Mechanisms of insertions at a DNA double-strand break.

Insertions and deletions (indels) are common sources of structural variation, and insertions originating from spontaneous DNA lesions are frequent in cancer. We developed a highly sensitive assay called insertion and deletion sequencing (Indel-seq) to monitor rearrangements in human cells at the TRIM37 acceptor locus that reports indels stemming from experimentally induced and spontaneous genome instability. Templated insertions, which derive from sequences genome wide, require contact between donor and acceptor loci, require homologous recombination, and are stimulated by DNA end-processing. Insertions are facilitated by transcription and involve a DNA/RNA hybrid intermediate. Indel-seq reveals that insertions are generated via multiple pathways. The broken acceptor site anneals with a resected DNA break or invades the displaced strand of a transcription bubble or R-loop, followed by DNA synthesis, displacement, and then ligation by non-homologous end joining. Our studies identify transcription-coupled insertions as a critical source of spontaneous genome instability that is distinct from cut-and-paste events.

Impact of Ring-Closing on the Photophysical Properties of One-Dimensional π-Conjugated Molecular Aggregate.

The self-assembled state of molecules plays a pivotal role in determining how inherent molecular properties transform and give rise to supramolecular functionalities and has long attracted attention. However, understanding the influence of morphologies spanning the nano- to mesoscopic scales of supramolecular assemblies derived from identical intermolecular interactions has been notoriously challenging due to dynamic structural change and monomer exchange of assemblies in solution. In this study, we demonstrate that curved one-dimensional molecular assemblies (supramolecular polymers) of lengths of around 70-200 nm, originating from the same luminescent molecule, exhibit distinct photoluminescent properties when they form closed circular structures (toroids) versus when they possess chain termini in solution (random coils). By exploiting the difference in kinetic stability between the toroids and random coils, we developed a dialysis protocol to selectively purify the former. It was revealed that these terminus-free closed structures manifest higher energy and more efficient luminescence compared with their mixed state with random coils. Time-resolved fluorescence measurements unveiled that random coils, due to their dynamic structural fluctuation in solution, generate local defects throughout the main chain, leading to luminescence from lower energy levels. In mixtures of the two assemblies, luminescence was exclusively observed from such a lower energy level of random coils, a result attributed to energy transfer between the assemblies. This work emphasizes that for identical supramolecular assemblies, only averaged properties have traditionally been considered, but their structures at the nano- to mesoscopic scale are important especially if they have a certain degree of shape persistency even in solution.

Effects of lunges inserted in walking (eccentric walking) on lower limb muscle strength, physical and cognitive function of regular walkers.

INTRODUCTION: Walking is a popular exercise but does not increase lower limb muscle strength and balance. We hypothesized that muscle strength, physical and cognitive function would be improved by inserting lunges in conventional walking. METHODS: Eleven regular walkers (54-88 years) who had more than 5000 steps in exercise walking a day at least 5 days a week participated in this study. They walked as usual for the first 4 weeks and included lunges and descending stairs or slope walking (i.e., eccentric walking) for the next 8 weeks. The steps of eccentric walking were gradually increased from 100 to 1000 steps per week over 8 weeks. RESULTS: The average steps per day were 10,535 ± 3516 in the first 4 weeks, and 10,118 ± 3199 in the eccentric walking period without a significant difference. No significant changes in maximal voluntary isometric contraction torque of the knee extensors (MVC), 30-s chair stand (CS), 2-min step, balance assessed by center of pressure movement area with eyes close, sit and reach, a digit symbol substitution test (DSST) for cognitive function were observed in the first 4 weeks. However, significant (P < 0.05) improvements were evident in MVC (18.6 ± 15.7%), CS (24.2 ± 17.3%), balance ( - 45.3 ± 34.5%), and DSST (20.8 ± 16.7%) from weeks 4 to 12. Serum complement component 1q concentration decreased (P < 0.05) from weeks 4 to 12, although no changes in serum glucose, triglyceride, and cholesterol concentrations were observed. CONCLUSION: These results supported the hypothesis, and suggest that eccentric walking provides effects that are not achieved by conventional walking.

