation, sleep disordered breathing, and nocturia, with sleep BP by simultaneous multiday measurements.A cross-sectional study evaluated 5959 community participants having home-measured data on nocturnal BP change (sleep BP - awaking BP), sleep characteristics, and sleep disordered breathing. Sleep characteristics including the fragmentation index were assessed using wrist-wearable actigraphy, whereas sleep disordered breathing was assessed by 3% oxygen desaturation index obtained using a finger-type monitor. The number of nocturnal urinations was recorded in a sleep diary.Mean nocturnal SBP change was -8.5 ± 7.9%. A 3% oxygen desaturation index was associated with the BP change independently of the basic covariates (β = 0.051, P = 0.001), although the association became insignificant (P = 0.196) after adjusting the fragmentation index (β = 0.105, P 0.001). The association of the fragmentation index was also insignificant (P = 0.153) after adjusting measurement season (middle season: β = 0.163, P 0.001; summer season: β = 0.249, P 0.001). In contrast, the frequency of urination showed strong and independent association (β = 0.140, P 0.001), with smaller nocturnal BP drop in participants with frequent urination.Subjective sleep estimates and frequent nocturnal urination may represent a potential risk for circadian BP abnormalities.

Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy. Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.

Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra. Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.

USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype&ndash, phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP.

Characteristics of high frequency (HF) component based on heart rate variability (HRV) in a large general population remain unclear, particularly on the relationship with daily physical activity. We aimed to characterize the distribution of HF component and examine the association with daily physical activity among community residents. We performed spectral analysis of HRV from 10-second ECG recordings among 9135 residents aged 30 to 74 years in Nagahama City, Japan. HF components were log-transformed to consider the distribution. Simple correlations between HF and age were determined. Age-adjusted mean values of HF component were calculated for each questionnaire item related to daily physical activity. Multiple regression analysis was performed to examine the effect of daily physical activity on HF component value. Mean values of logarithmically-transformed HF component (lnHF) were higher in women than in men (p < 0.001). lnHF was inversely associated with age (r = -0.40, -0.49 for men, women, respectively). Adjusted mean lnHF for physically active people was significantly higher than that in inactive people (p < 0.001). HF components from 10-second ECG recordings were moderately and negatively correlated with age in both sexes, and positively correlated with daily physical activity in the general adult population. Maintaining the level of daily physical activity, especially to exercise regularly could keep the parasympathetic function high.

Trisomy 18 (T18) and trisomy 13 (T13) are major concerns in prenatal genetic testing due to their poor prognosis; very low birth weight (VLBW) is also a concern in neonatology. The aim of this study was to investigate the mortality and morbidity of VLBW infants diagnosed with T18/T13 in Japan, compared with those with no birth defects (BD-). Maternal and neonatal data were collected prospectively from infants weighing

Sleep-disordered breathing (SDB) is a well-known risk factor for cardiovascular outcomes. Studies of patients with SDB have identified frequent night-time urination as a manifestation related to SDB. We aimed to clarify whether night-time frequency of urination is independently associated with SDB in a general population. We also investigated whether night-time frequency of urination can help presumptive diagnose SDB.Study participants consisted of 7151 community residents. Oxygen saturation during sleep was measured for four nights using a pulse oximeter. SDB was defined as ≥15 events per hour in which oxygen desaturation exceeded or equal to 3% during an actigraphy-determined sleep period. Night-time frequency of urination was recorded for one week using a sleep diary.Significant positive correlations were evident between night-time frequency of urination and SDB (none, 5.8%; once/night, 14.1%; twice/night, 20.1%; thrice/night, 28.7%;thrice/night, 44.1%, P 0.001). This association was independent of possible covariates, including sleep duration (adjusted odds ratio: once/night = 1.50, twice/night = 2.15, thrice/night = 3.07,thrice/night = 3.73, P 0.001). Other factors significantly associated with SDB were age, sex, obesity, observation of sleep apnea, and short sleep duration. The area under the curve of the risk score for SDB consisting of these conventional six items (0.834) significantly improved (0.842, P = 0.001) when night-time frequency of urination was considered as a risk score item.Night-time frequency of urination was associated with SDB. Our findings suggest that the urination frequency should be considered a manifestation of SDB even in a general population.

