Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Immunomodulators after the discontinuation of anti-tumor necrosis factor-alpha antibody treatment and relapse in ulcerative colitis: A multicenter cohort study.

BACKGROUND AND AIM: Strategies to reduce relapse using immunomodulators (IMs) after discontinuing anti-tumor necrosis factor-alpha (TNF-α) antibody treatment are controversial in patients with ulcerative colitis (UC). In this study, we assessed the association between IMs after discontinuing anti-TNF-α antibody treatment and relapse in patients with UC. METHODS: This retrospective, multicenter cohort study included 257 patients with UC in clinical remission. These patients discontinued anti-TNF-α antibody treatment between June 2010 and March 2019 and were followed up until March 2020. We evaluated the differences in relapse rates between patients with IMs (IM group) and those without IMs (non-IM group) after discontinuing the treatment. Relapse was defined as further undergoing an induction treatment or colectomy. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for relapse. Exploratory analyses were performed to identify other factors that could predict relapse. RESULTS: During the median follow-up period of 22 months (interquartile range: 10-41), 114 relapses occurred: 42/100 (42.0%) in the IM group and 72/157 (45.9%) in the non-IM group. In the multivariable analysis, IMs were not associated with relapse (HR, 0.95 [95% CI, 0.64-1.41]). In the exploratory analyses, discontinuation due to side effects (HR, 1.83 [95% CI, 1.18-2.82]) and younger age (HR, 0.99 [95% CI, 0.98-1.00]) predicted relapse. CONCLUSION: Immunomodulators were not associated with relapse after discontinuing anti-TNF-α antibody treatment in patients with UC. Careful patient follow-up is needed when discontinuing due to side effects or when the patient is of a younger age at the time of discontinuation.

Development and Initial Psychometric Validation of the COVID-19 Pandemic Burden Index for Healthcare Workers.

BACKGROUND: The burden of COVID-19 on healthcare workers (HCWs) is reported to be increasing, yet the psychometric scales now in use evaluate only single aspects; few measure the pandemic-specific burden on HCWs comprehensively. OBJECTIVE: To develop a scale to quantify the physical, mental, and socioeconomic burden of the COVID-19 pandemic on HCWs. DESIGN: Scale development and cross-sectional survey. PARTICIPANTS: Consenting HCWs aged ≥20. MAIN MEASURES: Development of an item-list based on literature reviews and HCW panel input, evaluation of content validity and item selection using the Delphi method, psychometric testing conducted on HCWs, validity assessment by factor analyses and hypothesis verification, internal consistency evaluation by Cronbach's alpha, test-retest analysis, and interpretability assessment. KEY RESULTS: Through the Delphi process, a 29-item pilot scale was generated. In psychometric testing, data from 863 HCWs contributed to the development of the final version of this scale, called Pandemic Burden Index twenty for HCWs (PBI-20), a 20-item scale to measure six domains: fatigue, fear of infection, inadequacy as a medical professional, mental health concerns, prejudice or discrimination, and anxiety about one's livelihood and daily life. Factor analysis showed each factor corresponded to the six domains of this scale. Hypothesis verification showed the PBI-20 total score to be moderately to highly correlated with the Short Form 36 vitality score and mental health score and with intention of turnover. The PBI-20 had good internal consistency (Cronbach's alpha 0.92). Test-retest analysis showed the intraclass correlation coefficient to be 0.70 and the minimal important change to be -7.0. CONCLUSIONS: The psychometrically sound questionnaire we developed to measure pandemic-specific burdens for HCWs provides an understanding of comprehensive burdens on HCWs and may serve to evaluate interventions to reduce the burdens.

Prophylactic endoscopic gallbladder stent placement for cholecystitis after covered metal stent placement for distal biliary obstruction (with video).