Supramolecular Polymer Polymorphism: Spontaneous Helix-Helicoid Transition through Dislocation of Hydrogen-Bonded π-Rosettes.

Polymorphism, a phenomenon whereby disparate self-assembled products can be formed from identical molecules, has incited interest in the field of supramolecular polymers. Conventionally, the monomers that constitute supramolecular polymers are engineered to facilitate one-dimensional aggregation and, consequently, their polymorphism surfaces primarily when the states of assembly differ significantly. This engenders polymorphs of divergent dimensionalities such as one- and two-dimensional aggregates. Notwithstanding, realizing supramolecular polymer polymorphism, wherein polymorphs maintain one-dimensional aggregation, persists as a daunting challenge. In this work, we expound upon the manifestation of two supramolecular polymer polymorphs formed from a large discotic supramolecular monomer (rosette), which consists of six hydrogen-bonded molecules with an extended π-conjugated core. These polymorphs are generated in mixtures of chloroform and methylcyclohexane, attributable to distinctly different disc stacking arrangements. The face-to-face (minimal displacement) and offset (large displacement) stacking arrangements can be predicated on their distinctive photophysical properties. The face-to-face stacking results in a twisted helix structure. Conversely, the offset stacking induces inherent curvature in the supramolecular fiber, thereby culminating in a hollow helical coil (helicoid). While both polymorphs exhibit bistability in nonpolar solvent compositions, the face-to-face stacking attains stability purely in a kinetic sense within a polar solvent composition and undergoes conversion into offset stacking through a dislocation of stacked rosettes. This occurs without the dissociation and nucleation of monomers, leading to unprecedented helicoidal folding of supramolecular polymers. Our findings augment our understanding of supramolecular polymer polymorphism, but they also highlight a distinctive method for achieving helicoidal folding in supramolecular polymers.

Nuclear-targeted 4E-BP1 is dephosphorylated, induces nuclear translocation of eIF4E, and alters mRNA translation.

Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). This leads to the release of eIF4E from 4E-BP1 and the initiation of eIF4E-dependent mRNA translation. In this study, we examined the expression of a 4E-BP1-based reporter (mTORC1 activity reporter; TORCAR) with various localization signal tags to clarify the relationship between the localization of 4E-BP1 and its phosphorylation. Phosphorylation of 4E-BP1 at threonine 37/46 and serine 65 was efficient at lysosomes and the plasma membrane, whereas it was significantly decreased in the nucleus. In addition, the localization of endogenous eIF4E shifted from the cytoplasm to the nucleus only when nuclear-localized TORCAR was expressed. Nuclear-localized TORCAR decreased cyclin D1 protein levels and altered cell cycle distribution. These data provide an experimental tool to manipulate the localization of endogenous eIF4E without affecting mTORC1 and highlight the important role of nuclear-cytoplasmic shuttling of eIF4E.

Measurement of the anchoring force of covered self-expandable and lumen-apposing metal stents for interventional endoscopic ultrasonography.

OBJECTIVES: Interventional endoscopic ultrasonography is performed for various situations that require drainage, after which stent migration is the most severe adverse event. Several lumen-apposing metal stents (LAMS) and covered self-expandable metal stents (CSEMS) provide antimigration systems; however, their anchoring ability has not been studied well. Therefore, we measured and compared the anchoring force (ACF) of commercially available LAMS and CSEMS. METHODS: Anchoring force was measured for five types of LAMS (NAGI, SPAXUS, Plumber, and AXIOS 8 and 10 mm) and seven types of CSEMS (BCL, SHCL, BCG, BPD [four types of HANAROSTENT], HILZO, Niti-S [Spring Stopper], and Wallflex). We created a phantom model for inducing stent migration. It has a rotatable part as a curved fixture, and we measured ACF at angles between 0° and 40°. RESULTS: The mean ACF at 0° and 20° were NAGI 1.50, 1.84 N, SPAXUS 1.73, 1.72 N, Plumber 2.64, 2.03 N, and AXIOS 3.96, 3.61 N, respectively; and BCL 0.48, 0.53 N, Wallflex 0.53, 0.48 N, SHCL 0.64, 0.73 N, HILZO 1.09, 1.09 N, BCG 1.22, 1.20 N, BPD 1.78, 1.67 N, and Spring Stopper 2.29, 2.51 N. CONCLUSION: We measured ACF in LAMS and CSEMS with a new phantom model. The highest value among the LAMS was for the AXIOS and among the CSEMS was for the Spring Stopper. Some of the ACF values varied with the direction of pull. These findings may have a significant impact on stent selection for interventional endoscopic ultrasonography, and this model can be used to evaluate newly developed stents.

