Factor Analysis of Patients Who Find Tablets or Capsules Difficult to Swallow Due to Their Large Size: Using the Personal Health Record Infrastructure of Electronic Medication Notebooks.

BACKGROUND: Understanding patient preference regarding taking tablet or capsule formulations plays a pivotal role in treatment efficacy and adherence. Therefore, these preferences should be taken into account when designing formulations and prescriptions. OBJECTIVE: This study investigates the factors affecting patient preference in patients who have difficulties swallowing large tablets or capsules and aims to identify appropriate sizes for tablets and capsules. METHODS: A robust data set was developed based on a questionnaire survey conducted from December 1, 2022, to December 7, 2022, using the harmo smartphone app operated by harmo Co, Ltd. The data set included patient input regarding their tablet and capsule preferences, personal health records (including dispensing history), and drug formulation information (available from package inserts). Based on the medication formulation information, 6 indices were set for each of the tablets or capsules that were considered difficult to swallow owing to their large size and concomitant tablets or capsules (used as controls). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of each index. The index demonstrating the highest area under the curve of the ROC was selected as the best index to determine the tablet or capsule size that leads to swallowing difficulties. From the generated ROCs, the point with the highest discriminative performance that maximized the Youden index was identified, and the optimal threshold for each index was calculated. Multivariate logistic regression analysis was performed to identify the risk factors contributing to difficulty in swallowing oversized tablets or capsules. Additionally, decision tree analysis was performed to estimate the combined risk from several factors, using risk factors that were significant in the multivariate logistic regression analysis. RESULTS: This study analyzed 147 large tablets or capsules and 624 control tablets or capsules. The "long diameter + short diameter + thickness" index (with a 21.5 mm threshold) was identified as the best indicator for causing swallowing difficulties in patients. The multivariate logistic regression analysis (including 132 patients with swallowing difficulties and 1283 patients without) results identified the following contributory risk factors: aged <50 years (odds ratio [OR] 1.59, 95% CI 1.03-2.44), female (OR 2.54, 95% CI 1.70-3.78), dysphagia (OR 3.54, 95% CI 2.22-5.65), and taking large tablets or capsules (OR 9.74, 95% CI 5.19-18.29). The decision tree analysis results suggested an elevated risk of swallowing difficulties for patients with taking large tablets or capsules. CONCLUSIONS: This study identified the most appropriate index and threshold for indicating that a given tablet or capsule size will cause swallowing difficulties, as well as the contributory risk factors. Although some sampling biases (eg, only including smartphone users) may exist, our results can guide the design of patient-friendly formulations and prescriptions, promoting better medication adherence.

Retrospective comparative study of new slim-delivery and conventional large-cell stents for stent-in-stent methods for hilar malignant biliary obstruction.

OBJECTIVES: Endoscopic management of unresectable hilar malignant biliary obstruction (HMBO) is technically challenging, and effectiveness of stent-in-stent using large-cell, metal stents was reported. A new, large-cell stent with a 6F tapered delivery system was recently developed. The aim of this study was to compare clinical outcomes of slim-delivery and conventional large-cell stents. METHODS: This was a multicenter retrospective comparative study of stent-in-stent methods using slim-delivery stents (Niti-S Large Cell SR Slim Delivery [LC slim-delivery]) and conventional stents (Niti-S large-cell D-type; LCD) for unresectable HMBO. RESULTS: Eighty-three patients with HMBO were included; 31 LC slim-delivery and 52 LCD. Overall technical and clinical success rates were 100% and 90% in LC slim-delivery group and 98% and 88% in LCD group. Use of the LC slim-delivery was associated with shorter stent placement time in the multiple regression analysis, with a stent placement time of 18 and 23 min in LC slim-delivery and LCD groups, respectively. The early adverse event (AE) rate of LC slim-delivery was 10%, with no cholangitis or cholecystitis as compared to 23% in the LCD group. Recurrent biliary obstruction (RBO) rates and time to RBO were comparable between the two groups: 35% and 44%, and 8.5 and 8.0 months in LC slim-delivery and LCD groups, respectively. The major cause of RBO was tumor ingrowth (82%) in the LC slim-delivery group and sludge (43%) and ingrowth (48%) in LCD group. CONCLUSION: Stent-in-stent methods using LC slim-delivery shortened stent placement time with low early AE rates and comparable time to RBO in patients with HMBO.