ObjectivesTo explore the negative recollections of prostate cancer patients regarding the attitudes and language used by the doctors in delivering their diagnoses in Japan, in order to improve patient-centred communication.Design and settingThis is a qualitative secondary analysis of the prostate cancer narrative data from the Database of Individual Patients’ Experiences-Japan archives. A thematic analysis was conducted regarding negative recollections of doctors’ words/attitudes when delivering a cancer diagnosis. Recruitment was based on maximum variation sampling. Participants were recruited from medical institutions, patient associations and through media advertisements.ParticipantsMen with a diagnosis of prostate cancer (n=51).FindingsOf the 51 participants, 17 had negative recollections of the doctors’ words/attitudes during the delivery of the cancer diagnosis. After thematic analysis, 11 categories emerged: ‘Surprised by the abrupt disclosure of the diagnosis’, ‘Displeased by the direct disclosure of the diagnosis to the patient in the absence of family members’, ‘Unable to accept the doctor’s negative words in the explanations’, ‘Unable to understand the doctor’s technical jargon’, ‘Distrust due to failure in diagnosis based on previous examinations’, ‘Aggrieved at the doctor’s unwillingness to allow questions’, ‘Dissatisfied with explanations involving facts only’, ‘Indignant over the unexpected disclosure of life expectancy’, ‘Unable to accept the doctor’s blame for the delay in the initial hospital visit’, ‘Uncomfortable with the usage of inappropriate metaphors’ and ‘Pessimistic thoughts despite optimistic explanations’.ConclusionsIt is clear that patients have recollections of a variety of negative experiences regarding the words/attitudes of their doctors at the time they received their prostate cancer diagnosis. Thus, the use of narrative data would facilitate the appropriate application of commonly used guidelines for the delivery of cancer diagnoses tailored to individual patients in clinical practice.

Background The accumulation of advanced glycation end product (AGE) might exert deleterious effects on musculoskeletal properties. Our study aims to clarify this possible association in a large general population. Methods This study investigated a general population of 9,203 patients (mean age, 57.8 years). Skeletal muscle mass was measured by bioelectrical impedance analysis, whereas accumulation of AGEs was assessed by skin autofluorescence (SAF-AGE). The muscle strength of upper and lower limbs and usual gait speed were measured in a portion of older (≥60 years of age) participants (n = 1,934). The speed of sound (SOS) in the calcaneal bone was assessed via a quantitative ultrasound technique. Results In the total population, the frequency of low skeletal muscle mass linearly increased with the SAF-AGE quartiles (Q1: 14.2%, Q2: 16.1%, Q3: 21.1%, Q4: 24.8%; p < .001), and this association was independent of covariates including glycemic traits (Q4: odds ratio [OR] = 1.48, p < .001). The association between the highest SAF-AGE quartile and low skeletal muscle mass remained significant in the older subpopulation (OR = 1.85, p = .002). A similar but weak association was observed for low SOS (Q1: 8.9%, Q2: 8.3%, Q3: 10.4%, Q4: 12.2%; p < .001). Similar inverse associations were also observed with grip strength (OR = 1.98, p = .003), hip flexion strength (OR = 1.50, p = .012), and hip abduction strength (OR = 1.78, p = .001), but not with usual gait speed. Conclusion Accumulation of AGEs might be a deleterious factor for musculoskeletal properties.

BACKGROUND Orthostatic hypertension was associated with worse cardiovascular outcomes, although the factors responsible for an orthostatic rise in blood pressure (BP) are uncertain. We investigated a possible relationship between a stooping posture and orthostatic BP change. METHODS Study participants consisted of 1,992 older individuals. Orthostatic BP change was calculated by systolic BP measured at sitting position, and again 1 and 3 minutes after standing up. Spinal alignment and curvature was assessed by guiding the SpinalMouse device on the surface of the skin along the spine. RESULTS Mean lumbar lordosis at standing position was 13.4° ± 12.4°. The degree of lumbar lordosis was significantly smaller in orthostatic hypertensive individuals (systolic BP change, ≥+20 mm Hg: 3.3° ± 15.6°, ≥+10 mm Hg: 10.4° ± 14.3°) than in individuals who were orthostatic normotensive (14.2° ± 11.9°). Multiple linear regression analysis identified lumbar lordosis (β = −0.171, P < 0.001) and thoracic kyphosis (β = 0.062, P = 0.007), but not sacral inclination (β = 0.033, P = 0.303), as independent determinants for orthostatic BP change. As waist circumference was another independent determinant, the frequency of orthostatic hypertensive individuals was linearly increased with the combination of abdominal obesity and small degree of lumbar lordosis (control: 9.9%, abdominal obesity: 17.4%, small degree of lordosis: 19.4%, both: 24.1%, P < 0.001). Participants who sustained orthostatic hypertension for 3 minutes after standing up had the smallest degree of lumbar lordosis (5.2° ± 16.4°). CONCLUSION Stooped posture was an overlooked determinant for orthostatic increases in BP.