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.

Risk factors for adverse outcomes at various phases of endoscopic ultrasound-guided treatment of pancreatic fluid collections: Data from a multi-institutional consortium.

OBJECTIVES: No comprehensive study has examined short- and long-term adverse outcomes of endoscopic ultrasound (EUS)-guided treatment of pancreatic fluid collections (PFCs) including walled-off necrosis (WON) and pseudocysts. METHODS: In a multi-institutional cohort of 357 patients receiving EUS-guided treatment of PFCs (228 with WON and 129 with pseudocysts), we examined PFC type-specific risk factors for procedure-related adverse events (AEs), clinical failure, and recurrence. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the logistic and Cox regression models, respectively, adjusting for potential confounders. RESULTS: Adverse events were observed predominantly in WON, and risk factors were WON extension to the pelvis (OR 2.49; 95% CI 1.00-6.19) and endoscopic necrosectomy (OR 5.15; 95% CI 1.61-16.5). Risk factors for clinical failure in WON treatment included higher Charlson Comorbidity Index (OR for ≥3 vs. ≤2, 2.58; 95% CI 1.05-6.35), extension to the pelvis (OR 3.63; 95% CI 1.57-8.43), nonuse of a lumen-apposing metal stent (OR 2.88; 95% CI 1.10-7.54), and percutaneous drainage (OR 3.73; 95% CI 1.27-10.9). Patients with pseudocysts extending to the paracolic gutter and the need for more than two endoscopic/percutaneous procedures had ORs for clinical failure of 5.28 (95% CI 1.10-25.3) and 5.52 (95% CI 1.61-18.9), respectively. Pseudocysts requiring the multigateway approach were associated with a high risk of recurrence (HR 4.00; 95% CI 1.11-11.6). CONCLUSION: The adverse outcomes at various phases of EUS-guided PFC treatment may be predictable based on clinical parameters. Further research is warranted to optimize treatment strategies for high-risk patients.

Comparison of bubble removal performances of five membrane oxygenators with and without a pre-filter.

When employing minimal invasive extracorporeal circulation (MiECC), the removal of bubbles in the circuit is important to prevent air embolism. We investigated the bubble removal performance of the FHP oxygenator with a pre-filter and compared it with that of four oxygenators, including the Fusion oxygenator, Quadrox oxygenator, Inspire oxygenator, and FX oxygenator. A closed test circuit filled with an aqueous glycerin solution was used. Air injection (10 mL) was performed prior to the oxygenator, and the number and volume of the bubbles were measured at the inlet and outlet of each oxygenator. At the inlet of the five oxygenators, there were no significant differences in the total number of bubbles detected. At the outlet, bubbles were classified into two groups according to the bubble size: ≥100 µm and <100 µm. Tests were performed at pump flow rates of 4 and 5 L/min. For bubbles ≥100 µm, which are considered clinically detrimental, the FHP was the lowest number and volume of bubbles at both pump flow rates compared to the other oxygenators. Regarding the bubbles <100 µm, the number of bubbles was higher in the FHP than those in others; however, the volume of bubbles was significantly lower at 4 L/min and tended to be lower at 5 L/min. The use of the FHP with the pre-filter removed more bubbles ≥100 µm in the circuit than that by the other oxygenators.

Harmonizing Topological Features of Self-Assembled Fibers by Rosette-Mediated Random Supramolecular Copolymerization and Self-Sorting of Monomers by Photo-Cross-Linking.