Development and external validation of a nomogram for prediction of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed for management of pancreatobiliary diseases; however, post-ERCP pancreatitis (PEP) remains as an unsolved problem. Although various risk factors for PEP have been reported, the prediction of PEP remains controversial. This study aimed to develop a predictive model for PEP. METHODS: Consecutive patients undergoing ERCP for biliary indications at two centers were retrospectively studied. Using data from a training cohort, we utilized a multivariable model to select five variables to construct a nomogram. The predictive model was internally and externally validated. Based on the nomogram, the patients were categorized into low-, moderate-, and high-risk groups. RESULTS: Using the data of 2224 patients in the training cohort, five variables were selected to generate a nomogram: 1) sex, 2) indication for ERCP, 3) difficult cannulation, 4) guidewire insertion into the pancreatic duct, and 5) endoscopic sphincterotomy or sphincteroplasty. The most significant risk factor was endoscopic papillary balloon dilation such as endoscopic sphincterotomy or sphincteroplasty. The bias-corrected concordance index was 0.72 in the training cohort and 0.72 in the validation cohort. Calibration curves for both cohorts demonstrated good agreement between the predicted and observed frequencies of the actual outcome. In the validation cohort, PEP developed in 5.0% and 14% of patients in the moderate- and high-risk groups, respectively. CONCLUSIONS: We successfully developed a good predictive model for PEP. The prevention of PEP in high risk patients should be investigated further.

Impact of telephone follow-up on hepatocellular carcinoma patients receiving oral chemotherapy from an ambulatory-care setting.

INTRODUCTION: In recent years, most molecular target drugs have been administered orally, as prescribed at ambulatory services in hospitals and at patients' homes. Telephone follow-up is increasingly being used in clinical practice for patients needing additional support post-discharge and for the prevention of hospital readmissions. The purpose of this study was to clarify the clinical benefits of telephone follow-up while administering oral anticancer drugs. METHODS: This was a single-center, observational, retrospective study. We evaluated hepatocellular carcinoma patients who received sorafenib or lenvatinib between March 2010 and February 2018. The primary endpoint was the incidence of adverse events. RESULTS: From the total of 130 patients, 83 patients received telephone follow-up and 47 did not. The incidence of hand-foot skin reactions significantly reduced in patients with telephone follow-up (odds ratio (OR) 3.69, 95% confidence interval (CI) 1.16-11.8, p = 0.020). The median durations (ranges) of adherence to oral chemotherapy were 259 days (15-1730) for the telephone follow-up group and 121 days (14-1105) for the no-telephone follow-up group (p < 0.001). Moreover, the disease control rate was significantly higher in the telephone follow-up group (OR 2.52, 95% CI 1.15-5.53, p = 0.020). CONCLUSIONS: Remote interventions, such as telephone follow-up, are useful means of managing adverse events in patients receiving oral anticancer drugs and can lead to improved treatment results.

Comparison of novel large-bore and conventional-bore covered self-expandable metal stents for malignant gastric outlet obstruction: Multicenter, retrospective study.

OBJECTIVES: Covered self-expandable metal stent (cSEMS) for gastric outlet obstruction (GOO) has been developed to overcome tumor ingrowth but is prone to be associated with an increased risk of migration. Clinical impact of the novel large-bore cSEMS for malignant GOO remains unclear. METHODS: A total of 117 patients undergoing endoscopic cSEMS placement for malignant GOO were enrolled in this multicenter retrospective study. Technical and clinical success, adverse events, recurrent GOO, and survival after stent placement were compared between 24 mm-cSEMS (n = 49) and 20 mm-cSEMS (n = 68). RESULTS: Patient characteristics were well-balanced and thus similar survival was observed between the two groups (136 days vs. 89 days, P = 0.60). Technical success rate of 100% and clinical success rate of 96% were achieved both in 24 mm-cSEMS and 20 mm-cSEMS, respectively. The median cumulative time to recurrent GOO was significantly longer in 24 mm-cSEMS than in 20 mm-cSEMS (380 days vs. 138 days, P = 0.01). The incidence of adverse events and recurrent GOO was comparable: 12% vs. 15% (P = 0.91), and 16% vs. 31% (P = 0.11); however, no stent migration was observed in 24 mm-cSEMS. In a subgroup analysis, the superiority of 24 mm-cSEMS to 20 mm-cSEMS was demonstrated in extrinsic cancers (380 days vs. 121 days, P = 0.01) but not in intrinsic cancers (151 days vs. not reached, P = 0.47). CONCLUSIONS: The 24 mm-cSEMS may improve time to recurrent GOO with ensuring acceptable safety in patients with malignant GOO.

