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Background Screening for intracranial aneurysms (IAs) in patients with risk factors of IA is recommended. However, genetic risk factors of IA in patients with autosomal dominant polycystic kidney disease (ADPKD) remain unclear, and genotype–phenotype relationships in IAs in patients with ADPKD have not been clarified. Therefore, we aimed to clarify the associations between germline mutations and IA formation in patients with ADPKD. Methods A total of 135 patients with ADPKD who were evaluated for ADPKD mutations were examined for IA formation in this single‐center observational study. Results The incidence of de novo IA formation was 1.3% per patient‐year. Age at IA diagnosis was younger in patients with frameshift (median, 36 years; P =0.003) and splicing mutations (median, 43 years; P =0.046) than in patients with substitutions (median, 63 years). Multivariable analyses showed that IA was associated with female sex (odds ratio [OR], 3.32 [95% CI, 1.10–10.01]; P =0.03), a family history of IA or subarachnoid hemorrhage (OR, 3.05 [95% CI, 1.07–8.71]; P =0.04), estimated glomerular filtration rate (OR, 0.69 [95% CI, 0.54–0.87]; P =0.002), and splicing mutations (OR, 9.30 [95% CI, 1.71–50.44]; P =0.01). Splicing mutations showed a significant association with IA formation even in subcohorts with minimal risk factors for IA, such as age P =0.001), nonhypertension (OR, 49.28 [95% CI, 3.60–673.98]; P =0.004), and nonsmoking behavior (OR, 27.79 [95% CI, 3.49–221.21]; P =0.002). Conversely, substitutions showed significant associations with IA formation in subcohorts such as age ≥50 years (OR, 8.66; 95% CI, 1.43–52.51; P =0.02) and chronic kidney disease stages 4 and 5 (OR, 10.70 [95% CI, 1.05–108.75]; P =0.045). Conclusions Genetic analyses in patients with ADPKD could contribute to IA screening and could be useful for evaluating the prognosis, including complications. IA screening should be recommended for patients with ADPKD who have splicing and frameshift mutations and for older patients or patients with advanced ADPKD who have substitutions.

OBJECTIVE Although evidence has linked anger and hostility with all-cause mortality risk, less research has examined whether anger frequency and expression (outwardly expressing angry feelings) are linked to all-cause and cause-specific mortality. METHODS In 1996, men (n = 17,352) free of medical conditions from the Health Professionals Follow-Up Study reported anger frequency and aggressive expression levels. Deaths were ascertained from participants' families, postal authorities, and death registries. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality risk until 2016 with a 2-year lag, adjusting for a range of relevant covariates. RESULTS There were 4881 deaths throughout follow-up. After adjustment for sociodemographics and health status, moderate and higher (versus lower) levels of anger frequency and aggressive expression were generally unrelated to the risk of death from all-cause, neurological, or respiratory diseases. However, cardiovascular mortality risk was greater with higher anger frequency (HR = 1.17, 95% CI = 1.01-1.34), whereas cancer mortality risk was greater with higher anger expression (HR = 1.14, 95% CI = 0.98-1.33). Results were similar after including all covariates and stronger when considering anger expression's interaction with frequency. CONCLUSIONS In this cohort of men, experiencing angry feelings and expressing them aggressively were related to an increased risk of dying from cardiovascular disease and cancer but not from other specific causes, over two decades. These results suggest that not only the experience of negative emotions but also how they are managed may be critical for some but not all health outcomes, highlighting the importance of considering causes of death separately when investigating psychosocial determinants of mortality.

Goal The goal of this study was to determine disparities in liver cancer surveillance among people with disabilities is the goal of this study. Background Using the linked administrative database in Korea, we sought to investigate (1) whether there are disparities in liver cancer surveillance according to degree and type of disability and (2) temporal trends in liver cancer surveillance among people with disabilities. Materials and methods We linked national disability registration data with national cancer surveillance data. We analyzed age-standardized participation rates for each year during the 2006-2015 period according to presence, type, and severity of the disability. We also examined factors associated with liver cancer surveillance by multivariate logistic regression using the most current data (2014-2015). Results The age-adjusted and sex-adjusted surveillance rate for liver cancer in people with disabilities increased from 25.7% in 2006 to 49.6% in 2015; however, during the same period, surveillance rate among people without disabilities increased from 24.9% to 54.5%. As a result, disparities in surveillance for liver cancer increased over time. The surveillance participation rate among people with disabilities was 12% lower than among people without disabilities. Surveillance rates were markedly lower among people with severe disabilities [adjusted odds ratio (aOR)=0.71] and people with renal disease (aOR=0.43), brain injuries (aOR=0.60), ostomy problems (aOR=0.60), and intellectual disabilities (aOR=0.69). Conclusions Despite the availability of a national liver cancer surveillance program, a marked disparity was found in liver cancer surveillance participation, especially among people with severe disabilities, renal disease, or brain-related or mental disabilities.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Lauren's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P