Random copolymerization is an effective approach to synthesize the desired polymers by harmonizing distinct properties of different monomers. For supramolecular polymers in which monomer binding is inherently dynamic, it is difficult to achieve random copolymerization of monomers with distinct molecular structures and properties due to an enthalpic advantage upon self-recognition (self-sorting). Herein, we demonstrate an example of thermodynamically controlled random supramolecular copolymerization of two monomers functionalized with barbituric acid via the formation of six-membered hydrogen-bonded rosette intermediates to exhibit structural harmonization of the two main-chain motifs, i.e., intrinsically curved and linear motifs. One monomer based on naphthalene chromophore exclusively forms toroidal fibers, whereas another one bearing additional photoreactive diacetylene moiety affords linearly elongated fibers. Supramolecular copolymerization of the two monomers is achieved by cooling hot monomer mixtures in a nonpolar solvent, which results in the formation of thermodynamically stable spirally folded yet elongated fibers. Atomic force microscopic observations and theoretical simulations of the experimental data obtained by absorption spectroscopy reveal the homopolymerization of the diacetylene-functionalized monomer in the high-temperature region, followed by the incorporation of the naphthalene monomer in the medium-temperature region to form supramolecular copolymers with random monomer sequence. Finally, we demonstrate that the random copolymerization process can be switched to a narcissistically self-sorting one by deactivating monomer exchange through the photo-cross-linking of the diacetylene-functionalized monomers.

Mental Health of Caregivers Working in Nursing Homes during the COVID-19 Pandemic.

INTRODUCTION: There have been numerous reports of cluster outbreaks of coronavirus disease 2019 (COVID-19) in hospitals and nursing homes. Healthcare workers fighting COVID-19 experience mental health issues. Caregivers in nursing homes experienced increased psychological distress and concern about deterioration of their mental health. We conducted a large-scale web-based survey exploring mental health among caregivers working in nursing homes during the COVID-19 pandemic with the aim of identifying their support needs. METHODS: Survey participants were caregivers working at 284 nursing homes in Ibaraki prefecture, Japan. The survey period was from September 2020 to March 2021. Participants responded to a questionnaire covering gender, age, occupation, infections at facilities, infection protection, changes in nursing home users, cooperation with other medical institutions, and prejudice/discrimination. The Hospital Anxiety and Depression Scale (HADS) was used to evaluate participants' depression and anxiety. RESULTS: In total, 676 participants completed the survey; 350 (52.5%) were with anxiety symptoms and 378 (56.7%) were with depressive symptoms (scores exceeding the HADS cut-off points). The risk for anxiety was associated with being care worker or social worker. The risk of anxiety or depression was high when family caregivers' mental state changed. DISCUSSION/CONCLUSION: This study found that caregivers working in nursing homes were exposed to high levels of stress during the COVID-19 pandemic and were at high risk for developing depression and anxiety.

Risk factors for the occurrence and protraction of patellar and patellar tendon pain in children and adolescents: a prospective cohort study of 3 years.

BACKGROUND: Patellar and patellar tendon pain is a common limitation to children's participation in social and physical activities. Some factors have been implicated in the occurrence and protraction of knee pain, but the causal relationship is unknown. The purpose of this study was to investigate whether participants' physical characteristics and activity level are risk factors for the occurrence and protraction of patellar and patellar tendon pain in children and adolescents. METHODS: A three-year prospective cohort study was conducted with healthy students who were aged 8-14 years old, in Japan. Height, weight, heel-buttock distance, straight leg raising angle, and dorsiflexion angle of the ankle joint were collected as individual physical factors at the beginning of each year. The presence of self-reported patellar and patellar tendon pain and the Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) was collected every month. Protraction was defined as either (1) pain lasting for more than three continuous months or (2) recurrent pain after more than three months of complete recovery. Participants who did not have any pain at the beginning of the observation period were included in the analysis. We analyzed the odds ratio (OR) of pain occurrence within a year of registration and protraction throughout the study period for all physical factors and HSS Pedi-FABS. RESULTS: We included 1133 participants in the analysis and 252 participants developed knee pain within a year. 34.8% of participants with pain experienced protraction during the follow-up period. A high HSS Pedi-FABS significantly predicted knee pain occurrence (OR 1.03, 95% confidence interval [CI] 1.01-1.05) and protraction (OR 1.03, 95% CI 1.00-1.05). In addition, younger children and girls were at a significantly higher risk of patellar and patellar tendon pain protraction (age, OR 0.81, 95% CI, 0.73-0.90; sex, OR 1.69, 95% CI, 1.09-2.64). Other physical factors did not significantly predict the occurrence or protraction of knee pain. CONCLUSIONS: This study showed that a greater physical activity level was a risk factor for the occurrence and protraction of patellar and patellar tendon pain in childhood. In addition, younger age and female sex predicted higher risk of protraction of pain.