BACKGROUND AND AIMS: Acute cholecystitis is occasionally observed after biliary drainage using a covered self-expandable metal stent (CSEMS) for distal biliary obstruction (DBO). Gallbladder drainage before CSEMS placement may reduce cholecystitis. This study aimed to examine the preventive effect of endoscopic gallbladder stent placement (EGBS) on cholecystitis with CSEMSs. METHODS: We retrospectively analyzed patients with DBO who underwent CSEMS placement across the orifice of the cystic duct between November 2014 and October 2021 and were negative for cholecystitis on biliary drainage. Prophylactic EGBS was attempted before CSEMS placement. The incidence of cholecystitis was compared between patients with and without EGBS. RESULTS: In total, 286 patients (128 men; median age, 75 years) were included in this study. EGBS was attempted in 32 patients before CSEMS placement, and technical success was achieved in 24 patients (75%). Adverse events were noted in 3 patients (9.4%; penetration of cystic duct in 1 and acute pancreatitis in 2). The cumulative incidence of cholecystitis was significantly lower in patients with EGBS than in those without EGBS (1 [4.2%] vs 56 [21.4%], P = .045). In multivariable analysis, EGBS was a significant protective factor against cholecystitis (hazard ratio, .11; 95% confidence interval, .01-.79; P = .028). CONCLUSIONS: Although the transpapillary approach to the gallbladder is not easy for patients with DBO, EGBS is effective in preventing cholecystitis associated with CSEMS placement.

Innovative method for the diagnosis of bile duct lesions using a novel tapered-tip sheath system to facilitate biliary biopsies.

BACKGROUND AND AIMS: Pathologic evaluation of bile duct lesions is crucial for a definitive diagnosis and determination of an appropriate therapeutic strategy; however, current methods are limited by several challenges. This study evaluated the impact of a novel tapered-tip sheath system on biliary stricture diagnosis. METHODS: This observational study evaluated 47 consecutive patients who underwent transpapillary biliary stricture biopsy using the novel tapered-tip sheath system from July 2020 to March 2022 compared with 51 historical control subjects undergoing conventional biopsies. Technical success rate, total biopsy time, number of biopsy specimens, adequate tissue sampling rate, adverse events, and diagnostic performance for biliary strictures were assessed. RESULTS: The technical success rate was favorable in both groups, showing no significant difference (97.9% [46 of 47] vs 88.2% [45 of 51], P = .114). However, the total biopsy time was significantly shorter in the novel system group (3.7 vs 7.7 minutes, P < .001). The number of biopsy specimens did not differ between the groups; however, the novel system group had significantly more cases in which ≥3 tissue samples could be obtained (71.7% [33 of 46] vs 51.1% [23 of 45], P = .043), a higher adequate tissue sampling rate (88.2% vs 66.4%, P < .001), and fewer adverse events (6.4% vs 21.6%, P = .043). Although the diagnostic specificity of both groups was 100%, the novel system group had significantly higher diagnostic sensitivity and accuracy (82.1% vs 50% [P = .004] and 84.8% vs 55.5% [P = .005], respectively). CONCLUSIONS: The novel tapered-tip sheath system is a promising tool for biliary stricture diagnosis.

Prehospital shock index predicts 24-h mortality in trauma patients with a normal shock index upon emergency department arrival.

BACKGROUND: The shock index (heart rate divided by systolic blood pressure) of trauma patients upon emergency department arrival predicts blood loss and death. However, some patients with normal shock indices (0.4 < shock index <0.9) upon emergency department arrival also have poor prognoses. This study aimed to determine whether abnormal prehospital shock indices in trauma patients with normal shock indices upon emergency department arrival were predictors of a high risk of mortality. METHODS: We conducted a retrospective cohort study of emergency department-admitted trauma patients from 2004 to 2017. The study included 89,495 consecutive trauma patients aged ≥16 years, with Abbreviated Injury Scale score of ≥3, who were transported to the emergency department directly from the field and had a normal shock index upon emergency department arrival. According to the prehospital shock index scores, the patients were categorized into low shock index (≤ 0.4), normal shock index, and high shock index (≥0.9) groups. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. RESULTS: The 89,495 patients had a median age of 64 (interquartile range: 43-79) years, and 55,484 (62.0%) of the patients were male. There were 1350 (1.5%) 24-h deaths in total; 176/4263 (4.1%), 1017/78,901 (1.3%), and 157/6331 (2.5%) patients were in the low, normal, and high prehospital shock index groups, respectively. The adjusted odds ratios for 24-h mortality compared with the normal shock index group were 1.63 (95% confidence interval: 1.34-1.99) in the low shock index group and 1.62 (95% confidence interval: 1.31-1.99) in the high shock index group. CONCLUSION: Trauma patients with abnormal prehospital shock indices but normal shock indices upon emergency department arrival are at a higher risk of 24-h mortality. Identifying these indices could improve triage and targeted care for patients.

