A novel self-assembling peptide hemostatic gel as rescue therapy for fistula bleeding after endoscopic ultrasound-guided hepaticogastrostomy.

The novel synthetic self-assembling peptide PuraStat has been approved for hemostasis in endoscopic procedures. Nakahara and colleagues describe their application of PuraStat for hemostasis of refractory fistula bleeding after endoscopic ultrasound-guided hepaticogastrostomy. The effective and technically easy procedure is a useful option when hemostasis cannot be achieved by other means.

Clinical outcomes and predictors of technical failure of endoscopic transpapillary gallbladder drainage in acute cholecystitis.

BACKGROUND AND AIMS: Endoscopic transpapillary gallbladder drainage (ETGBD) has been performed as an alternative therapy against cholecystectomy in patients with acute cholecystitis. To date, few studies have reported the safety, efficacy, and factors affecting ETGBD. We evaluated the clinical outcomes and predictors of technical failure of ETGBD. METHODS: Patients with acute cholecystitis who underwent ETGBD were retrospectively reviewed, and consecutive patients were included in the study. The technical success rate, clinical success rate, adverse events, and the predictors associated with the technical failure of ETGBD were investigated. RESULTS: A total of 242 patients were enrolled in the study. The technical success rate of ETGBD and clinical success rate of technically successful ETGBD cases were 87% and 93%, respectively. We experienced cystic duct injury in 24 patients as an ETGBD-related adverse event, and pancreatitis in 12 patients as an endoscopic retrograde cholangiopancreatography-related adverse event. Multivariate analysis indicated that cystic duct injury was the independent predictor associated with the technical failure of ETGBD (odds ratio, 11; 95% confidence interval, 3.9-29; p < 0.001). CONCLUSIONS: ETGBD was a safe and effective treatment method for acute cholecystitis with acceptable adverse events. There was no predictor based on the information from patient characteristics; however, cystic duct injury was associated with the technical failure of ETGBD.

Long-term outcomes of endoscopic transpapillary gallbladder drainage using a novel spiral plastic stent in acute calculus cholecystitis.

BACKGROUND: Endoscopic transpapillary gallbladder stenting (EGBS) is considered for patients with contraindications to early surgery for acute calculus cholecystitis. However, evidence regarding the long-term outcomes of EGBS is insufficient to date. The aim of the study was to evaluate the feasibility of EGBS as a bridge to or alternative to surgery when there are contraindications. METHODS: We reviewed the cases of patients who underwent EGBS using a novel spiral-shaped plastic stent for acute calculus cholecystitis between January 2011 and December 2019. We retrospectively evaluated the long-term outcomes of EGBS using a novel spiral-shaped plastic stent. RESULTS: Forty-nine patients were included. The clinical success rate of EGBS was 97%. After EGBS, 25 patients (surgery group) underwent elective cholecystectomy and 24 patients did not (follow-up group). In the surgery group, the median period from EGBS to surgery was 93 days. There was a single late adverse event with cholecystitis recurrence. In the follow-up group, the median follow-up period was 236 days. Late adverse events were observed in eight patients, including recurrence of cholecystitis (four patients), duodenal penetration by the distal stent end (two patients), and distal stent migration (two patient). In the follow-up group, the time to recurrence of biliary obstruction was 527 days. CONCLUSIONS: EGBS with a novel spiral-shaped plastic stent is safe and effective for long-term acute calculus cholecystitis. There is a possibility of EGBS to be a bridge to surgery and a surgical alternative for acute calculus cholecystitis in patients with contraindications to early cholecystectomy.

Technique of straightening the guidewire using a balloon catheter for successful endoscopic transpapillary gallbladder stenting.

Video 1The technique of straightening the guidewire, looped in the neck of the gallbladder because of segmental adenomyomatosis, using a balloon catheter during endoscopic transpapillary gallbladder stent placement.

Gender Differences in Smoking Initiation and Cessation Associated with the Intergenerational Transfer of Smoking across Three Generations: The Nagahama Study.