High sodium intake is a simple modifiable risk factor for hypertension. Although not confirmed, lower socioeconomic status may be a factor that increases sodium intake. We aimed to clarify the association between socioeconomic status and urinary sodium-to-potassium ratio by cross-sectional and longitudinal analyses. The study included 9410 community residents. Spot urine sodium-to-potassium ratios were measured twice with a 5-year interval. Socioeconomic status was investigated using a self-administered questionnaire. Cross-sectional analysis revealed that educational attainment was inversely associated with urinary sodium-to-potassium ratio (years of education ≤ 9: 3.0 ± 1.8, ≤ 12: 2.9 ± 1.6, ≥ 13: 2.8 ± 1.6; P

Cardio-ankle vascular index (CAVI) has been increasingly used as an index for arterial stiffness. However, the degree of longitudinal changes and factors affecting these changes in CAVI (ΔCAVI) are largely unknown. The aim of this study was to descriptively clarify factors associated with longitudinal ΔCAVI for the precise use of this index in the assessment of arterial stiffness.Study participants comprised 9501 community residents (53.1 ± 13.3 years), with 8004 patients included in the longitudinal analysis. CAVI was calculated by the transient time interval of arterial waveform measured at four extremities.Factors showing a strong association with baseline CAVI (7.38 ± 1.10) included age (β = 0.586), SBP (β = 0.175), and male sex (β = 0.142), whereas BMI showed an inverse association (β = -0.208) (all P 0.001). During the 1815 ± 135 days follow-up period, CAVI increased by 0.47 ± 0.68. Multivariate analysis identified age (β = 0.508), male sex (β = 0.089), Brinkman index (β = 0.074), and SBP (β = 0.037) as positive determinants, whereas BMI (β = -0.079) and baseline CAVI (β = -0.590) as inverse determinants for ΔCAVI (all P 0.001). Further data accumulation is needed to determine a reference value of CAVI due to its large population differences.Several factors were commonly associated with baseline and longitudinal ΔCAVI. These factors should be carefully considered when CAVI is used for the assessment of arterial stiffness.

e22524 Background: Presumed germline pathogenic variants (PGPVs) can be detected in tumor tissues using comprehensive genomic profiling. Clinicians and patients can decide whether to conduct confirmatory germline testing or not. However, the promoting and obstructive factors for confirmatory germline testing are unclear. Methods: This single institutional retrospective study aimed to identify factors related to confirmatory germline testing in patients with PGPVs. Between April 2015 and April 2019, 270 consecutive patients with cancers of unknown primary site, rare tumors, or solid tumors refractory to standard chemotherapy, who underwent tumor-only comprehensive genomic profiling were reviewed. PGPVs were proposed to be disclosed as variants to the patients by our institutional molecular tumor board. Univariate logistic regression analysis was conducted to investigate the relationship between each patient’s characteristics and confirmatory germline testing. Factors showing a statistical relationship (p < 0.10 in univariate analyses) were included in multivariate logistic regression analysis with a backward selection of variables. Statistical significance was set at p < 0.05. Results: Of the 270 patients who underwent tumor-only comprehensive genomic profiling, 77 possessed PGPVs. The most common PGPVs were TP53 (n = 56), APC (n = 9), PTEN (n = 7), RB1 (n = 6), and BRCA2 (n = 6). Among the 77 patients, only 11 (14.3%) chose to undergo confirmatory germline testing. Multivariate logistic regression analysis revealed that the person disclosing the results (experienced oncologists with knowledge of cancer genome medicine vs. others, odds ratio [OR]: 27.7, 95% confidence interval [CI]: 4.60–167) and study period (OR: 0.110, 95% CI: 0.015–0.787) were independently and significantly associated with confirmatory germline testing. Conclusions: These findings indicate that fostering genomic competency in oncologists and collaborating with genetic experts would facilitate cancer patients and their families to receive genetic medical services in the process of cancer genomic profiling.