Efficacy of pancreatic duct stenting to prevent postendoscopic retrograde cholangiopancreatography pancreatitis after covered self-expandable metal stent deployment.

OBJECTIVES: Although covered self-expandable metal stents (CSEMSs) are associated with the risk of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis due to pancreatic duct (PD) orifice obstruction, they are often used for biliary drainage treatment in malignant biliary obstruction (MBO). This study aimed to investigate the efficacy of PD stenting in preventing post-ERCP pancreatitis after CSEMS implantation. METHODS: This retrospective cohort study analyzed 554 patients with transpapillary CSEMS for MBO. Patients with noninitial deployment, benign disease, CSEMS deployment above the papilla, surgically altered anatomy, uncovered self-expandable metal stents, multiple thin self-expandable metal stents, and unavailable procedure videos were excluded. Logistic regression analysis estimated the association between PD stenting and post-ERCP pancreatitis incidence. We adjusted for age, sex, pancreatitis history, prophylactic rectal nonsteroidal anti-inflammatory drug use, naïve papilla, MBO etiology, and prolonged biliary cannulation time. RESULTS: Among 554 patients, 67 (12.1%) experienced post-ERCP pancreatitis. Post-ERCP pancreatitis was recorded in 13.7% of patients in the non-PD stenting and 4.3% in the PD stenting groups. Pancreatic duct stenting was associated with lower risks of post-ERCP pancreatitis (odds ratio [OR] 0.28; 95% confidence interval [CI] 0.099-0.79; P = 0.028). In multivariable analysis, the association between PD stenting and lower post-ERCP pancreatitis incidence was consistent (OR 0.19; 95% CI 0.062-0.58; P = 0.0034). CONCLUSIONS: Pancreatic duct stenting could reduce the risk of post-ERCP pancreatitis after CSEMSs.

Loss of biological control of enamel mineralization in amelogenin-phosphorylation-deficient mice.

Amelogenin, the most abundant enamel matrix protein, plays several critical roles in enamel formation. Importantly, we previously found that the singular phosphorylation site at Ser16 in amelogenin plays an essential role in amelogenesis. Studies of genetically knock-in (KI) modified mice in which Ser16 in amelogenin is substituted with Ala that prevents amelogenin phosphorylation, and in vitro mineralization experiments, have shown that phosphorylated amelogenin transiently stabilizes amorphous calcium phosphate (ACP), the initial mineral phase in forming enamel. Furthermore, KI mice exhibit dramatic differences in the enamel structure compared with wild type (WT) mice, including thinner enamel lacking enamel rods and ectopic surface calcifications. Here, we now demonstrate that amelogenin phosphorylation also affects the organization and composition of mature enamel mineral. We compared WT, KI, and heterozygous (HET) enamel and found that in the WT elongated crystals are co-oriented within each rod, however, their c-axes are not aligned with the rods' axes. In contrast, in rod-less KI enamel, crystalline c-axes are less co-oriented, with misorientation progressively increasing toward the enamel surface, which contains spherulites, with a morphology consistent with abiotic formation. Furthermore, we found significant differences in enamel hardness and carbonate content between the genotypes. ACP was also observed in the interrod of WT and HET enamel, and throughout aprismatic KI enamel. In conclusion, amelogenin phosphorylation plays crucial roles in controlling structural, crystallographic, mechanical, and compositional characteristics of dental enamel. Thus, loss of amelogenin phosphorylation leads to a reduction in the biological control over the enamel mineralization process.

Identification of an Anti-Integrin αvß6 Autoantibody in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. METHODS: Using 23 recombinant integrin proteins, we performed enzyme-linked immunosorbent assays on sera from patients with ulcerative colitis and controls. Integrin expression and IgG binding in the colon tissues of patients with ulcerative colitis and controls were examined using immunofluorescence and coimmunoprecipitation, respectively. The blocking activity of autoantibodies was examined using solid-phase binding and cell adhesion assays. RESULTS: Screening revealed that patients with ulcerative colitis had IgG antibodies against integrin αvß6. In the training and validation groups, 103 of 112 (92.0%) patients with ulcerative colitis and only 8 of 155 (5.2%) controls had anti-integrin αvß6 antibodies (P < .001), resulting in a sensitivity of 92.0% and a specificity of 94.8% for diagnosing ulcerative colitis. Anti-integrin αvß6 antibody titers coincided with ulcerative colitis disease activity, and IgG1 was the major subclass. Patient IgG bound to the integrin αvß6 expressed on colonic epithelial cells. Moreover, IgG of patients with ulcerative colitis blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif and inhibited cell adhesion. CONCLUSIONS: A significant majority of patients with ulcerative colitis had autoantibodies against integrin αvß6, which may serve as a potential diagnostic biomarker with high sensitivity and specificity.