The Mental Health of Long-Term Evacuees outside Fukushima Prefecture after the Great East Japan Earthquake.

Ten years after the Great East Japan Earthquake, thousands of residents of Fukushima Prefecture were still living as evacuees. Among them, unignorable numbers of people were living outside of the prefecture. A survey was conducted with evacuees to Ibaraki, the neighboring prefecture of Fukushima, to investigate their medium- to long-term mental care needs. A questionnaire was sent to 1,470 households that had been living in Fukushima on March 11, 2011, and who were evacuated to Ibaraki by October 2016. Binary logistic regression analyses were performed to identify risk factors for major depressive disorder, post-traumatic stress disorder (PTSD), and suicidal ideation. Of the participants, 16.5% had a high risk for major depressive disorder, 39.0% exhibited a high risk for PTSD, and 19.7% indicated suicidal ideation. "Own injuries and illnesses" and "Worries about the hometown" were risk factors for major depressive disorder, PTSD, and suicidal ideation. "Not receiving compensation for damages" was a risk factor common to major depressive disorder and suicidal ideation. There is a high possibility that many people who have evacuated to other prefectures might still be suffering from psychological symptoms after the disaster. Worries about their hometowns were highly related to their mental disorders.

Towards an understanding of the pathological basis of senile depression and incident dementia: Implications for treatment.

Senile depression (SD) is a heterogeneous syndrome. Several clinical profiles are more likely to appear in SD than in early-life depression, but it remains unclear whether the pathophysiology is different. The prevalence of dementia increases with aging, and the underlying pathophysiological processes in the preclinical phase begin even before cognitive deficits or neurological signs appear. SD may be either a risk factor for developing dementia or a prodromal stage of dementia. The inconsistent findings regarding the association between SD and incident dementia may be attributable to the neuropathological heterogeneity underlying SD. Most studies have focused on patients with the clinical diagnosis of Alzheimer disease (AD) as an outcome, but several clinicopathological studies suggest that primary age-related tauopathy and argyrophilic grain disease may account for a proportion of cases clinically misdiagnosed as AD in the elderly population. Furthermore, most AD cases have additional neuropathologic changes such as cerebrovascular disease and Lewy body disease. Here, we review the neuropathological findings linking SD to incident dementia, focusing on common age-related neuropathologies. In particular, the roles of disturbance of neural circuity, imbalance of monoaminergic systems, dysregulation of the hypothalamic-pituitary-adrenal axis, and elevated neuroinflammatory status are discussed. Finally, we review the current treatment of SD in the context of age-related neuropathological changes.

Lessons learned from psychosocial support and mental health surveys during the 10 years since the Great East Japan Earthquake: Establishing evidence-based disaster psychiatry.

Post-disaster mental health and psychosocial support have drawn attention in Japan after the 1995 Great Hanshin-Awaji Earthquake, with mental health care centers for the affected communities being organized. After the catastrophe, a reconstruction budget was allocated to organize mental health care centers to provide psychosocial support for communities affected by the 2007 Chuetsu offshore earthquake, the 2011 Great East Japan Earthquake, and the 2016 Kumamoto Earthquake. There were several major improvements in post-disaster mental health measures after the Great East Japan Earthquake. The Disaster Psychiatric Assistance Team system was organized after the earthquake to orchestrate disaster response related to the psychiatric health system and mental health of the affected communities. Special mental health care efforts were drawn to the communities affected by the nuclear power plant accident through Chemical, Biological, Radiological, Nuclear, and high yield Explosives, being succeeded by measures against the coronavirus pandemic. As another new movement after the Great East Japan Earthquake, the number of surveys involving communities affected by disasters has soared. More than 10 times the number of scientific publications were made in English during the decade following the Great East Japan Earthquake, compared with the previous decades. In this review, we examined the results and issues acquired in the 10 years since the Great East Japan Earthquake, proposing evidence-based disaster psychiatry as the direction of future mental health measures related to emergency preparedness and response.