In addition to its antiatherogenic action, high-density lipoprotein (HDL) may also have an antidiabetes function. Although the biological actions of small HDL (HDL3) and large HDL (HDL2) subclasses may be different, evidence in support of that hypothesis is lacking. The aim of this study was to clarify the difference in prognostic significance of HDL subclasses for exacerbation of insulin resistance and incidence of type 2 diabetes in the general population.Study participants included 8365 community residents 52±13years of age not taking lipid lowering drugs. Serum HDL cholesterol subclasses and low-density lipoprotein subclasses, were measured by a homogeneous assay. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR).Cross-sectional analysis adjusted for possible covariates found that HDL2 cholesterol (HDL2-C) levels were inversely associated with HOMA-IR (β=-0.169, p0.001), whereas HDL3-C had the opposite association (β=0.054, p0.001). Similar results were found in an analysis for type 2 diabetes (HDL2-C, odds ratio=0.96, p=0.001; HDL3-C, odds ratio=1.04, p=0.181). In a longitudinal analysis with 5.0years of follow-up, HDL2-C was inversely associated with exacerbation of insulin resistance (β=-0.163, p0.001); HDL3-C had the opposite association (β=0.026, p=0.037). During follow-up, 205 individuals were newly diagnosed with diabetes, and HDL2-C level was associated with an inverse risk of type 2 diabetes incidence (odds ratio=0.98, p=0.006).HDL may have an antidiabetic function; the prognostic value of HDL2-C for diabetes and insulin resistance might be better than that of HDL3-C.

In tumor-only next-generation sequencing (NGS), identified variants have the potential to be secondary findings (SFs), but they require verification through additional germline testing. In the present study, 194 patients with advanced cancer who underwent tumor-only NGS between April 2015 and March 2018 were enrolled, and the incidences of possible and true SFs were evaluated. Among them, 120 patients (61.9%) harbored at least one possible SF. TP53 was the most frequent gene in which 97 variants were found in 91 patients (49.5%). Nine patients provided informed consent to undergo additional germline testing, and a total of 14 variants (BRCA1, n = 1; BRCA2, n = 2; PTEN, n = 2; RB1, n = 1; SMAD4, n = 1; STK11, n = 1; TP53, n = 6) were analyzed. Three variants (BRCA1, n = 1; BRCA2, n = 2) were confirmed to be SFs, whereas TP53 variants were confirmed to be somatic variants. To confirm the low prevalence of SFs in TP53, we analyzed 24 patients with TP53 variants who underwent a paired tumor–normal NGS assay. As expected, all TP53 variants were confirmed to be somatic variants. A total of 30 patients were tested for germline variants in TP53, but none of them resulted in true SFs, suggesting the low prevalence of SFs in this gene. Therefore, the significance of additional germline testing for TP53 variants appears to be relatively low in daily clinical practice using a tumor-only NGS assay, unless patients have any relevant medical or family history.

Nocturia in older adults has been reported to be a risk factor for cardiovascular outcomes, and the stiffening of large arteries might be an underlying mechanism. To clarify the possible association between nocturia and arterial stiffness, we analyzed a dataset from the Japanese general population. Study participants consisted of 5928 community residents (mean age: 60.0 ± 11.8 years). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. Arterial stiffness was assessed by brachial-to-ankle pulse wave velocity (baPWV). Sleep blood pressure was measured automatically at 0000, 0200, and 0400 hours by wearing a cuff on the upper arm during sleep. The mean baPWV was 1278 ± 227 cm/s. The frequency of nocturnal urination showed a linear positive association with baPWV (P 0.001). The association between a sleep diary-based nocturnal urination frequency 1.5 times/night (corresponding to a ≥ 2 times/night frequency obtained by the questionnaire) and baPWV remained significant after adjusting for major covariates, including office blood pressure (β = 0.051, P 0.001) and sleep blood pressure (β = 0.040, P 0.001). This association was more prominent in men (β = 0.069, P 0.001) than in women (β = 0.023, P = 0.013), particularly in older (β = 0.068, P = 0.006) compared with younger (β = 0.029, P = 0.270) men. Frequent nocturnal urination was independently associated with baPWV in older men. Nocturia may be a marker for cardiovascular disease risks that cannot be assessed by conventional risk factors such as blood pressure.