Early corticosteroid dose tapering in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively). CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Certolizumab pegol for maintenance of medically induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood. OBJECTIVES: To assess the efficacy and safety of CZP for maintenance of remission in people with CD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework. MAIN RESULTS: We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo. The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow. AUTHORS' CONCLUSIONS: CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.

Resting respiration rate predicts all-cause mortality in older outpatients.

BACKGROUND: Although respiratory rate has been a sensitive predictor for prognosis in acute settings, resting respiratory rate (RRR) is undervalued in chronic care. The clinical significance of RRR among older people is not well documented. AIM: We investigated the association between RRR and all-cause mortality among older outpatients. METHODS: A retrospective cohort study exhaustively included patients who had undergone medical checkups in a facility between April 2017 and March 2018 and followed up for at least 2 years. We excluded patients who were less than 60 years of age or had not undergone regular outpatient appointments. Sex, age, smoking habits, history of hospitalization, polypharmacy, long-term care insurance certification status, Mazzaglia index, pulse rate, systolic blood pressure, and Charlson Comorbidity Index were measured at the baseline medical checkup. Survival was confirmed by chart review and by contacting physicians in charge. The risk ratios were estimated by converting the odds ratios derived from the multivariable logistic regression models. RESULTS: Of the 853 patients who underwent baseline checkups, 749 were enrolled in the analyses; death occurred in 53 patients (7.1%), with no loss to follow-up. The RRR was independently associated with all-cause mortality after adjusting for covariates [adjusted risk ratio of RRR per 1 bpm = 1.14, 95% confidence interval (CI): 1.06 - 1.22]. DISCUSSION: Given the independent association of RRR for existing predictors, this simple index seems worthy of consideration in further studies aimed at defining its predictive role in older people and in different settings. CONCLUSION: RRR was independently associated with all-cause mortality.

Pediatric cardiac tamponade caused by metallic wire penetration into the heart: A case report and literature review.

Thin, metallic wires can easily penetrate the gastrointestinal system if ingested and cause serious cardiac issues in children. We report a pediatric case of such an object that caused cardiac tamponade after lodging in the left ventricle. The wire was extracted without cardiopulmonary bypass and a full recovery was made. Cardiac issues after ingestion of foreign objects are rare but immediate surgery is required for resolution.

Amelogenin phosphorylation regulates tooth enamel formation by stabilizing a transient amorphous mineral precursor.

Dental enamel comprises interwoven arrays of extremely long and narrow crystals of carbonated hydroxyapatite called enamel rods. Amelogenin (AMELX) is the predominant extracellular enamel matrix protein and plays an essential role in enamel formation (amelogenesis). Previously, we have demonstrated that full-length AMELX forms higher-order supramolecular assemblies that regulate ordered mineralization in vitro, as observed in enamel rods. Phosphorylation of the sole AMELX phosphorylation site (Ser-16) in vitro greatly enhances its capacity to stabilize amorphous calcium phosphate (ACP), the first mineral phase formed in developing enamel, and prevents apatitic crystal formation. To test our hypothesis that AMELX phosphorylation is critical for amelogenesis, we generated and characterized a hemizygous knockin (KI) mouse model with a phosphorylation-defective Ser-16 to Ala-16 substitution in AMELX. Using EM analysis, we demonstrate that in the absence of phosphorylated AMELX, KI enamel lacks enamel rods, the hallmark component of mammalian enamel, and, unlike WT enamel, appears to be composed of less organized arrays of shorter crystals oriented normal to the dentinoenamel junction. KI enamel also exhibited hypoplasia and numerous surface defects, whereas heterozygous enamel displayed highly variable mosaic structures with both KI and WT features. Importantly, ACP-to-apatitic crystal transformation occurred significantly faster in KI enamel. Secretory KI ameloblasts also lacked Tomes' processes, consistent with the absence of enamel rods, and underwent progressive cell pathology throughout enamel development. In conclusion, AMELX phosphorylation plays critical mechanistic roles in regulating ACP-phase transformation and enamel crystal growth, and in maintaining ameloblast integrity and function during amelogenesis.