Comparison of annual eGFR decline among primary kidney diseases in patients with CKD G3b-5: results from a REACH-J CKD cohort study.

BACKGROUND: Disease-specific trajectories of renal function in advanced chronic kidney disease (CKD) are not well defined. Here, we compared these trajectories in the estimated glomerular filtration rate (eGFR) by CKD stages. METHODS: Patients with multiple eGFR measurements during the 5-year preregistration period of the REACH-J study were enrolled. Mean annual eGFR declines were calculated from linear mixed effect models with the adjustment variables of baseline CKD stage, age, sex and the current CKD stage and the level of proteinuria (CKDA1-3). RESULTS: Among 1,969 eligible patients with CKDG3b-5, the adjusted eGFR decline (ml/min/1.73 m2/year) was significantly faster in diabetic kidney disease (DKD) patients and polycystic kidney disease (PKD) patients than in patients with other kidney diseases (DKD, - 2.96 ± 0.13; PKD, - 2.82 ± 0.17; and others, - 1.95 ± 0.05, p < 0.01). The declines were faster with higher CKD stages. In DKD patients, the eGFR decline was significantly faster in CKDG5 than CKDG4 (- 4.10 ± 0.18 vs - 2.76 ± 0.20, p < 0.01), while these declines in PKD patients were similar. The eGFR declines in PKD patients were significantly faster than DKD patients in CKDG4 (- 2.92 ± 0.23 vs - 2.76 ± 0.20, p < 0.01) and in CKDA2 (- 3.36 ± 0.35 vs - 1.40 ± 0.26, p < 0.01). CONCLUSION: Our study revealed the disease-specific annual eGFR declines by CKD stages and the level of proteinuria. Comparing to the other kidney diseases, the declines in PKD patients were getting faster from early stages of CKD. These results suggest the importance of CKD managements in PKD patients from the early stages.

Clinical impact of monitoring frequency per day as a prospective audit and feedback strategy for patients receiving antimicrobial agents by injection.

BACKGROUND: Implementation of antimicrobial stewardship programmes improve antimicrobial therapies and thus result in better patient outcomes and safety. The impact of prospective audit and feedback (PAF) is likely dependent on how frequently it is conducted, and how quickly after antibiotic prescription it is initiated. To our knowledge, however, no report has yet investigated the impact of an increase in monitoring frequency per day on PAF strategy. Here, we evaluated the clinical impact of an increase in monitoring frequency per day as a PAF strategy in patients receiving antimicrobial injections. METHODS: We conducted a single-centre, retrospective observational pre-post study to evaluate the impact of increasing the frequency of monitoring from once daily (once daily review group) to twice daily (twice daily review group). Time to intervention and clinical outcomes were compared before and after implementation of twice daily review. RESULTS: Time to intervention for inappropriate antimicrobial therapy was significantly shorter in the twice daily review group than the once daily review group (5.1 ± 6.1 hours vs 29.9 ± 21.5 hours, HR: 4.53, 95% CI: 2.90-7.07, P < .001). The twice daily review group had a significantly lower rate of clinical failure (16.2% vs 38.3%, P = .004) and hepatotoxicity (4.1% vs 15.0%, P = .035) than the once daily review group. CONCLUSIONS: An increase in monitoring frequency from once daily to twice daily significantly shortened the time to intervention for inappropriate antimicrobial therapy, with a concomitant reduction in clinical failure and hepatotoxicity.

Development of a Scoring System to Predict Prolonged Post-Stroke Dysphagia Remaining at Discharge from a Subacute Care Hospital to the Home.