Nocturia is a common phenomenon in older individuals, and is associated with poor quality of life. Nocturia is a multifactorial disorder, wherein the frailty of skeletal muscles, particularly muscle weakness in the lower trunk and hip regions, might be a risk factor in women. We analyzed a dataset of the general Japanese population to clarify the hypothesis.Study participants included 1207 older women (mean age 67.4 ± 5.2 years). The frequency of nocturnal urination was assessed using a sleep diary for 1 week, and associations with lower muscle strength, skeletal muscle index, sarcopenia and physical performance (one-leg standing time and Timed Up and Go test) were investigated.The frequency of nocturnal urination more than one voiding per night was 28.1%; this frequency was inversely associated with hip abduction strength quartiles (Q1: 37.0, Q2: 30.5, Q3: 25.1 and Q4: 19.9%, P 0.001). When a sleep diary-based nocturnal urination frequency 1.5 times/night (corresponding to a ≥2 times/night frequency obtained by questionnaire) was considered as nocturia, logistic regression analysis adjusted for major covariates identified hip abduction strength as an independent inverse determinant of nocturia (odds ratio 0.75, 95% CI 0.52-0.90, P = 0.002). In contrast, no significant association was observed with knee extension (P = 0.322) and hip flexion (P = 0.603) strengths. Physical performance, skeletal muscle index and sarcopenia did not show significant associations with nocturia.Weak hip abduction strength might be a factor associated with nocturnal urination frequency in older women. Geriatr Gerontol Int 2019; 19: 1010-1016.

Dietary habits and lifestyles are considered to affect the frequency of epigastric symptoms. In our previous study, we found that three amino acids in Japanese broth promoted gastric emptying. We hypothesized that a higher consumption of miso soup which was mainly composed of Japanese broth and miso paste would be associated with a lower frequency of epigastric symptoms. We conducted a cross-sectional study of the association between frequency of miso soup intake and reflux or dyspepsia symptoms in a general Japanese population. Sixteen items of dietary habits were assessed using a self-reported questionnaire, and epigastric symptoms were evaluated using the Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (FSSG). We fitted generalized linear models to analyze the association between miso soup intake and FSSG, reflux, or dyspepsia scores adjusted by age, sex, body mass index (BMI), another 15 dietary habits, smoking, drinking alcohol, and unfavorable dietary behaviors. A total of 9,364 subjects were included in the analysis. Trend analysis revealed that higher frequency of miso soup intake was associated with lower FSSG scores (p

To evaluate the mortality and morbidity of very low birth weight (VLBW) preterm infants with birth defects in Japan.Data were collected prospectively for infants weighing1501 g and born at37 weeks of gestation admitted to centers of the Neonatal Research Network of Japan during 2003-2016. We compared outcomes of infants with and without birth defects using Pearson χAmong 57 730 VLBW preterm infants, 3557 infants (6.2%) were born with birth defects. Chromosomal abnormalities, congenital heart defects, and congenital malformation of the digestive system were the most common categories. Among diseases, Trisomy 18, Down syndrome, and cleft palate were the most prevalent. There were significant differences between perinatal characteristics of infants with and without birth defects. Most categories of morbidity occurred more frequently in infants with birth defects compared with those without birth defects. The aOR for mortality during the neonatal intensive care unit admission was 10.6 (95% CI 9.5-11.7) for infants with birth defects. A stratified analysis identified birth defect categories with good, moderate, and poor prognoses.This detailed information about mortality and morbidity of preterm VLBW infants with birth defects should be useful for genetic counseling as well as prenatal and neonatal care, with the limitation that we lacked information about the timing of diagnosis, abortion, or stillbirth.

Background Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. Methods A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. Results As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. Conclusion The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% confidence interval, 1.27-2.62) and 2.20 (95% confidence interval, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% confidence interval, 3.01-5.52) when mouth breathing and allergic rhinitis co-existed. Mouth breathing in non-asthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the "one airway, one disease" concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population. This article is protected by copyright. All rights reserved.

[Background]Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia. [Methods] A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. [Results] As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥ 12 h, P < 0.001) or near-fasting (5–11 h, P < 0.001) conditions, and not in those taken under non-fasting (< 5 h, P = 0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (β = 0.052, P < 0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA⁎glucose; β = 0.036, P < 0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s. [Conclusions] Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature.