Inverse Association Between Fatty Liver at Baseline Ultrasonography and Remission of Type 2 Diabetes Over a 2-Year Follow-up Period.

BACKGROUND & AIMS: Improvement of fatty liver may be required for remission of type-2 diabetes. However, there is no longitudinal evidence on whether fatty liver reduces the chances for remission of type-2 diabetes. We investigated the association between fatty liver and remission of type-2 diabetes (the primary analysis), and also the association between improvement of fatty liver and remission of type-2 diabetes (the secondary analysis). METHODS: We collected data from 66961 people who underwent screening for type-2 diabetes from 2008 through 2016 at a single center in Japan. The primary analysis included 2567 patients with type-2 diabetes without chronic renal failure or a history of hemodialysis who underwent ultrasonography to detect fatty liver, all of whom had follow-up testing, including blood testing, for a median 24.5 months after the baseline ultrasonography. The secondary analysis included 1833 participants with fatty liver at baseline who underwent a second ultrasonography, and participants who had fatty liver at baseline but not at the second visit were considered to have had improvement of fatty liver. Remission of type-2 diabetes was defined as a fasting plasma glucose level below 126 mg/dL and an HbA1c level below 6.5% for more than 6 months without anti-diabetic drugs. Odds ratios (ORs) of remission of type-2 diabetes were estimated using logistic-regression models. RESULTS: A lower proportion of patients who had fatty liver detected by ultrasonography at baseline (8.7%, 167/1910) had remission of type-2 diabetes during the follow-up period than patients without fatty liver (13.1%, 86/657). Fatty liver at baseline was associated with a lower odds of remission of type-2 diabetes (multivariable-adjusted OR, 0.51; 95% CI, 0.37-0.72). A higher proportion of patients who had improvement of fatty liver had remission of type-2 diabetes (21.1%, 32/152) than patients with no improvement of fatty liver (7.7%, 129/1681). Improvement of fatty liver was associated with a higher odds of remission of type-2 diabetes (multivariable-adjusted OR, 3.08; 95% CI, 1.94-4.88). CONCLUSIONS: Over a follow-up period of approximate 2 years, remission of type-2 diabetes was less common in people with fatty liver detected by ultrasonography, and improvement of fatty liver was independently associated with type-2 diabetes remission.

Accuracy of Ultrasound for Evaluation of Colorectal Segments in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The accuracy of ultrasound for evaluation of individual colorectal segments in patients with inflammatory bowel diseases (IBD) has not been evaluated in a systematic review. We evaluated the diagnostic accuracy of ultrasound in different colorectal segments of patients with IBD. METHODS: We searched publication databases from inception through March 2019 for studies that assessed the accuracy of ultrasound in detection of inflammation in right, transverse, and left colon and in rectum in patients with IBD, using findings from colonoscopy as the reference standard. Subgroup analyses were performed including IBD type, patient age, body mass index, and study design. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Nineteen studies (1101 patients) were included in the qualitative synthesis. After we assessed the risk of bias, 7 studies (comprising 84 patients with Crohn's disease and 420 patients with ulcerative colitis) were included in the meta-analysis. Bowel wall thickness ≥ 3 mm identified colorectal segments with inflammation with 86.4% pooled sensitivity (95% CI, 76.1%-92.7%) and 88.3% pooled specificity (95% CI, 58.1%-97.6%). In rectum only, bowel wall thickness ≥ 3 mm identified inflammation with 74.5% sensitivity (95% CI, 53.0%-88.3%) and 69.5% specificity (95% CI, 33.6%-91.1%). Diagnostic accuracy was comparable among subgroups. Increased bowel wall flow and loss of stratification had higher true-positive odds ratios. CONCLUSIONS: Based on meta-analysis of patient-level data, ultrasound has higher diagnostic accuracy for detecting inflammation in colon than rectum in patients with IBD. Studies are needed to increase the accuracy of ultrasound detection of inflammation in rectum.

Histopathologic features and fragmentation of polyps with cold snare defect protrusions.