BACKGROUND: Prolonged dysphagia is an important stroke-related complication that imposes a substantial burden on patients and families. However, simple scoring tool to predict prolonged dysphagia is not existing. MATERIALS AND METHODS: This retrospective cohort study used data from April 2010 to March 2016. Adult patients with first-ever stroke were included. The outcome was swallowing function at discharge from the subacute care hospital to the patient's home. We collected the following factors obtained at discharge from the University of Fukui Hospital: age, sex, type of stroke, comorbidities, smoking status, alcohol use, denture use, functional dependency in daily living before admission, National Institutes of Health Stroke Scale score (NIHSS) at admission, and Functional Independence Measure(FIM). Data were divided into a training set (70%) and test set (30%). Lasso and logistic regression were used for feature selection, a scoring system was then developed, and its prediction performance evaluated. RESULTS: This study enrolled 462 patients with acute stroke. Using lasso and logistic regression, three variables (functional dependency before admission, Functional Independence Measure [FIM]-cognitive and FIM-motor scores at transfer) remained statistically significant predictors of prolonged dysphagia. Risk scores were categorized as low risk (0-2), moderate risk (3-4), and high risk (5-7), with dysphagia rates of 0%-1%, 13%-29%, and 50%-100%, respectively. A newly developed score ≥3 was the optimal cutoff for identifying patients with the potential risk of prolonged dysphagia (C-statistics, 0.92 in the test set). CONCLUSION: The developed scoring system is simple and has a high performance in predicting prolonged dysphagia after acute stroke.

Long-term outcomes of a long, partially covered metal stent for EUS-guided hepaticogastrostomy in patients with malignant biliary obstruction (with video).

BACKGROUND AND AIMS: We previously reported safety and effectiveness of EUS-guided hepaticogastrostomy (EUS-HGS) using a long, partially covered metal stent (LP-CMS) for malignant biliary obstruction (MBO). In this study, we aimed to evaluate long-term outcomes of EUS-HGS in an expanded cohort. METHODS: One hundred ten patients undergoing EUS-HGS using an LP-CMS in 2 centers were retrospectively studied. Technical and functional success, adverse events, recurrent biliary obstruction (RBO), and reinterventions were evaluated. RESULTS: The cause of MBO was pancreatic cancer in 50%, and the location of MBO was distal in 68%. The stent length was 8 cm in 2%, 10 cm in 84%, and 12 cm in 15%, with a median intragastric stent length of 54 mm. Technical and functional success rates were 100% and 94%, respectively. The adverse event rate was 25% (mild 15%, moderate 7%, severe 3%), but about one-half of adverse events were mild transient fever and abdominal pain. RBO developed in 33%, with a median cumulative time to RBO of 6.3 months. The major cause of RBO was hyperplasia at an uncovered portion. The presence of prior biliary drainage and short intragastric stent length were significantly associated with RBO. Reintervention for RBO was successfully achieved through the EUS-HGS route in 92%. The remaining reintervention procedures were 1 EUS-HGS and 2 percutaneous transhepatic biliary drainage all in cases with hilar MBO. CONCLUSIONS: EUS-HGS using an LP-CMS for unresectable MBO was safe and effective. RBO was not uncommon, but reintervention through the EUS-HGS route was technically possible in most cases.

Multicenter randomized trial of endoscopic papillary large balloon dilation without sphincterotomy versus endoscopic sphincterotomy for removal of bile duct stones: MARVELOUS trial.

BACKGROUND : Endoscopic papillary large balloon dilation (EPLBD) has been increasingly used for the management of large common bile duct (CBD) stones. Although EPLBD is often preceded by endoscopic sphincterotomy (EST), EPLBD alone without EST has been increasingly reported as an alternative to EST for large CBD stones. METHODS : This multicenter randomized trial was conducted at 19 Japanese institutions to compare the efficacy and safety of EPLBD alone versus EST for the removal of large (≥ 10 mm) CBD stones. The primary end point was complete stone removal in a single session. The secondary end points included: overall complete stone removal, lithotripsy use, procedure time, adverse events, and cost. RESULTS: 171 patients with large CBD stones were included in the analysis. The rate of single-session complete stone removal was significantly higher in the EPLBD-alone group than in the EST group (90.7 % vs. 78.8 %; P = 0.04). Lithotripsy use was significantly less frequent in the EPLBD group than in the EST group (30.2 % vs. 48.2 %; P = 0.02). The rates of early adverse events were comparable between the two groups: rates of overall adverse events were 9.3 % vs. 9.4 % and of pancreatitis were 4.7 % vs. 5.9 % in the EPLBD and EST groups, respectively. The procedure costs were $1442 vs. $1661 in the EPLBD and EST groups, respectively (P = 0.12). CONCLUSION : EPLBD without EST for the endoscopic treatment of large CBD stones achieved a significantly higher rate of complete stone removal in a single session compared with EST, without increasing adverse events.