Backgrounds Sarcopenia in older adults is a risk factor for age-related morbidity and mortality. This study aimed to clarify the diagnostic significance of the revised diagnostic algorithm for sarcopenia from Asian Working Group for Sarcopenia by comparing physical and clinical characteristics of individuals diagnosed with sarcopenia by the initial and revised algorithms. Methods Study participants were 2061 older community residents. Skeletal muscle mass was measured by bioimpedance analysis. Handgrip strength and physical function required for the diagnosis of sarcopenia were measured by conventional methods. Carotid intima-media thickness was used as a marker of atherosclerosis in a large artery. Results Using the initial algorithm, 60 of the participants were diagnosed with sarcopenia, but based on the revised algorithm, 89 had sarcopenia and 21 severe sarcopenia. The higher frequency of sarcopenia was attributed to changes in the cut-off values for slow gait speed and the addition of the 5-time chair-stand test as part of the assessment of physical performance. Physical characteristics of individuals diagnosed with sarcopenia by either algorithm did not differ markedly, but those with severe sarcopenia had significantly poorer physical performance even with a muscle mass similar to those with sarcopenia. There was a linear correlation between the severity of sarcopenia and carotid intima-media thickness (no sarcopenia: 0.94 ± 0.31, sarcopenia: 1.04 ± 0.41, and severe sarcopenia: 1.07 ± 0.55 mm, P = 0.003). Conclusion The revised diagnostic algorithm was superior to the initial version at identifying individuals with sarcopenia and severe sarcopenia with a worse cardiovascular profile.

832 Background: From June, 2019, two comprehensive genomic profiling (CGP) assays, "FoundationOne CDx" and “OncoGuide NCC Oncopanel”, were reimbursed by the national insurance system in Japan for patients who were refractory to standard chemotherapy. However, their clinical utility for chemotherapy-naïve cancer patients is unknown. Methods: We conducted a single institutional prospective observational study to evaluate the clinical utility of FoundationOne CDx assay (Cambridge, MA, USA) for the patients with chemotherapy-naïve advanced gastrointestinal malignancies. Patients with adequate H.E. sample were registered in this study. Primary outcome was the detection rate of at least one actionable/druggable cancer genomic alterations. The evidence levels were classified according to clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 1.0) (Sunami K. Cancer Sci. 2018). Results: From October 2018 to June 2019, a total of 238 patients were screened and the following 158 patients were registered: colorectal cancer (n = 60), gastric cancer (n = 19), esophageal cancer (n = 23), pancreatic cancer (n = 30), biliary tract cancer (n = 11), rare gastrointestinal malignancies (n = 15). The CGP data were obtained for 113 patients . Median turn-around time was 14 days (range 10-247 days). Actionable/druggable cancer genomic alterations were observed in 113 patients (100%)/ 65 patients (57.5%), respectively. Clinically relevant biomarkers and genomic alterations were identified in 22 patients (19.5%); BRCA2 (n = 4), ERBB2 (n = 4) , BRAF (n = 3) , EGFR (n = 3), FGFR2 (n = 2), MET (n = 2), NTRK (n = 2) , MSI-H (n = 2 ), TMB-high (n = 2), ALK (n = 1) , KIT (n = 1) and ROS1 (n = 1). Of note, novel biomarkers such as ROS1- GOPC fusion and PALB2 rearrangement were obtained in the patients with esophageal squamous cell carcinoma. Conclusions: This is the first study to evaluate the clinical utility of CGP in patient with chemotherapy-naïve advanced gastrointestinal malignancies. Our result indicated that CGP might provide a chance of potentially effective drugs as a novel approach in precision cancer medicine. Clinical trial information: UMIN000034830.

We aimed to analyze associations of sleep disturbance, including sleep disordered breathing, sleep fragmentation, and sleep efficiency, with abnormal nocturnal blood pressure (BP) profiles that may be risk factors for adverse cardiovascular outcomes.The study included 5854 community residents with 20,725 multi-day measurements. Sleep fragmentation and efficiency were evaluated using a wrist-worn activity monitor. Sleep disordered breathing was assessed using the 3% oxygen desaturation index corrected for actigraphy-determined sleep duration. A timer-equipped standard cuff-oscillometric device was used for home and sleep BP monitoring.Mean nocturnal systolic BP (SBP) change was -8.6 ± 9.7% (-11.1 ± 12.6 mmHg), and inter-day correlation coefficient of the nocturnal SBP change was 0.443. Results of a linear mixed model analysis using daily measured values identified lower sleep efficiency (coefficient = -0.130, p 0.001) as a determinant for decreased nocturnal SBP dipping beyond the interday variations of these parameters. Number of nocturnal urinations was another strong determinant (coefficient = 1.191, p 0.001), although the association of sleep efficiency was independent of nocturnal urination, awake SBP, and sleep disordered breathing (coefficient = -0.102, p 0.001). Sleep efficiency was also independently associated with sleep SBP level (coefficient = -0.138, p 0.001). Estimated differences in nocturnal SBP dipping and sleep SBP level as a function of the degree of sleep efficiency (less than 80%) reached 1.63% (1.09-2.17%) and 2.16 mmHg (1.49-2.82%), respectively.More attention should be paid to sleep efficiency as a factor in maintaining circadian BP rhythm.