Objective To examine the association between occupational class and high-sensitivity C-reactive protein (hsCRP) in Korean workers. Methods We used a nationally representative sample of Koreans (n = 2591) aged 19 to 65 years from the 2015 Korea National Health and Nutrition Examination Survey. The concentration of hsCRP (mg/L) was assessed by a high sensitivity immunoturbidimetric assay. Current occupation was categorized as: white-collar (managers/professionals), pink-collar (clerks/service/sales), blue-collar (craft/equipment/machine-assembling, agricultural/forestry/fishery, and elementary-level labor), or unemployed. Cross-sectional linear regression models adjusted for sociodemographic/work-related/health conditions and behaviors. Results Compared with blue-collar workers, white-collar workers showed significantly higher levels of hsCRP (β = 0.16, 95% CI: 0.02, 0.30) after adjusting for all covariates, whereby the pattern was more pronounced among professionals. However, the association was not significant for unemployed and pink-collar workers. Conclusions Findings suggest that Korean white-collar workers, particularly professionals, have elevated levels of inflammation.

ObjectivesLeigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).MethodsData from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.ResultsThe proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.DiscussionThese findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear. Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy. Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1–promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy. Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.

Biological studies have provided confirmation of alcohol-related carcinogenesis in the stomach, but the association between alcohol consumption and the risk of stomach cancer remains controversial. We aimed to investigate whether quantitative alcohol intake is associated with the risk of stomach cancer in a large prospective cohort study among a Japanese population. Study participants included 30 714 participants (14 171 men and 16 543 women) aged 35 years or older, who were enrolled in the Takayama study launched on 1 September 1992. Alcohol consumption was assessed quantitatively using a validated food frequency questionnaire. According to alcohol intake (g/day), male participants were classified into quartile groups: Q1, Q2, Q3, or Q4. Female participants were classified into three groups: nondrinkers, and drinkers below or above the median alcohol level. We estimated the hazard ratios and 95% confidence intervals (CIs) for stomach cancer adjusted for age, smoking, BMI, education, total energy intake, salt intake, physical activity, and medical history of diabetes mellitus for each alcohol intake group using the Cox proportional hazards regression model. By the end of March 2008, a total of 678 participants had been diagnosed with stomach cancer. For men, the multivariate-adjusted HRs of stomach cancer for Q2, Q3, and Q4 relative to Q1 were 1.39 (95% CI: 1.07-1.81), 1.35 (95% CI: 1.02-1.79), and 1.38 (95% CI: 1.02-1.87), respectively. In women, no associations were observed. These data suggest that alcohol consumption could be associated with an increased risk of stomach cancer among Japanese men.

Background Pneumothorax is a rare complication of coronavirus disease 2019, and many of its associated factors are related to mechanical ventilation. We investigated the incidence and clinical features of patients with pneumothorax and coronavirus disease 2019 at a field hospital for patients who did not require intubation. Materials and methods An isolated field hospital for COVID-19 patients who did not require ventilation was constructed. Patients who developed pneumothorax were extracted and reviewed retrospectively. Results Between May 2020 and February 2021, 1061 patients were admitted to this field hospital. Among them, eight patients (0.75%, three men and four women) developed pneumothorax. The mean age at incidence was 79.9 (range: 20–96) years; all patients were over the age of 80 years, except one 20-year-old woman. Six of these eight patients (75%) died. Conclusion Although pneumothorax is a rare complication of coronavirus disease-2019, it is predictive of a poor prognosis in older-adult patients.