Global tobacco policies lowered overall and male smoking rates, but female smoking rates have remained unchanged. Parent-child studies revealed the effects of parental smoking, but gender differences had mixed results. We investigated the effects of long-term smoking behavior in families over three generations in order to clarify gender differences. A cross-sectional study in a community-based genome cohort was conducted using a self-reported questionnaire. A total of 8652 respondents were stratified by gender regarding smoking initiation. A logistic regression analysis was performed to analyze the family smoking history. A total of 2987 current smokers and ever-smokers were compared regarding smoking cessation. With respect to smoking initiation, women were affected by their smoking mothers (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.8-3.2) and grandmothers (OR, 1.7; CI, 1.1-2.4). Women who continued smoking were affected only by their smoking mothers (OR, 1.6; CI, 1.05-2.49). In conclusion, gender differences in smoking initiation and cessation are possibly associated with family smoking history. Mothers and grandmothers were shown to have a strong influence on women with respect to both smoking initiation and cessation. Future research should focus on providing evidence for effective gender-specific intervention programs to curb long-term smoking in women.

Double-guidewire technique for endoscopic transpapillary gallbladder stenting.

Highlight Endoscopic transpapillary gallbladder stenting is effective for acute cholecystitis with high surgical risk. However, looping of the guidewire in the cystic duct sometimes impedes placement of the stent. Nakahara and colleagues present a case of successful endoscopic transpapillary gallbladder stenting after straightening the looped guidewire using a double-guidewire technique.

Incidence and management of cystic duct perforation during endoscopic transpapillary gallbladder drainage for acute cholecystitis.

BACKGROUND AND AIM: Evidence regarding the incidence and clinical outcome of cystic duct perforation (CDP) during endoscopic transpapillary gallbladder drainage (ETGBD) is inadequate. The present study aimed to evaluate the incidence and management of CDP during ETGBD. METHODS: Between March 2011 and December 2019, 249 patients underwent initial ETGBD for acute cholecystitis. The incidence of CDP was retrospectively examined and the outcomes between the CDP and non-CDP groups were compared. RESULTS: CDP during ETGBD occurred in 23 (9.2%) of 249 patients (caused by guidewire in 15 and cannula in 8). ETGBD was successful in 10 patients following CDP. In 13 patients who failed ETGBD, 11 underwent bile duct drainage during the same session; nine patients underwent gallbladder decompression by other methods, such as percutaneous drainage. Clinical resolution for acute cholecystitis was achieved in 20 patients, and no bile peritonitis was noted. ETGBD technical success rates (45.3% vs. 91.2%, p < 0.001), ETGBD procedure times (66.5 vs. 54.8 min, p = 0.041), and hospitalization periods (24.5 vs. 18.7 days, p = 0.028) were significantly inferior in the CDP group (n = 23) compared with the non-CDP group (n = 216). There were no differences in clinical success and adverse events other than CDP between both groups. CONCLUSIONS: Cystic duct perforation reduced the ETGBD technical success rate. However, even in patients with cystic duct perforation, an improvement of acute cholecystitis was achieved by subsequent successful ETGBD or additional procedures, such as percutaneous drainage.

The Influence of Pre-Procedural Imaging and Cystic Duct Cholangiography on Endoscopic Transpapillary Gallbladder Drainage in Acute Cholecystitis.

Endoscopic transpapillary gallbladder drainage (ETGBD) for acute cholecystitis is challenging. We evaluated the influence of pre-procedural imaging and cystic duct cholangiography on ETGBD. Patients who underwent ETGBD for acute cholecystitis were retrospectively examined. The rate of gallbladder contrast on cholangiography, the accuracy of cystic duct direction and location by computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP), and the relationship between pre-procedural imaging and the technical success of ETGBD were investigated. A total of 145 patients were enrolled in this study. Gallbladder contrast on cholangiography was observed in 29 patients. The accuracy of cystic duct direction and location (proximal or distal, right or left, and cranial or caudal) by CT were, respectively, 79%, 60%, and 58% by CT and 68%, 55%, and 58% by MRCP. Patients showing gallbladder contrast on cholangiography underwent ETGBD with a significantly shorter procedure time and a lower rate of cystic duct injury. No other factors affecting procedure time, technical success, and cystic duct injury were identified. Pre-procedural evaluation of cystic duct direction and location by CT or MRCP was difficult in patients with acute cholecystitis. Patients who showed gallbladder contrast on cholangiography showed a shorter procedure time and a lower rate of cystic duct injury.