Rapidly Progressive Stenosis of the Left Main Trunk Ostium Starting 21 Months After Stent Implantation.

Rapidly progressive in-stent restenosis (ISR) after stent deployment from the left main trunk (LMT) to the left anterior descending artery (LAD) without plaque at the LMT ostium has not been reported. A 60-year-old Japanese man with a history of scleroderma, pulmonary fibrosis, and type 2 diabetes developed acute myocardial infarction of the right coronary artery (RCA) and was treated by emergency percutaneous coronary intervention (PCI) for RCA. Nine days later he underwent PCI from the LMT to the LAD. Follow-up coronary angiography (CAG) at 9 and 21 months post-PCI did not reveal ISR in any lesion, but the patient experienced cardiac arrest at 25 months post-PCI. Emergency CAG after resuscitation revealed ISR of the LMT ostium; emergency PCI was conducted. The development of ISR at the ostium of the LMT although the patient was free of plaque 4 months before is extremely unusual. This rare ISR of the LMT ostium progressed rapidly after follow-up CAG revealed no ISR at 21 months post-stent implantation.

Increased Cuticle Permeability Caused by a New Allele of ACETYL-COA CARBOXYLASE1 Enhances CO2 Uptake.

Carbon dioxide (CO2) is an essential substrate for photosynthesis in plants. CO2 is absorbed mainly through the stomata in land plants because all other aerial surfaces are covered by a waxy layer called the cuticle. The cuticle is an important barrier that protects against extreme water loss; however, this anaerobic layer limits CO2 uptake. Simply, in the process of adapting to a terrestrial environment, plants have acquired drought tolerance in exchange for reduced CO2 uptake efficiency. To evaluate the extent to which increased cuticle permeability enhances CO2 uptake efficiency, we investigated the CO2 assimilation rate, carbon content, and dry weight of the Arabidopsis (Arabidopsis thaliana) mutant excessive transpiration1 (extra1), whose cuticle is remarkably permeable to water vapor. We isolated the mutant as a new allele of ACETYL-COA CARBOXYLASE1, encoding a critical enzyme for fatty acid synthesis, thereby affecting cuticle wax synthesis. Under saturated water vapor conditions, the extra1 mutant demonstrated a higher CO2 assimilation rate, carbon content, and greater dry weight than did the wild-type plant. On the other hand, the stomatal mutant slow-type anion channel-associated1, whose stomata are continuously open, also exhibited a higher CO2 assimilation rate than the wild-type plant; however, the increase was only half of the amount exhibited by extra1 These results indicate that the efficiency of CO2 uptake via a permeable cuticle is greater than the efficiency via stomata and confirm that land plants suffer a greater loss of CO2 uptake efficiency by developing a cuticle barrier.

Endoscopic ultrasound-guided antegrade procedures for managing bile duct stones in patients with surgically altered anatomy: Comparison with double-balloon enteroscopy-assisted endoscopic retrograde cholangiography (with video).