Background and Purpose— Depression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year. Methods— We used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at ≥10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival. Results— During follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95% confidence interval, 0.66–1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95% confidence interval, 0.97–2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95% confidence interval, 1.06–2.56). No evidence for effect modification by race, age, or sex was found. Conclusions— Persistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.

BACKGROUND Evidence for an association between neighborhood disadvantage and smoking is mixed and mainly based on cross-sectional studies. To shed light on the causality of this association, we examined whether change in neighborhood socioeconomic disadvantage is associated with within-individual change in smoking behaviors. METHODS The study population comprised participants of the Finnish Public Sector study who reported a change in their smoking behavior between surveys in 2008/2009 and 2012/2013. We linked participants' residential addresses to a total population database on neighborhood disadvantage with 250 × 250-m resolution. The outcome variables were changes in smoking status (being a smoker vs. not) as well as the intensity (heavy/moderate vs. light smoker). We used longitudinal case-crossover design, a method that accounts for time-invariant confounders by design. We adjusted models for time-varying covariates. RESULTS Of the 3,443 participants, 1,714 quit, while 967 began to smoke between surveys. Smoking intensity increased among 398 and decreased among 364 participants. The level of neighborhood disadvantage changed for 1,078 participants because they moved residence. Increased disadvantage was associated with increased odds of being a smoker (odds ratio of taking up smoking 1.23 [95% confidence interval: 1.2, 1.5] per 1 SD increase in standardized national disadvantage score). Odds ratio for being a heavy/moderate (vs. light) smoker was 1.14 (95% confidence interval: 0.85, 1.52) when disadvantage increased by 1 SD. CONCLUSIONS These within-individual results link an increase in neighborhood socioeconomic disadvantage, due to move in residence, with subsequent smoking behaviors.

Background In contemporary Western settings, higher occupational class is associated with lower risk for cardiovascular disease ( CVD ) incidence, including coronary heart disease ( CHD ) and stroke. However, in non‐Western settings (including Japan), the occupational class gradient for cardiovascular disease risk has not been characterized. Methods and Results Using a nationwide, multicenter hospital inpatient data set (1984–2016) in Japan, we conducted a matched hospital case‐control study with ≈1.1 million study subjects. Based on a standard national classification, we coded patients according to their longest‐held occupational class (blue‐collar, service, professional, manager) within each industrial sector (blue‐collar, service, white‐collar). Using blue‐collar workers in blue‐collar industries as the referent group, odds ratios and 95% CI s were estimated by conditional logistic regression with multiple imputation, matched for sex, age, admission date, and admitting hospital. Smoking and drinking were additionally controlled. Higher occupational class (professionals and managers) was associated with excess risk for CHD . Even after controlling for smoking and drinking, the excess odds across all industries remained significantly associated with CHD , being most pronounced among managers employed in service industries (odds ratio, 1.19; 95% CI , 1.08–1.31). On the other hand, the excess CHD risk in higher occupational class was offset by their lower risk for stroke (eg, odds ratio for professionals in blue‐collar industries, 0.77; 95% CI , 0.70–0.85). Conclusions The occupational “gradient” in cardiovascular disease (with lower risk observed in higher status occupations) may not be a universal phenomenon. In contemporary Japanese society, managers and professionals may experience higher risk for CHD .

INTRODUCTION: We investigated potential disparities in the diagnosis, treatment, and survival of gastric cancer (GC) patients with and without disabilities. METHODS: We linked Korean National Disability Registry data with the Korean National Health Insurance database and Korean Central Cancer Registry data. This study included a total of 16,849 people with disabilities and 58,872 age- and sex-matched control subjects in whom GC had been diagnosed. RESULTS: When compared to GC patients without disabilities, patients with disabilities tended to be diagnosed at a later stage (localized stage 53.7% vs 59.0% or stage unknown 10.7% vs 6.9%), especially those with severe disabilities (P < 0.001). This was more evident in patients with mental impairment (localized stage 41.7% and stage unknown 15.2%). In addition, not receiving treatment was more common in patients with disabilities than those without disabilities (29.3% vs 27.2%, P < 0.001), and this disparity was more evident in those with severe disabilities (35.4%) and in those with communication (36.9%) and mental (32.3%) impairment. Patients with disabilities were at slightly higher risk of overall mortality as well as GC-specific mortality compared to people without disabilities (adjusted hazard ratio [aHR] = 1.18, 95% confidence interval: 1.14–1.21 and aHR = 1.12, 95% confidence interval: 1.09–1.16, respectively), and these disparities were more pronounced in those with severe disabilities (aHR = 1.62 and 1.51, respectively). DISCUSSION: Patients with disabilities, especially severe disabilities, were diagnosed with GC at a later stage, received less staging evaluation and treatment, and their overall survival rate was slightly worse compared to those without disabilities.