Serum lipidomics for exploring biomarkers of bortezomib therapy in patients with multiple myeloma.

Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ-induced peripheral neuropathy (BiPN), a frequent side-effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty-nine serum samples were collected from patients with MM prior to receiving BTZ plus low-dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients' sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet-activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.

Reduction in Gastroesophageal Reflux Disease Symptoms Is Associated with Miso Soup Intake in a Population-Based Cross-Sectional Study: The Nagahama Study.

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<0.001). In a generalized linear model, daily intake of miso soup was associated with lower FSSG, reflux, and dyspepsia scores independent of age, sex, BMI, other 15 dietary habits, smoking, drinking alcohol, and unfavorable dietary behaviors (estimate=-0.46, -0.22, and -0.27, respectively; 95% CI=-0.83, -0.12; -0.38, -0.07; and -0.47, and -0.08, respectively). Dairy intake of miso soup was associated with lower epigastric symptoms.

SLCO1B1 Polymorphism Is a Drug Response Predictive Marker for Advanced Pancreatic Cancer Patients Treated With Gemcitabine, S-1, or Gemcitabine Plus S-1.

OBJECTIVES: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach. METHODS: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model. RESULTS: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72). CONCLUSIONS: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Dietary habits associated with reduced insulin resistance: The Nagahama study.

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-ß 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.

Relationship Among Chlamydia and Mycoplasma Pneumoniae Seropositivity, IKZF1 Genotype and Chronic Obstructive Pulmonary Disease in A General Japanese Population: The Nagahama Study.

Chronic obstructive pulmonary disease (COPD) is a possible risk factor for cardiovascular disease. The association of COPD with the pathogenicity of infection with Chlamydia pneumoniae and Mycoplasma pneumoniae is controversial. We conducted a cross-sectional study to clarify the association between atypical pneumoniae seropositivity and COPD in a general population. We also investigated genetic polymorphisms conferring susceptibility to a pneumonia titer. The study included 9040 Japanese subjects (54 ±â€Š13 years). COPD was defined as a ratio of forced expiratory volume in 1 second to forced vital capacity of less than 70%. Serum levels of IgA and IgG antibodies to C pneumoniae were determined using an enzyme-linked immunoassay, and M pneumoniae seropositivity was assessed by a particle agglutination test. Subjects seropositive for C pneumoniae (26.1%) had a higher prevalence of COPD (seropositive, 5.8%; seronegative, 3.1%; P < 0.001) after adjustment for age, sex, height, weight, and smoking status. The association between M pneumoniae seropositivity (20.4%) and COPD was also significant in covariate-adjusted analysis (P < 0.001). A genome-wide association analysis of the C pneumoniae IgA index identified a susceptible genotype (rs17634369) near the IKZF1 gene, and the seropositive rate of C pneumoniae significantly differed among genotypes (AA, 22.5; AG, 25.3; GG, 29.7%, P < 0.001). On multiple regression analysis, seropositivity for both C pneumoniae (odds ratio = 1.41, P = 0.004) and M pneumoniae (odds ratio = 1.60, P = 0.002) was an independent determinant for COPD, while no direct association was found with the rs17634369 genotype. Seropositivity for both C pneumoniae and M pneumoniae is an independent risk factor for COPD in the general population.

Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population - The Nagahama study.

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.

Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population.

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.

Targeted next-generation sequencing and fine linkage disequilibrium mapping reveals association of PNPLA3 and PARVB with the severity of nonalcoholic fatty liver disease.

