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While angioectasia is an important cause of acute hematochezia, relevant clinical features remain unclear. This study aims to reveal risk factors, clinical outcomes, and the effectiveness of therapeutic endoscopy for patients with acute hematochezia due to angioectasia.This retrospective cohort study was conducted at 49 Japanese hospitals between January 2010 and December 2019, enrolling patients hospitalized for acute hematochezia (CODE BLUE-J study). Baseline factors and clinical outcomes for angioectasia were analyzed.Among 10,342 patients with acute hematochezia, 129 patients (1.2%) were diagnosed with angioectasia by colonoscopy. The following factors were significantly associated with angioectasia: chronic kidney disease, liver disease, female, body mass index 25, and anticoagulant use. Patients with angioectasia were at a significant increased risk of blood transfusions compared to those without angioectasia (odds ratio [OR] 2.61; 95% confidence interval [CI] 1.69-4.02). Among patients with angioectasia, 36 patients (28%) experienced rebleeding during 1-year follow-up. The 1-year cumulative rebleeding rates were 37.0% in the endoscopic clipping group, 14.3% in the coagulation group, and 32.8% in the conservative management group. Compared to conservative management, coagulation therapy significantly reduced rebleeding risk (P = 0.038), while clipping did not (P = 0.81). Multivariate analysis showed coagulation therapy was an independent factor for reducing rebleeding risk (hazard ratio [HR] 0.40; 95% CI 0.16-0.96).Our data showed patients with angioectasia had a greater comorbidity burden and needed more blood transfusions in comparison with those without angioectasia. To reduce rebleeding risk, coagulation therapy can be superior for controlling hematochezia secondary to angioectasia.

Patients with ulcerative colitis often develop medically refractory colonic inflammation or colorectal neoplasia, and approximately 10% to 15% of patients require surgery. The most common surgical procedure is a restorative proctocolectomy with IPAA. Even if the preoperative diagnosis is ulcerative colitis, approximately 10% of patients can develop inflammatory pouch conditions resembling a Crohn's disease phenotype.This study aimed to review the diagnostic approach, prognosis, and management of IPAA with Crohn's disease-like features.The data sources include search in electronic databases.This narrative review included studies focusing on pouches with Crohn's disease-like features.The main topics in this review included the pathogenesis, risk factors, diagnosis, phenotypes, prognosis, and medications of pouches with Crohn's disease-like features.A diagnostic approach for the pouch conditions resembling a Crohn's disease phenotype should be based on history-taking to evaluate its risk factors and endoscopic assessment of the pouch. Prior disease history and pathology, location of pouch complications, and timing of complications offer clues for the differential diagnosis of this phenotype. We advocate for the more descriptive term "pouch with Crohn's disease-like features" and reserve the term "Crohn's disease of the pouch" for patients who undergo IPAA and have a precolectomy diagnosis of Crohn's disease or whose colectomy pathology revealed Crohn's disease. Medications, which are often used for traditional Crohn's disease, show efficacy in pouches with Crohn's disease-like features as well. The poor prognosis associated with pouches with Crohn's disease-like features, particularly the fistulizing phenotype, underscores the importance of proactive monitoring and therapeutic intervention.The limitations include no explicit criteria for article selection.This review suggests future research should seek to understand the natural history and meaningful shorter and longer term therapeutic targets for these types of pouch phenotypes. Long-term follow-up and prospective preoperative and postoperative interventional trials of treatments and prevention strategies are needed.