BACKGROUND AND AIMS: Cold snare defect protrusions (CSDPs) include muscularis mucosa (MM) and submucosa tissue. CSDPs are thought to result from fragmentation of the specimen during shallow excision. Our aim in this study was to clarify whether CSDPs are associated with polyp fragmentation. METHODS: We retrospectively analyzed 1026 neoplastic colorectal polyps resected by cold snare polypectomy for which the presence or absence of CSDPs was assessed from the endoscopic image. All prepared specimens were reviewed and assessed for the presence or absence of polyp fragmentation, and the proportion of MM on the stump was measured. In addition, the risk factors for CSDP occurrence were evaluated. RESULTS: CSDPs occurred in 116 of the 1026 polyps (11.3%). Polyp fragmentation was significantly associated with the occurrence of CSDP on univariate analysis (odds ratio [OR], 3.74; P < .001) and multivariate analysis (OR, 3.13; P < .001). The proportion of MM >50% was significantly lower in the CSDP group than in the non-CSDP group (51.5% vs 70.9%, P < .001). CSDPs were significantly associated with a large polyp size (OR, 1.32; P = .007) and a large specimen size (OR, 1.24; P < .001) on multivariate analysis. CONCLUSIONS: The occurrence of CSDP was associated with less MM on the stump and fragmentation of the specimen. Clinically, the presence of CSDP is a good indicator of polyp fragmentation.

Impact of Primary Tumor Resection on Mortality in Patients with Stage IV Colorectal Cancer with Unresectable Metastases: A Multicenter Retrospective Cohort Study.

BACKGROUND: Primary tumor resection (PTR) before commencing systemic chemotherapy in patients with stage IV colorectal cancer and unresectable metastases (mCRC) remains controversial. This study aimed to assess whether PTR before systemic chemotherapy is associated with mortality in mCRC patients, after adjusting for confounding factors, such as the severity of the primary tumor and metastatic lesions. METHODS: We analyzed hospital-based cancer registries from nine designated cancer hospitals in Fukushima Prefecture, Japan. Patients were divided into two groups (PTR and non-PTR), based on whether PTR was performed as initial therapy for mCRC or not. The primary outcome was all-cause mortality. Kaplan-Meier survival analysis was performed, and survival estimates were compared using the log-rank test. Adjusted hazard ratios were calculated using Cox regression to adjust for confounding factors. All tests were two-sided; P-values < 0.05 were considered statistically significant. RESULTS: Between 2008 and 2015, 616 mCRC patients were included (PTR: 414 [67.2%]; non-PTR: 202 [32.8%]). The median follow-up time was 18.0 (interquartile range [IQR]: 8.4-29.7) months, and 492 patients (79.9%) died during the study period. Median overall survival in the PTR and non-PTR groups was 23.9 (IQR: 12.2-39.9) and 12.3 (IQR: 6.2-23.8) months, respectively (P < 0.001, log-rank test). PTR was significantly associated with improved overall survival (adjusted hazard ratio: 0.51; 95% confidence interval: 0.42-0.64, P < 0.001). CONCLUSIONS: PTR before systemic chemotherapy in patients with mCRC was associated with improved survival.

Intraoperative end-tidal carbon dioxide and postoperative mortality in major abdominal surgery: a historical cohort study.

PURPOSE: There is a paucity of data on the effect of intraoperative end-tidal carbon dioxide (EtCO2) levels on postoperative mortality. The purpose of this study was to investigate the relationship between intraoperative EtCO2 and 90-day mortality in patients undergoing major abdominal surgery under general anesthesia. METHODS: We conducted a historical cohort study of patients undergoing major abdominal surgery under general anesthesia at Kyoto University Hospital. We measured the intraoperative EtCO2, and patients with a mean EtCO2 value < 35 mm Hg were classified as low EtCO2. The time effect was determined based on minutes below an EtCO2 of 35 mm Hg, and cumulative effects were evaluated by measuring the area under the threshold of 35 mm Hg for each patient. RESULTS: Of 4,710 patients, 1,374 (29%) had low EtCO2 and 55 (1.2%) died within 90 days of surgery. Multivariable Cox regression analysis-adjusted for age, American Society of Anesthesiologists Physical Status classification, sex, laparoscopic surgery, emergency surgery, blood loss, mean arterial pressure, duration of surgery, type of surgery, and chronic obstructive pulmonary disease-revealed an association between low EtCO2 and 90-day mortality (adjusted hazard ratio, 2.2; 95% confidence interval [CI], 1.2 to 3.8; P = 0.006). In addition, severity of low EtCO2 was associated with an increased 90-day mortality (area under the threshold; adjusted hazard ratio; 2.9, 95% CI, 1.2 to 7.4; P =0.02); for long-term exposure to an EtCO2 < 35 mm Hg (≥ 226 min), the adjusted hazard ratio for increased 90-day mortality was 2.3 (95% CI, 0.9 to 6.0; P = 0.08). CONCLUSION: A mean intraoperative EtCO2 < 35 mm Hg was associated with increased postoperative 90-day mortality.