Retrospective Comparative Study of Side-by-Side and Stent-in-Stent Metal Stent Placement for Hilar Malignant Biliary Obstruction.

BACKGROUND: In patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial. STUDY: Clinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS. RESULTS: A total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively. CONCLUSIONS: Other than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

Early pancreatic stent placement in wire-guided biliary cannulation: A multicenter retrospective study.

BACKGROUND AND AIM: Guidewire insertion to a pancreatic duct under wire-guided cannulation (WGC) during endoscopic retrograde cholangiopancreatography (ERCP) is associated with a high incidence of post-ERCP pancreatitis (PEP). Pancreatic stent placement followed by WGC (PS-WGC) is considered for these cases to reduce PEP. This study was aimed to examine the effectiveness of PS-WGC compared with repeated WGC. METHODS: The consecutive data of patients without history of ERCP who underwent ERCP for biliary intervention were retrospectively collected from five centers. Patients without guidewire insertion to the pancreatic duct were excluded. Pancreatic stent was immediately placed after guidewire insertion to the pancreatic duct in the PS-WGC group. The association between the method of biliary cannulation (PS-WGC or repeated WGC) and PEP was analyzed using multivariable logistic regression model. RESULTS: A total of 590 patients (183 in the PS-WGC and 407 in the repeated WGC group) were included. PS-WGC decreased PEP (8.7% vs 19%, P = 0.001) and improved its severity (moderate and severe PEP; 2.2% vs 6.4%, P = 0.04) compared with repeated WGC. PS-WGC was associated with reduction of PEP in the multivariable model (Odds ratio 0.31, P < 0.001). The rates of difficult cannulation and overall successful biliary cannulation were not different between the two groups (66% vs 70%, P = 0.39 and 98% vs 96%, P = 0.21 in the PS-WGC and repeated WGC group, respectively). CONCLUSIONS: Pancreatic stent placement followed by WGC reduced PEP in patients with guidewire insertion to the pancreatic duct during WGC for native papilla compared with repeated WGC.

Endoscopic papillary large balloon dilation without sphincterotomy for users of antithrombotic agents: A multicenter retrospective study.

BACKGROUND AND AIM: With an aging population, an increasing number of individuals on antithrombotic agents are diagnosed with large bile duct stones. Studies have shown the effectiveness of endoscopic papillary large balloon dilation (EPLBD) for removal of large bile duct stones. EPLBD without endoscopic sphincterotomy (EST) may reduce the risk of procedure-related bleeding, but the safety of this procedure for users of antithrombotic agents remains unclear. METHODS: In this multicenter retrospective study, we included patients who underwent EPLBD without EST for bile duct stones between March 2008 and December 2017. We compared adverse events and other clinical outcomes between users and non-users of antithrombotic agents (antiplatelet agents and anticoagulants). RESULTS: We analyzed a total of 144 patients (47 users and 97 non-users of antithrombotic agents). Among the users, the agents were continued in 13% and were replaced with heparin in 62% during the periprocedural period. We did not observe clinically significant bleeding and thrombotic events irrespective of the use of antithrombotic agents. Overall rate of early adverse events did not differ between users and non-users (6.4% and 7.2%, P = 0.99). Procedural outcomes did not differ between the groups (necessity for lithotripsy, 28% vs. 29%; and complete stone removal in a single session, 72% vs. 71%, for users and non-users, respectively). CONCLUSIONS: Endoscopic papillary large balloon dilation without EST may be done without a substantial increase in procedure-related bleeding for users of antithrombotic agents. A larger study is required to refine the management strategy for those agents during the periprocedural period.

Antireflux covered metal stent for nonresectable distal malignant biliary obstruction: Multicenter randomized controlled trial.