Calcineurin inhibitors (CNIs) are often used for solid organ transplantation recipients or patients with immune-mediated diseases. This systematic review and meta-analysis aims to understand how CNIs affect pregnancy and neonatal outcomes.Electronic databases were searched for observational studies assessing pregnancy and neonatal outcomes in CNI-treated patients. The pooled rate of each outcome was determined. Metaregression was conducted to identify contributing factors to the outcomes.We analysed 98 studies with a total of 5355 pregnancies in 4450 CNI-treated patients. The pooled rates of live birth and spontaneous abortion were 82.1% (95% confidence interval [CI] 76.7-86.4%) and 11.7% (95% CI 8.7-15.5%), respectively. The rates of preterm delivery (33.2%, 95% CI 29.2-37.5%), low birth weight (35.8%, 95% CI 27.7-44.8%) and preeclampsia (13.5%, 95% CI 9.4-19.2%) were 3-4 times higher than the rates of general population. Nearly half of the CNI-treated patients required caesarean delivery (43.5%, 95% CI 36.9-50.3%). The rates of stillbirth, neonatal and maternal death were 4.2% (95% CI 2.8-6.2%), 2.9% (95% CI 1.8-4.8%) and 2.3% (95% CI 1.3-4.1%), respectively. Metaregression showed that preeclampsia was significantly associated with the risks of preterm delivery and low birth weight. Older maternal age, prepregnancy hypertension and cyclosporine use increased the risk of preeclampsia.Given the higher mortalities in CNI-treated patients and their children than the general averages, their pregnancy is considered high risk. The risks of preterm delivery and low birth weight were primarily attributed to preeclampsia. Since prepregnancy hypertension increased its risk, an appropriate preconception blood pressure management may improve their outcomes.

Autoimmune pancreatitis (AIP) and inflammatory bowel disease (IBD) are categorized into immune-mediated inflammatory disorders (IMIDs). While AIP is a pancreato-biliary IMID with an increased incidence and prevalence among patients with IBD, its features are still unclear. This systematic review and meta-analysis aims to assess the prevalence and clinical characteristics of AIP-IBD patients.Electronic databases were searched to identify observational studies assessing AIP and IBD. The primary outcome was the prevalence of IBD among AIP patients, and vice versa. Secondary outcomes included clinical findings and outcomes of each IMID in AIP-IBD patients. The pooled rate of each outcome was determined using a random effects model.For primary outcomes, 40 observational studies with 4031 AIP patients were included and the pooled prevalence of IBD was 10.5% (95% CI 7.2-15.0%). Meanwhile, five studies with 10,551 IBD patients were included and the pooled prevalence of AIP was 0.6% (95% CI 0.2-1.9%). For secondary outcomes, 53 observational studies with 469 AIP-IBD patients were assessed. The rates of type 2 AIP and ulcerative colitis were 79.2% (95% CI 69.1-86.6%) and 74.8% (95% CI 68.2-80.4%), respectively. We also demonstrated AIP-IBD patients were at a significant increased risk of AIP recurrence and colectomy compared with patients with either AIP or IBD (RR = 1.9, 95% CI 1.1-3.1 and P = 0.014 and RR = 3.7, 95% CI 1.9-6.9, P 0.001, respectively).Our meta-analysis reported the prevalence of AIP-IBD patients and demonstrated patients with both IMIDs had a high risk of poor outcomes.

Magnifying endoscopy is a useful technique to differentiate neoplasia from non-neoplastic lesions. Data regarding the clinical utility of magnifying endoscopy for neoplasia in patients with inflammatory bowel disease (IBD) has been emerging. While Kudo's pit pattern types III-V are findings suggestive of neoplasia in non-IBD patients, these pit patterns are predictive of IBD-associated neoplasia as well. However, active chronic inflammatory processes, particularly regenerative changes, can mimic neoplastic pit patterns and may affect a meticulous evaluation of pit pattern diagnosis in patients with IBD. The clinical evidence regarding the utility of magnifying endoscopy with narrow band imaging or endocytoscopy has also been evolving in regard to the diagnosis of IBD-associated neoplasia. These advanced endoscopic techniques are promising for multiple reasons; not only for making an accurate diagnosis of neoplasia, but also in determining if endoscopic resection is appropriate for such lesions in patients with IBD. In this review, we discuss the diagnostic accuracy and limitations of magnifying endoscopy in assessing IBD-associated neoplasia and examine the feasibility and outcomes of endoscopic resection for these lesions.

Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people. Genome-wide association studies (GWAS) have been highly successful in identifying genetic risk factors. However, GWAS investigate common variants, which tend to have small effect sizes, and rare variants with potentially larger phenotypic effects have not been sufficiently investigated. Whole-genome sequencing (WGS) enables us to detect those rare variants. Here, we performed rare-variant association studies by using WGS data from 140 individuals with probable AD and 798 cognitively normal elder controls (CN), as well as single-nucleotide polymorphism genotyping data from an independent large Japanese AD cohort of 1604 AD and 1235 CN subjects. We identified two rare variants as candidates for AD association: a missense variant inOR51G1(rs146006146, c.815 G > A, p.R272H) and a stop-gain variant inMLKL(rs763812068, c.142 C > T, p.Q48X). Subsequent in vitro functional analysis revealed that theMLKLstop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40. We further detected AD candidate genes through gene-based association tests of rare variants; a network-based meta-analysis using these candidates identified four functionally important hub genes (NCOR2,PLEC,DMD, andNEDD4). Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.

This case series showed that tofacitinib was effective and safe for some of patients with chronic pouchitis or Crohn’s disease–like pouch inflammation. Further research is warranted to better understand the long-term efficacy and safety of tofacitinib for chronic inflammatory pouch conditions.

There are many subtypes of dementia, and identification of diagnostic biomarkers that are minimally-invasive, low-cost, and efficient is desired. Circulating microRNAs (miRNAs) have recently gained attention as easily accessible and non-invasive biomarkers. We conducted a comprehensive miRNA expression analysis of serum samples from 1348 Japanese dementia patients, composed of four subtypes—Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and normal pressure hydrocephalus—and 246 control subjects. We used this data to construct dementia subtype prediction models based on penalized regression models with the multiclass classification. We constructed a final prediction model using 46 miRNAs, which classified dementia patients from an independent validation set into four subtypes of dementia. Network analysis of miRNA target genes revealed important hub genes, SRC and CHD3, associated with the AD pathogenesis. Moreover, MCU and CASP3, which are known to be associated with DLB pathogenesis, were identified from our DLB-specific target genes. Our study demonstrates the potential of blood-based biomarkers for use in dementia-subtype prediction models. We believe that further investigation using larger sample sizes will contribute to the accurate classification of subtypes of dementia.

Mild cognitive impairment (MCI) is a clinical precursor of Alzheimer’s disease (AD). Recent genetic studies have reported on associations between AD risk genes and immunity. Here, we obtained samples and data from 317 AD, 432 MCI, and 107 cognitively normal (CN) subjects and investigated immune-cell type composition and immune clonal diversity of T-cell receptor (TRA, TRB, TRG, and TRD) and B-cell receptor (IGH, IGK, and IGL) repertoires through bulk RNA sequencing. We found the proportions of plasma cells, γδ T cells, neutrophils, and B cells were significantly different and the diversities of IGH, IGK, and TRA were significantly small with AD progression. We then identified a differentially expressed gene, WDR37, in terms of risk of MCI-to-AD conversion. Our prognosis prediction model using the potential blood-based biomarkers for early AD diagnosis, which combined two immune repertoires (IGK and TRA), WDR37, and clinical information, successfully classified MCI patients into two groups, low and high, in terms of risk of MCI-to-AD conversion (log-rank test P = 2.57e-3). It achieved a concordance index of 0.694 in a discovery cohort and of 0.643 in an independent validation cohort. We believe that further investigation, using larger sample sizes, will lead to practical clinical use in the near future.