RéSUMé: OBJECTIF: Il n'existe que très peu de données s'intéressant à l'effet du niveau peropératoire télé-expiratoire du dioxyde de carbone (EtCO2) sur la mortalité postopératoire. L'objectif de cette étude était d'examiner la relation entre l'EtCO2 peropératoire et la mortalité à 90 jours chez des patients subissant une chirurgie abdominale majeure sous anesthésie générale. MéTHODE: Nous avons réalisé une étude de cohorte historique portant sur des patients subissant une chirurgie abdominale majeure sous anesthésie générale à l'Hôpital universitaire de Kyoto. Nous avons mesuré l'EtCO2 peropératoire, et les patients avec une valeur moyenne d'EtCO2 < 35 mmHg ont été catégorisés comme EtCO2 faible. L'effet temps a été déterminé en fonction de la durée, en minutes, avec une EtCO2 inférieure à 35 mmHg, et les effets cumulatifs ont été évalués en mesurant l'aire sous le seuil de 35 mmHg pour chaque patient. RéSULTATS: Sur 4710 patients, 1374 (29 %) avaient une EtCO2 faible et 55 (1,2 %) sont décédés dans les 90 jours suivant la chirurgie. Une analyse de régression multivariée de Cox, ajustée pour tenir compte des facteurs suivants : âge, statut physique selon l'American Society of Anesthesiologists, sexe, chirurgie par laparoscopie, chirurgie d'urgence, pertes de sang, tension artérielle moyenne, durée de la chirurgie, type de chirurgie et maladie pulmonaire obstructive chronique, a révélé une association entre une EtCO2 faible et la mortalité à 90 jours (rapport de risque ajusté, 2,2; intervalle de confiance [IC] à 95 %, 1,2 à 3,8; P = 0,006). De plus, la sévérité de l'EtCO2 basse était associée à une augmentation de la mortalité à 90 jours (aire sous le seuil; rapport de risque ajusté; 2,9, IC 95 %, 1,2 à 7,4; P =0,02); pour une exposition à long terme à une EtCO2 < 35 mmHg (≥ 226 minutes), le rapport de risque ajusté pour une mortalité accrue à 90 jours était de 2,3 (IC 95 %, 0,9 à 6,0 ; P = 0,08). CONCLUSION: Une EtCO2 peropératoire moyenne < 35 mmHg était associée à une augmentation de la mortalité postopératoire à 90 jours.

Trafficking and secretion of keratin 75 by ameloblasts in vivo.

A highly specialized cytoskeletal protein, keratin 75 (K75), expressed primarily in hair follicles, nail beds, and lingual papillae, was recently discovered in dental enamel, the most highly mineralized hard tissue in the human body. Among many questions this discovery poses, the fundamental question regarding the trafficking and secretion of this protein, which lacks a signal peptide, is of an utmost importance. Here, we present evidence that K75 is expressed during the secretory stage of enamel formation and is present in the forming enamel matrix. We further show that K75 is secreted together with major enamel matrix proteins amelogenin and ameloblastin, and it was detected in Golgi and the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) but not in rough ER (rER). Inhibition of ER-Golgi transport by brefeldin A did not affect the association of K75 with Golgi, whereas ameloblastin accumulated in rER, and its transport from rER into Golgi was disrupted. Together, these results indicate that K75, a cytosolic protein lacking a signal sequence, is secreted into the forming enamel matrix utilizing portions of the conventional ER-Golgi secretory pathway. To the best of our knowledge, this is the first study providing insights into mechanisms of keratin secretion.