BACKGROUND The aim of this study is to clarify associations between orthostatic blood pressure (BP) change, as well as possible physiological factors, and day-to-day home BP variability, a promising risk factor for cardiovascular outcomes. METHODS Study participants were 6,465 community residents (age 58.3 years). Home BP was measured every morning and evening for 7 days. Orthostatic BP was calculated as the maximum difference between BP measured while sitting and remeasured after 1 and 3 minutes standing. RESULTS Frequency of individuals who showed orthostatic BP decline was as follows: systolic BP (SBP) change ≥−20 mm Hg: 2.6%, ≥−10 mm Hg: 14.1%. These subgroups showed larger home SBP variability (average real variability: 11.3 ± 5.3, 8.7 ± 3.9 mm Hg) when compared with orthostatic normotensives (7.6 ± 3.7 mm Hg) (all P < 0.001). Multiple linear regression analysis adjusted for major covariates, including seated BP, identified orthostatic BP drop as an independent determinant for morning BP variability (≥−20 mm Hg: β = 0.037, P = 0.003; ≥−10 mm Hg: β = 0.026, P = 0.036) but not for evening BP variability. Carotid hypertrophy was significantly associated with home BP variability (morning: β = 0.052, P = 0.001; evening: β = 0.065, P < 0.001) and showed a U-shaped association with orthostatic BP change. Plasma B-type natriuretic peptide level, a previously suggested factor for BP variability, did not show significant association with morning and evening BP variability. CONCLUSION Orthostatic BP decline was significantly associated with morning BP variability. Large artery atherosclerosis was a common risk factor.

Aims To investigate the association between insulin resistance assessed by a homeostasis model and dietary habits. Methods Cross-sectional analysis using a community-based cohort, the Nagahama Prospective Cohort for Comprehensive Human Bioscience. Multiple linear regression analysis was performed with log HOMA-IR or log HOMA-β as the dependent variable and 20 dietary habits, tobacco smoking, medical history, family medical history of diabetes, age and BMI as the simultaneous independent variables in each sex separately. Results Females (n = 2956) eating fish dishes every day had a HOMA-IR 0.90 times that of the reference group (P = 0.043). Females eating miso-soup every day had a HOMA-IR 0.95 times that of the reference group (P = 0.038). Males (n = 1371) eating vegetable dishes every day had a HOMA-IR 0.91 times that of the reference group (P = 0.003). Males eating egg dishes 4 to 5 times per week had a HOMA-IR 1.14 times that of the reference group (P = 0.011). Males eating fruits every day had a HOMA-IR 1.13 that of the reference group (P = 0.008). Conclusions Dietary habits associated with lower insulin resistance were eating fish dishes, miso soup or vegetable dishes every day and eating staple foods for dinner, egg dishes or fruits less frequently.

Anti-citrullinated peptide antibody (ACPA) is a highly specific autoantibody to rheumatoid arthritis (RA). Recent studies have revealed that periodontal disease (PD) is closely associated with RA and production of ACPA in RA. Analyses of associations between PD and ACPA production in a healthy population may deepen our understandings. Here, we analyzed a total of 9554 adult healthy subjects. ACPA and IgM-rheumatoid factor (RF) was quantified and PD status was evaluated using the number of missing teeth (MT), the Community Periodontal Index (CPI) and Loss of Attachment (LA) for these subjects. PD status was analyzed for its association with the positivity and categorical levels of ACPA and RF conditioned for covariates which were shown to be associated with PD, ACPA or RF. As a result, all of MT, CPI and LA showed suggestive or significant associations with positivity (p=0.024, 0.0042 and 0.037, respectively) and levels of ACPA (p≤0.00031), but none of the PD parameters were associated with those of RF. These association patterns were also observed when we analyzed 6206 non-smokers of the participants. The significant associations between PD parameters and positivity and levels of ACPA in healthy population support the fundamental involvement of PD with ACPA production., 歯周病と関節リウマチ発症との相関を示す. 京都大学プレスリリース. 2015-04-21.

Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber.The study included 8054 Japanese participants. Central BP was estimated by the radial arterial waveform by calibrating brachial BP. Central retinal arteriolar equivalent (CRAE) was computationally measured using fundus photography.CRAE was most strongly associated with central SBP (r = -0.324, P 0.001), followed by DBP (r = -0.292, P 0.001) and central pulse pressure (PP; r = -0.226, P 0.001). The correlation coefficient between SBP and CRAE was significantly greater in central SBP than in brachial SBP (r = -0.300, P 0.001). After adjustment for possible covariates, brachial SBP (β = -0.221, P 0.001) and central SBP (β = -0.239, P 0.001) were independently associated with CRAE. Further, higher brachial SBP (β = -0.226, P 0.001) and smaller PP amplification (β = 0.092, P 0.001) were identified as independent determinants of narrowing of CRAE in the same equation, which indicated the superiority of central BP. Central BP-determined hypertensive individuals had a significantly narrower CRAE independent of brachial BP (central/brachial: hypertension/hypertension 121.4 ± 11.5, hypertension/normotension 120.9 ± 11.2, normotension/hypertension 125.1 ± 11.9, normotension/normotension 128.1 ± 11.5 μm).Central BP was more closely associated with the narrowing of CRAE than brachial BP. Slight increases in central BP might be involved in the morphological changes in small retinal arteries, even in individuals with optimal brachial BP.

Objective Anti–citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are markers to rheumatoid arthritis (RA). Smoking and shared epitope (SE) in HLA–DRB1 are associated with the production of these autoantibodies in RA. Detailed distribution and characterization of ACPA and RF in the general population have remained unclear. We aimed to evaluate positivity of ACPA and RF in a general Japanese population and to detect correlates, including genetic components. Methods ACPA and RF were quantified in 9,804 Japanese volunteers ages 30–75 years. Logistic regression analyses were performed to evaluate the effects of candidates of correlates on the autoantibody positivity. A genome-wide association study (GWAS) was performed using 394,239 single nucleotide polymorphisms for 3,170 participants, and HLA–DRB1 alleles were imputed based on the GWAS data. Results A total of 1.7% and 6.4% of subjects were positive for ACPA and RF, respectively, and the 2 markers showed a significant correlation (P = 2.0 × 10−23). Old age was associated with ACPA positivity (P = 0.00062). Sex, smoking, SE, and other candidates of correlates did not have significant effects. Interaction between smoking and SE positivity was not apparent, but smoking showed a significant association with high levels of ACPA (P = 0.0019). Conclusion ACPA and RF could be detected in 1.7% and 6.4% of the Japanese adult population without RA, respectively. ACPA and RF were suggested to share mechanisms even in healthy populations. Old age was associated with increasing ACPA positivity. While positivity of ACPA and RF was not associated with SE and smoking, an association between high ACPA and smoking was observed.

STUDY OBJECTIVES To examine relationships among gastroesophageal reflux disease (GERD) symptoms, dietary behaviors, and sleep duration in the general population. DESIGN Cross-sectional. SETTING Community-based. PARTICIPANTS There were 9,643 participants selected from the general population (54 ± 13 y). INTERVENTIONS None. MEASUREMENTS AND RESULTS Sleep duration, sleep habits, and unfavorable dietary behaviors of each participant were assessed with a structured questionnaire. Participants were categorized into five groups according to their sleep duration: less than 5 h, 5 to less than 6 h, 6 to less than 7 h, 7 to less than 8 h, and 8 or more h per day. GERD was evaluated using the Frequency Scale for the Symptoms of GERD (FSSG) and participants having an FSSG score of 8 or more or those under treatment of GERD were defined as having GERD. Trend analysis showed that both the FSSG score and the number of unfavorable dietary habits increased with decreasing sleep duration. Further, multiple logistic regression analysis showed that both the presence of GERD (odds ratio = 1.19, 95% confidence interval (CI) = 1.07-1.32) and the number of unfavorable dietary behaviors (odds ratio = 1.19, 95% CI = 1.13-1.26) were independent and potent factors to identify participants with short sleep duration even after controlling for other confounding factors. CONCLUSION The current study showed that both GERD symptoms and unfavorable dietary behaviors were significant correlates of short sleep duration independently of each other in a large sample from the general population.