Evidence regarding the utility of endoscopic submucosal dissection (ESD) for neoplasia in patients with inflammatory bowel disease (IBD) is limited. This meta-analysis aims to understand the feasibility, safety, and long-term outcomes of ESD in IBD patients.Electronic databases were searched for observational and case-controlled studies. Primary endpoints were en bloc resection and margin-negative resection of neoplastic lesions. Secondary endpoints included procedure-related bleeding and perforation, local recurrence, and metachronous neoplasia.We analyzed 25 studies with a total of 585 neoplastic lesions in 552 patients. The rates of en bloc resection and margin-negative resection were 0.88 [95% confidence interval (CI) 0.82-0.92] and 0.78 (95% CI 0.72-0.83), respectively. Meta-regression analysis showed longer disease duration was significantly associated with the higher rate of en bloc resection. The rates of procedure-related bleeding and perforation were 0.080 (95% CI 0.057-0.11) and 0.055 (95% CI 0.038-0.081), respectively. The rates of local recurrence and metachronous neoplasia were 0.008 events/person-year (95% CI 0.002-0.013) and 0.031 event/person-year (95% CI 0.016-0.046), respectively. Meta-analysis of case-controlled studies found no significant differences in the endpoints between IBD patients treated by ESD and those treated by endoscopic mucosal resection, or non-IBD patients treated by ESD.ESD is a feasible and safe procedure to remove neoplastic lesions in IBD patients. Given there is a considerable risk of metachronous neoplasia development, postoperative surveillance colonoscopy with an appropriate consultation with surgeons is essential to monitor not only local recurrence but also neoplastic changes in the remaining colon.

Hepatitis B virus reactivation (HBVr) can occur in patients treated with immunosuppressive medications. Risk stratification for HBVr based on hepatitis B virus (HBV) serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use. Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies. Tumor necrosis factor (TNF)-α inhibitors have been widely used for patients with inflammatory bowel disease, psoriasis, and rheumatic diseases. Further, the clinical benefits of interleukin (IL)-12/23, IL-17, or Janus kinases inhibitors have been demonstrated in these patients. It is well known that TNF-α inhibitor use can lead to HBVr, however, the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood. In this review, we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics, and immunological mechanisms of these medications causing HBVr.

Background Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL)-12/23 or IL-23 antagonists have been reported in autoimmune diseases. Objective To assess the risk of RTIs and non-infectious ILD with these drugs. Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Risk of RTIs and non-infectious ILD was compared to placebo by Mantel-Haenszel (MH) risk difference (RD). We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Non-infectious ILD included ILD, eosinophilic pneumonia, and pneumonitis. Results We identified 54 RCTs including 10,907 patients with six IL-12/23 or IL-23 antagonists and 5,175 patients with placebo. These drugs significantly increased the risk of RTIs (MH RD 0.019, 95% confidence interval 0.005-0.033, P = 0.007) which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and non-infectious ILD between two groups. Limitations Due to the rarity of infectious pneumonia and ILD, sensitivity analysis was required. Conclusion The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and non-infectious ILD.

Patients with inflammatory bowel disease (IBD) occasionally need a restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) because of medically refractory colitis or dysplasia/cancer. However, pouchitis may develop in up to 70% of patients after this procedure and significantly impair quality of life, more so if the inflammation becomes a chronic condition. About 10% of patients with IBD who develop pouchitis require pouch excision, and several risk factors of the failure have been reported. A phenotype that has features similar to Crohn’s disease may develop in a subset of ulcerative colitis patients following proctocolectomy with IPAA and is the most frequent reason for pouch failure. In this review, we discuss the diagnosis and prognosis of pouchitis, risk factors for pouchitis development, and treatment options for pouchitis, including the newer biological agents.