Lower parental education is associated with higher adolescent blood pressure (BP). We examined the contribution of modifiable risk factors from infancy to adolescence that could potentially explain the link between parental education and SBP and DBP in the offspring.In a prospective Chinese birth cohort, 'Children of 1997' of 5604 adolescents (68% follow-up), we analyzed the relation between parental educational attainment and sex-specific, age-specific and height-specific BP z-scores at ∼13 years. Using mediation analysis, we examined the contribution of household income at birth (both absolute income and relative income deprivation), exposures during infancy (breastfeeding and early life second-hand smoking), lifestyles during childhood (diet, physical activity and screen-time), weight or BMI status during fetal, infancy, childhood and puberty, pubertal stage as well as parental BMI.We found that adolescent BMI, but not birth weight or infant growth or childhood BMI, mediated the inverse association of parental education with adolescent SBP (proportion mediated: 24%), followed by maternal BMI (proportion mediated: 18%). Factors explaining the link between parental education and DBP were less clear. Absolute income, breastfeeding, childhood diet and physical activity, pubertal stage and paternal BMI did not mediate the association between parental education and adolescent BP.Low parental education is a risk factor for high SBP and, to a lesser extent, DBP in adolescents. Important mediators of this relation include adolescent and maternal body weight.

Evidence on whether genetic predictors of Alzheimer disease (AD) also predict memory decline is inconsistent, and limited data are available for African ancestry populations. For 8253 non-Hispanic white (NHW) and non-Hispanic black (NHB) Health and Retirement Study participants with memory scores measured 1 to 8 times between 1998 and 2012 (average baseline age=62), we calculated weighted polygenic risk scores [AD Genetic Risk Score (AD-GRS)] using the top 22 AD-associated loci, and an alternative score excluding apolipoprotein E (APOE) (AD-GRSexAPOE). We used generalized linear models with AD-GRS-by-age and AD-GRS-by-age interactions (age centered at 70) to predict memory decline. Average NHB decline was 26% faster than NHW decline (P

Objective: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses. Methods: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques. Results: Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients9 antibodies. All 5 patients (median age 44 years, range 23–50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7–17 to patients9 IgG showed a decrease of neurexin-3α clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients9 IgG. Neuronal survival, dendritic morphology, and spine density were unaffected. Conclusion: Neurexin-3α autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3α and alter synapse development.

Purpose: To identify attributes related to glaucoma diagnosis or early glaucoma treatment patterns that are associated with changes in health-related quality of life among those with newly diagnosed primary open-angle glaucoma. Methods: Among Nurses' Health Study participants with incident medical record-confirmed primary open-angle glaucoma diagnosed in 1992 to 2000, we included 317 women who completed the Short Form-36 Health Survey prediagnosis and postdiagnosis. The 2 primary outcomes were 4-year changes (1992 to 1996 or 1996 to 2000) in the physical and mental component summary scores. Multiple regression models were used to estimate differences in score changes by early treatment pattern history and characteristics as of diagnosis (ie, number of eyes affected, history of cataract, macular degeneration, cup-to-disc ratio, intraocular pressure, visual field loss type). Results: In multivariable models, no ophthalmologic characteristics were associated with physical component score change. However, compared with treatment with eye drops or pills only, laser trabeculoplasty treatment (concomitant with history of treatment with eye drops or pills in 84%) was associated with a worse mental component score change over 4 years (-2.5 units; 95% confidence interval: -4.6, -0.3); this association was stronger with a family history of glaucoma (P-interaction=0.04) or with bilateral disease (P-interaction=0.001). Conclusions: Among patients with incident glaucoma, no major factors were associated with change in physical well being. However, compared with medical treatment only, a history of laser trabeculoplasty, which was commonly accompanied with a history of medical treatment and likely represented the need for a second line of treatment, was associated with a worse decline in mental well being.