BACKGROUND AND AIM: An antireflux metal stent (ARMS) for nonresectable distal malignant biliary obstruction (MBO) may prevent recurrent biliary obstruction (RBO) as a result of duodenobiliary reflux and prolong time to RBO (TRBO). Superiority of ARMS over conventional covered self-expandable metal stents (SEMS) has not been fully examined. METHODS: We conducted a multicenter randomized controlled trial to examine whether TRBO of an ARMS with a funnel-shaped valve was longer than that of a covered SEMS in SEMS-naïve patients. We enrolled 104 patients (52 patients per arm) at 11 hospitals in Japan. Secondary outcomes included causes of RBO, adverse events, and patient survival. RESULTS: TRBO did not differ significantly between the ARMS and covered SEMS groups (median, 251 vs 351 days, respectively; P = 0.11). RBO as a result of biliary sludge or food impaction was observed in 13% and 9.8% of patients who received an ARMS and covered SEMS, respectively (P = 0.83). ARMS was associated with a higher rate of stent migration compared with the covered SEMS (31% vs 12%, P = 0.038). Overall rates of adverse events were 20% and 18% in the ARMS and covered SEMS groups, respectively (P = 0.97). No significant between-group difference in patient survival was observed (P = 0.26). CONCLUSIONS: The current ARMS was not associated with longer TRBO compared with the covered SEMS. Modifications including addition of an anti-migration system are required to use the current ARMS as first-line palliative treatment of distal MBO (UMIN-CTR clinical trial registration number: UMIN000014784).

Region-specific deletions of the glutamate transporter GLT1 differentially affect seizure activity and neurodegeneration in mice.

Glial glutamate transporter GLT1 plays a key role in the maintenance of extracellular glutamate homeostasis. Recent human genetic studies have suggested that de novo mutations in GLT1 (EAAT2) cause early-onset epilepsy with multiple seizure types. Consistent with these findings, global GLT1 null mice show lethal spontaneous seizures. The consequences of GLT1 dysfunction vary between different brain regions, suggesting that the role of GLT1 dysfunction in epilepsy may also vary with brain regions. In this study, we generated region-specific GLT1 knockout mice by crossing floxed-GLT1 mice with mice that express the Cre recombinase in a particular domain of the ventricular zone. Selective deletion of GLT1 in the diencephalon, brainstem and spinal cord is sufficient to reproduce the phenotypes (excess mortality, decreased body weight, and lethal spontaneous seizure) of the global GLT1 null mice. By contrast, dorsal forebrain-specific GLT1 knockout mice showed nonlethal complex seizures including myoclonic jerks, hyperkinetic running, spasm and clonic convulsion via the activation of NMDA receptors during a limited period from P12 to P14 and selective neuronal death in cortical layer II/III and the hippocampus. Thus, GLT1 dysfunction in the dorsal forebrain is involved in the pathogenesis of infantile epilepsy and GLT1 in the diencephalon, brainstem and spinal cord may play a critical role in preventing seizure-induced sudden death.

Nosyl (2-Nitrobenzenesulfonyl) Annulation Strategy toward Winding Vine-Shaped Bithiophenes.

Winding vine-shaped bithiophene was synthesized through the nosyl (2-nitrobenzenesulfonyl) cyclization protocol. The reaction of bithiophene bearing bromomethyl groups at the 3,3'-positions with nosylated 1,2-ethylenediamine in the presence of potassium carbonate afforded the annulated product in excellent yield. The obtained bithiophene was found to contain a 10-membered ring, which was confirmed by X-ray analysis. The related nosyldiamine bearing a tri- or tetramethylene group also reacted in a similar manner, affording an 11- or 12-membered macrocycle, respectively.

International study of endoscopic management of distal malignant biliary obstruction combined with duodenal obstruction.