ObjectivesThe prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases who are frequently treated with disease modifying therapies remains poorly understood. This meta-analysis aims to assess the prevalence and clinical outcomes of COVID-19 in autoimmune diseases.MethodsElectronic databases were searched for observational and case–controlled studies. We sorted medications into glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic or targeted synthetic DMARDs (b/tsDMARDs), which was also divided into monotherapy and b/tsDMARDs–csDMARDs combination therapy.ResultsWe analysed 62 observational studies with a total of 319 025 patients with autoimmune diseases. The prevalence of COVID-19 was 0.011 (95% CI: 0.005 to 0.025). Meta-analysis of seven case–controlled studies demonstrated that the risk of COVID-19 in autoimmune diseases was significantly higher than in control patients (OR: 2.19, 95% CI: 1.05 to 4.58, p=0.038). Meta-regression analysis showed glucocorticoids were significantly associated with the risk of COVID-19. For clinical outcomes, we assessed 65 studies with 2766 patients with autoimmune diseases diagnosed with COVID-19. The rates of hospitalisation and mortality were 0.35 (95% CI: 0.23 to 0.50) and 0.066 (95% CI: 0.036 to 0.12), respectively. Glucocorticoids, csDMARDs and b/tsDMARDs–csDMARDs combination therapy increased the risk of these outcomes, whereas b/tsDMARDs monotherapy, particularly antitumour necrosis factor agents, were associated with a lower risk of hospitalisation and death.ConclusionsOur meta-analysis demonstrated that patients with autoimmune diseases had an increased risk of COVID-19, primarily attributed to glucocorticoid use. b/tsDMARDs monotherapy was associated with a lower risk of severe COVID-19 suggesting its safety in the COVID-19 pandemic.

Background With demographic shifts toward older populations, the number of people with dementia is steadily increasing. Alzheimer’s disease (AD) is the most common cause of dementia, and no curative treatment is available. The current best strategy is to delay disease progression and to practice early intervention to reduce the number of patients that ultimately develop AD. Therefore, promising novel biomarkers for early diagnosis are urgently required. Methods To identify blood-based biomarkers for early diagnosis of AD, we performed RNA sequencing (RNA-seq) analysis of 610 blood samples, representing 271 patients with AD, 91 cognitively normal (CN) adults, and 248 subjects with mild cognitive impairment (MCI). We first estimated cell-type proportions among AD, MCI, and CN samples from the bulk RNA-seq data using CIBERSORT and then examined the differentially expressed genes (DEGs) between AD and CN samples. To gain further insight into the biological functions of the DEGs, we performed gene set enrichment analysis (GSEA) and network-based meta-analysis. Results In the cell-type distribution analysis, we found a significant association between the proportion of neutrophils and AD prognosis at a false discovery rate (FDR) n = 3,099: AD, 1,605; MCI, 994; CN, 500). In addition, GSEA and network-based meta-analysis based on DEGs between AD and CN samples revealed functional modules and important hub genes associated with the pathogenesis of AD. The risk prediction model constructed by using the proportion of neutrophils and the most important hub genes (EEF2 and RPL7) achieved a high AUC of 0.878 in a validation cohort; when further applied to a prospective cohort, the model achieved a high accuracy of 0.727. Conclusions Our model was demonstrated to be effective in prospective AD risk prediction. These findings indicate the discovery of potential biomarkers for early diagnosis of AD, and their further improvement may lead to future practical clinical use.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia in elderly people, following Alzheimer's disease. Only three genes, SNCA (α-synuclein), APOE (apolipoprotein E), and GBA (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Here, we applied whole-genome sequencing to blood samples from 61 DLB patients and 45 cognitively normal controls. We used accumulation of candidate mutations to detect novel DLB-associated genes. Subsequent single nucleotide polymorphism (SNP) genotyping and association studies in a large number of samples from Japanese individuals revealed novel heterozygous variants in MFSD3 (rs143475431, c.888TA:p.C296*; n = 5,421, p = 0.00063) and MRPL43 (chr10:102746730, c.241AC:p.N81H; n = 4,782, p = 0.0029). We further found that the MFSD3 variant increased plasma levels of butyrylcholinesterase (n = 1,206, p = 0.029). We believe that our findings will contribute to the understanding of DLB and provide insight into its pathogenic mechanism for future studies.

Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss.We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC.We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype.This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes.We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.