The genomic regions containing PNPLA3, SAMM50 and PARVB are susceptibility loci for the development and progression of nonalcoholic fatty liver disease (NAFLD). In order to search for all common variations in this region, we amplified the genomic DNA of 28 NAFLD patients by long-range PCR, covering the entire susceptibility region and sequenced the DNA using indexed multiplex next-generation sequencing. We found 329 variations, including four novel variations. Fine mapping of variations including insertion/deletions was performed for 540 NAFLD patients (488 with nonalcoholic steatohepatitis (NASH) and 52 with simple steatosis) and 1012 control subjects. HaploView analysis showed that linkage disequilibrium (LD) block 1 and 2 occurred in PNPLA3, block 3 in SAMM50 and block 4 in PARVB. Variations in LD blocks 1-4 were significantly associated with NAFLD as compared with control subjects (P<1 × 10(-8)). Variations in LD block 2 were significantly associated with the NAFLD activity score (NAS), aspartate aminotransferase and alanine aminotransferase. Variations in LD block 1 were significantly associated with the fibrosis stage. The strongest associations were observed for variations in LD block 4, with NASH as compared with simple steatosis (P=7.1 × 10(-6)) and NAS (P=3.4 × 10(-6)). Our results suggested that variations, including insertion/deletions, in PARVB, as well as those in PNPLA3, are important in the progression of NAFLD.

Airflow limitation in smokers is associated with arterial stiffness: the Nagahama Study.

BACKGROUND: Pathophysiological mechanisms of associations between airflow limitation (AL) and arterial stiffness remain unclear. One factor that might affect both AL and arterial stiffness is habitual smoking. The aim of this study is to investigate a possible interaction of smoking on the association between AL and arterial stiffness. METHODS: Study subjects consisted of 8790 apparently healthy community residents. Airflow limitation was defined as a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of less than 70%. Brachial-to-ankle pulse wave velocity (baPWV) was used as an index of arterial stiffness. Smoking habit was investigated using a structured questionnaire. RESULTS: Subjects with AL had significantly higher baPWV (AL 1381 ± 334, control 1261 ± 227 cm/s, p < 0.001). In a separate analysis by smoking habit, advanced arterial stiffness in AL was observed only in smokers (non-smokers: AL 1300 ± 220, control 1260 ± 218; smokers: AL 1436 ± 384, control 1264 ± 243 cm/s). Other clinical features of subjects with AL were older age; increased plasma hsCRP levels; and a high prevalence of male sex, hypertension, and smoking experience. Multiple linear regression analysis adjusted for these covariates identified the smoking × AL interaction as an independent determinant of baPWV (ß = 0.066, p < 0.001). Conversely, baPWV was an independent determinant of AL in current and past smokers, but not in never smokers. CONCLUSIONS: AL arising from cigarette smoking, but not AL in non-smokers, was associated with arterial stiffness in a general population independently of established risk factors. Measurement of subclinical arterial change in smokers may be useful in identifying persons at risk for AL.

NUDT3 rs206936 is associated with body mass index in obese Japanese women.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference, waist-hip ratio measurements and visceral fat area (VFA); the latter can be accurately measured by performing computed tomography (CT). In addition to environmental factors, genetic factors play an important role in obesity and fat distribution. New genetic loci associated with body mass index (BMI) and adiposity have been identified by genome-wide association studies (GWASs). This study utilized CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to higher BMI are associated with VFA, subcutaneous fat area (SFA), and the ratio of VFA to SFA (V/S ratio). We measured the VFA and SFA of 1424 obese Japanese subjects (BMI ≥ 25 kg/m(2), 635 men and 789 women) who were genotyped for 13 single nucleotide polymorphisms (SNPs) reported by recent GWASs, namely, TNNI3K rs1514175, PTBP2 rs1555543, ADCY3 rs713586, IRS1 rs2943650, POC5 rs2112347, NUDT3 rs206936, LINGO2 rs10968576, STK33 rs4929949, MTIF3 rs4771122, SPRY2 rs534870, MAP2K5 rs2241423, QPCTL rs2287019, and ZC3H4 rs3810291. The G-allele of NUDT3 rs206936 was significantly associated with increased BMI (P = 5.3 × 10(-5)) and SFA (P = 0.00039) in the obese Japanese women. After adjustment with BMI, the association between rs206936 and SFA was not observed. This significant association was not observed in the men. The other SNPs analyzed were not significantly associated with BMI, VFA, SFA, or V/S ratio. Our results suggest that NUDT3 rs206936 is associated with BMI in Japanese women.