OBJECTIVE: Endoscopic transpapillary or endoscopic ultrasound (EUS)-guided stent placement is used for nonresectable distal malignant biliary obstruction. We conducted a retrospective study to evaluate endoscopic biliary drainage in patients with duodenal obstruction. METHODS: We included consecutive patients who underwent endoscopic biliary drainage combined with a duodenal stent at 16 referral centers in four Asian countries. The primary outcome was time to recurrent biliary obstruction (TRBO). We assessed TRBO according to the sequence of biliary and duodenal obstruction (group 1/2/3, biliary obstruction first/concurrent/duodenal obstruction first, respectively) or the location of duodenal obstruction (type I/II/III, proximal to/affecting/distal to the ampulla, respectively). We also evaluated functional success and adverse events. RESULTS: We included 110 patients (group1/2/3, 67/29/14 patients; type I/II/III, 45/46/19 patients; endoscopic retrograde cholangiopancreatography [ERCP]/EUS-guided choledocoduodenostomy/EUS-guided hepaticogastrostomy, 90/10/10 patients, respectively). The median TRBO of all cases was 450 days (interquartile range, 212-666 days) and functional success was achieved in 105 cases (95%). The TRBO did not differ significantly by the timing or location of duodenal obstruction (p = .30 and .79, respectively). The TRBO of metal stents (n = 96) tended to be longer compared with plastic stents (n = 14, p = .083). Compared with ERCP, EUS-guided biliary drainage was associated with a higher rate of adverse events. CONCLUSION: Transpapillary or transmural endoscopic biliary drainage with a duodenal stent was effective, irrespective of the timing or location of duodenal obstruction. A prospective study is required considering the tradeoff of technical success rate, stent patency, and adverse events (ClinicalTrials.gov number, NCT02376907).

Multicenter study of endoscopic preoperative biliary drainage for malignant hilar biliary obstruction: E-POD hilar study.

BACKGROUND AND AIM: Endoscopic nasobiliary drainage (ENBD) is often recommended in preoperative biliary drainage (PBD) for hilar malignant biliary obstruction (MBO), but endoscopic biliary stent (EBS) is also used in the clinical practice. We conducted this large-scale multicenter study to compare ENBD and EBS in this setting. METHODS: A total of 374 cases undergoing PBD including 281 ENBD and 76 EBS for hilar MBO in 29 centers were retrospectively studied. RESULTS: Extrahepatic cholangiocarcinoma (ECC) accounted for 69.8% and Bismuth-Corlette classification was III or more in 58.8% of the study population. Endoscopic PBD was technically successful in 94.6%, and adverse event rate was 21.9%. The rate of post-endoscopic retrograde cholangiopancreatography pancreatitis was 16.0%, and non-endoscopic sphincterotomy was the only risk factor (odds ratio [OR] 2.51). Preoperative re-intervention was performed in 61.5%: planned re-interventions in 48.4% and unplanned re-interventions in 31.0%. Percutaneous transhepatic biliary drainage was placed in 6.4% at the time of surgery. The risk factors for unplanned procedures were ECC (OR 2.64) and total bilirubin ≥ 10 mg/dL (OR 2.18). In surgically resected cases, prognostic factors were ECC (hazard ratio [HR] 0.57), predraiange magnetic resonance cholangiopancreatography (HR 1.62) and unplanned re-interventions (HR 1.81). EBS was not associated with increased adverse events, unplanned re-interventions, or a poor prognosis. CONCLUSIONS: Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO.

A nationwide prospective cohort study of patients with advanced chronic kidney disease in Japan: The Reach-J CKD cohort study.

BACKGROUND: Epidemiology and outcomes of Japanese patients with advanced chronic kidney disease (CKD)-an estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2-has remained largely unexamined. METHODS: We conducted a nationwide survey to determine the distribution of Japanese CKD patients, and are conducting a cohort study of these patients. A questionnaire eliciting details about facilities and their CKD practices was sent to all clinics/hospitals with nephrologists. Based on the survey results, we recruited 2400 advanced CKD patients receiving nephrologist care from at least 30 representative facilities throughout Japan, selected randomly with stratification by region and facility size. Through patient questionnaires and nephrologist-practice surveys aligned with the international CKD Outcomes and Practice Patterns Study (CKDopps), we shall annually or semi-annually collect patient, physician and clinic data prospectively, detailing CKD practices for 5 years, with a primary outcome of death or renal replacement therapy initiation, and secondary outcomes being decline of eGFR by 30% or 50%, CKD progression to CKD G5, or a cardiovascular event. RESULTS: Of 790 eligible, responding facilities, 330 (41.8%) treat ≥80 advanced CKD patients in the average 3-month period. Regional distribution of these facilities is similar to that of persons in the general population. Hence, the 30 facilities selected for data collection appear to be geographically representative in Japan. CONCLUSIONS: Our study will enhance understanding of various CKD practices and biological data associated with CKD progression, and allow international comparisons using the CKDopps platform. This will provide evidences to improve the health and quality of life for patients with advanced CKD.