Alzheimer’s disease (AD) is the most common subtype of dementia, followed by Vascular Dementia (VaD), and Dementia with Lewy Bodies (DLB). Recently, microRNAs (miRNAs) have received a lot of attention as the novel biomarkers for dementia. Here, using serum miRNA expression of 1,601 Japanese individuals, we investigated potential miRNA biomarkers and constructed risk prediction models, based on a supervised principal component analysis (PCA) logistic regression method, according to the subtype of dementia. The final risk prediction model achieved a high accuracy of 0.873 on a validation cohort in AD, when using 78 miRNAs: Accuracy = 0.836 with 86 miRNAs in VaD; Accuracy = 0.825 with 110 miRNAs in DLB. To our knowledge, this is the first report applying miRNA-based risk prediction models to a dementia prospective cohort. Our study demonstrates our models to be effective in prospective disease risk prediction, and with further improvement may contribute to practical clinical use in dementia., Daichi Shigemizu et al. developed a risk prediction model using potential miRNA biomarkers of different dementias identified by a supervised principal component analysis logistic regression method. Their models achieved high accuracy when tested on a validation cohort and demonstrate the potential application of miRNA-based risk prediction models.

BackgroundIdentification of germline variation and somatic mutations is a major issue in human genetics. However, due to the limitations of DNA sequencing technologies and computational algorithms, our understanding of genetic variation and somatic mutations is far from complete.MethodsIn the present study, we performed whole-genome sequencing using long-read sequencing technology (Oxford Nanopore) for 11 Japanese liver cancers and matched normal samples which were previously sequenced for the International Cancer Genome Consortium (ICGC). We constructed an analysis pipeline for the long-read data and identified germline and somatic structural variations (SVs).ResultsIn polymorphic germline SVs, our analysis identified 8004 insertions, 6389 deletions, 27 inversions, and 32 intra-chromosomal translocations. By comparing to the chimpanzee genome, we correctly inferred events that caused insertions and deletions and found that most insertions were caused by transposons andAluis the most predominant source, while other types of insertions, such as tandem duplications and processed pseudogenes, are rare. We inferred mechanisms of deletion generations and found that most non-allelic homolog recombination (NAHR) events were caused by recombination errors in SINEs. Analysis of somatic mutations in liver cancers showed that long reads could detect larger numbers of SVs than a previous short-read study and that mechanisms of cancer SV generation were different from that of germline deletions.ConclusionsOur analysis provides a comprehensive catalog of polymorphic and somatic SVs, as well as their possible causes. Our software are available athttps://github.com/afujimoto/CAMPHORandhttps://github.com/afujimoto/CAMPHORsomatic.

BACKGROUND AND AIM Approximately half of patients with Crohn's disease (CD) who have surgery will experience clinical recurrence within 10 years of their surgery. This study aimed to assess the postoperative outcomes according to disease location and validated the simple endoscopic score for CD (SES-CD) to predict disease-related outcomes. METHODS We retrospectively assessed medical records of CD patients who underwent ileocolonoscopy within 12 months after surgery at the University of Chicago between 2005 and 2016. We defined patients with postoperative colonic inflammation at the first postoperative ileocolonoscopy or had Montreal classification L2 as colon-dominant disease and patients without colonic involvement or who had L1 as small intestine (SI)-dominant disease. The outcomes included clinical and surgical recurrence. RESULTS Among 207 CD patients, 51 (24.6%) and 156 (75.4%) patients had colon-dominant and SI-dominant disease, respectively. Patients with colon-dominant disease had a greater risk of postoperative clinical recurrence compared with those with SI-dominant disease (P = 0.018). Colon-dominant disease was a risk of earlier surgical recurrence compared with SI-dominant disease, although there were no significant differences in the recurrence-free survivals. SES-CD > 2 at the first postoperative ileocolonoscopy was a significant risk of clinical recurrence on log-rank test (P

Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.