BACKGROUND AND STUDY AIM: Management of bile duct stones (BDSs) in patients with surgically altered anatomies (SAAs) remains challenging. An endoscopic ultrasound-guided antegrade (EUS-AG) procedure and double-balloon enteroscopy-assisted endoscopic retrograde cholangiography (DB-ERC) have been used to remove BDSs from patients with SAAs. However, few comparative data have been reported. Therefore, we compared the efficacy and safety of the techniques. METHODS: This was a single-center retrospective study. Patients with SAA who underwent the EUS-AG procedure or DB-ERC to remove intra- or extra-BDSs between November 2010 and March 2020 were included. The primary outcome was the technical success rate, defined as stent insertion or stone removal during the initial session. The secondary outcomes were the procedure time, incidence of adverse events (AEs), and complete stone removal rate. RESULTS: Of the 54 patients enrolled, 23 underwent the EUS-AG procedure and 31 DB-ERC. The technical success rates of EUS-AG and DB-ERC were 87.0% and 64.5%, respectively (P = 0.11). The procedure time was significantly shorter in the EUS-AG group than in the DB-ERC group (51.9 ± 15.4 vs 72.6 ± 32.2 min; P = 0.01), and the early AE rates were 26.1% and 12.9%, respectively (P = 0.71). The complete stone removal rates in patients who underwent previous stone removal were 94.1% in the EUS-AG group and 85.7% in the DB-ERC group (P = 0.61). CONCLUSION: The EUS-AG afforded technical success and complete stone removal rates comparable with those of DB-ERC, but the former procedure was shorter. The AE rate was acceptable.

Prognostic significance of serum tyrosine concentration in patients with primary biliary cholangitis under ursodeoxycholic acid therapy.

AIM: Chronic liver insufficiency is often associated with alteration in amino acid metabolism. We evaluated the prognostic value of changes in serum amino acid concentrations in patients with primary biliary cholangitis. METHODS: A total of 75 primary biliary cholangitis patients who started urusodeoxycholic acid therapy were retrospectively enrolled. Baseline serum concentrations of branched-chain amino acids and tyrosine, and branched-chain amino acid-to-tyrosine ratio were determined. The hazard ratios of factors associated with liver-related events were analyzed by Cox proportional hazard analysis. RESULTS: Of the 75 patients enrolled, 12 showed a decrease in serum branched-chain amino acid levels, and 15 showed an increase in serum tyrosine levels. The branched-chain amino acid-to-tyrosine ratio decreased in 16 patients. During a median 5.6-year follow up, liver-related events occurred in 11 patients. Multivariate analysis showed that high serum tyrosine levels at baseline and high alkaline phosphatase levels 48 weeks after starting urusodeoxycholic acid therapy were independent risk factors for event occurrence. From the receiver operator characteristics curve analysis, serum tyrosine concentration >110 µmol/L was identified as a cut-off value with an adjusted hazard ratio of 20.9 (95% confidence interval 4.3-101.5, P < 0.001). Kaplan-Meier analysis showed that the 5-year cumulative incidences of event occurrence in patients with high and low serum tyrosine concentration were 56.5% and 5.5%, respectively (P < 0.001). The 10-year survival probabilities also showed significant differences between patients with high and low serum tyrosine concentration (44.9% vs. 92.0%, P < 0.001). CONCLUSION: Elevation of serum tyrosine concentration indicates a high risk of liver-related events in primary biliary cholangitis patients receiving urusodeoxycholic acid therapy.

Handheld flow meter improves COPD detectability regardless of using a conventional questionnaire: A split-sample validation study.

BACKGROUND AND OBJECTIVE: Improved detectability of chronic obstructive pulmonary disease (COPD) using a handheld flow meter (HFM) with symptom-based questionnaires has not been sufficiently evaluated. This study aimed to identify the benefit of using an HFM in COPD screening. METHODS: A total of 2008 participants, who were ≥ 40 years of age, from Isumi City, Japan, were recruited. We developed two novel point systems for detecting COPD, one incorporated score of HFM alone (sHFM) and the other incorporated the score of International Primary Care Airway Group questionnaire (IPAG) and HFM (sIPAG + HFM). Validation using random sample allocation (split-sample validation) was carried out to assess the predictive performance of these models. RESULTS: Participants were assigned to a data set for model creation (n = 1007) or a data set for model assessment (n = 1001) to perform split-sample validation. Decision curve analysis showed that the net benefits of sHFM and sIPAG + HFM were higher than that of the IPAG score (sIPAG) and specificity of the former two were also significantly higher than that of sIPAG. However, the curves of sHFM and sIPAG + HFM were crossing and practically the same with no significant difference in sensitivity and specificity. CONCLUSION: This study confirms that HFM is significantly advantageous in detecting COPD despite the use of a conventional questionnaire.