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While the World Health Organization's recommendation of syndromic sentinel surveillance for influenza is an efficient method to collect high-quality data, limitations exist. Aligned with the Research Recommendation 1.1.2 of the WHO Public Health Research Agenda for Influenza-to identify reliable complementary influenza surveillance systems which provide real-time estimates of influenza activity-we performed a scoping review to map the extent and nature of published literature on the use of non-traditional sources of syndromic surveillance data for influenza.We searched three electronic databases (PubMed, Web of Science, and Scopus) for articles in English, French, and Spanish, published between January 1 2007 and January 28 2022. Studies were included if they directly compared at least one non-traditional with a traditional influenza surveillance system in terms of correlation in activity or timeliness.We retrieved 823 articles of which 57 were included for analysis. Fifteen articles considered electronic health records (EHR), 11 participatory surveillance, 10 online searches and webpage traffic, seven Twitter, five absenteeism, four telephone health lines, three medication sales, two media reporting, and five looked at other miscellaneous sources of data. Several articles considered more than one non-traditional surveillance method.We identified eight categories and a miscellaneous group of non-traditional influenza surveillance systems with varying levels of evidence on timeliness and correlation to traditional surveillance systems. Analyses of EHR and participatory surveillance systems appeared to have the most agreement on timeliness and correlation to traditional systems. Studies suggested non-traditional surveillance systems as complements rather than replacements to traditional systems.

BACKGROUND The efficacy and factors associated with patient outcomes for a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) compared with traditional dietary advice (TDA) based on modified National Institute for Clinical Excellence guidelines for irritable bowel syndrome with diarrhea (IBS-D) in regions consuming a non-Western diet are unclear. OBJECTIVES We aimed to determine the efficacy of an LFD compared with TDA for the treatment of IBS-D in Chinese patients and to investigate the factors associated with favorable outcomes. METHODS One hundred and eight Chinese IBS-D patients (Rome III criteria) were randomly assigned to an LFD or TDA. The primary endpoint was a ≥50-point reduction in the IBS Severity Scoring System at 3 wk. Fecal samples collected before and after the dietary intervention were assessed for changes in SCFAs and microbiota profiles. A logistic regression model was used to identify predictors of outcomes. RESULTS Among the 100 patients who completed the study, the primary endpoint was met in a similar number of LFD (30 of 51, 59%) and TDA (26 of 49, 53%) patients (∆6%; 95% CI: -13%, 24%). Patients in the LFD group achieved earlier symptomatic improvement in stool frequency and excessive wind than those following TDA. LFD reduced carbohydrate-fermenting bacteria such as Bifidobacterium and Bacteroides, and decreased saccharolytic fermentation activity. This was associated with symptomatic improvement in the responders. High saccharolytic fermentation activity at baseline was associated with a higher symptom burden (P = 0.01) and a favorable therapeutic response to the LFD (log OR: 4.9; 95% CI: -0.1, 9.9; P = 0.05). CONCLUSIONS An LFD and TDA each reduced symptoms in Chinese IBS-D patients; however, the LFD achieved earlier symptomatic improvements in stool frequency and excessive wind. The therapeutic effect of the LFD was associated with changes in the fecal microbiota and the fecal fermentation index. At baseline, the presence of severe symptoms and microbial metabolic dysbiosis characterized by high saccharolytic capability predicted favorable outcomes to LFD intervention.This trial was registered at clinicaltrials.gov as NCT03304041.

Type 2 resistant starch (RS2) is a fermentable dietary fiber conferring health benefits. We investigated the effects of RS2 on host, gut microbiota, and metabolites in aged mice on high-fat diet. In eighteen-month old mice randomly assigned to control, high-fat (HF), or high-fat+20% RS2 (HFRS) diet for 16 weeks, RS2 reversed the weight gain and hepatic steatosis induced by high-fat diet. Serum and fecal LPS, colonic IL-2 and hepatic IL-4 mRNA expressions decreased while colonic mucin 2 mRNA and protein expressions increased in the HFRS compared to the HF and the control group. 16s rRNA sequencing of fecal microbial DNA demonstrated that RS2 decreased the abundance of pathogen taxa associated with obesity, inflammation, and aging including Desulfovibrio (Proteobacteria phylum), Ruminiclostridium 9, Lachnoclostridium, Helicobacteria, Oscillibacter, Alistipes, Peptococcus, and Rikenella. Additionally, RS2 increased the colonic butyric acid by 2.6-fold while decreasing the isobutyric and isovaleric acid levels by half compared to the HF group. Functional analyses based on Clusters of Orthologous Groups showed that RS2 increased carbohydrate while decreasing amino acid metabolism. These findings demonstrate that RS2 can reverse weight gain, hepatic steatosis, inflammation, and increased intestinal permeability in aged mice on high-fat diet mediated by changes in gut microbiome and metabolites.

An array of isoforms of the nuclear estrogen receptor alpha (ER-α) protein contribute to heterogeneous response in breast cancer (BCa); yet, a single-cell analysis tool that distinguishes the full-length ER-α66 protein from the activation function-1 deficient ER-α46 isoform has not been reported. Specific detection of protein isoforms is a gap in single-cell analysis tools, as the de facto standard immunoassay requires isoform-specific antibody probes. Consequently, to scrutinize hormone response heterogeneity among BCa tumor cells, we develop a precision tool to specifically measure ER-α66, ER- α46, and eight ER-signaling proteins with single-cell resolution in the highly hetero-clonal MCF-7 BCa cell line. With a literature-validated pan-ER immunoprobe, we distinguish ER-α66 from ER-α46 in each individual cell. We identify ER-α46 in 5.5% of hormone-sensitive (MCF-7) and 4.2% of hormone-insensitive (MDA-MB-231) BCa cell lines. To examine whether the single-cell immunoblotting can capture cellular responses to hormones, we treat cells with tamoxifen and identify different sub-populations of ER-α46: (i) ER-α46 induces phospho-AKT at Ser473, (ii) S6-ribosomal protein, an upstream ER target, activates both ER-α66 and ER-α46 in MCF-7 cells, and (iii) ER-α46 partitions MDA-MB-231 subpopulations, which are responsive to tamoxifen. Unlike other single-cell immunoassays, multiplexed single-cell immunoblotting reports–in the same cell–tamoxifen effects on ER signaling proteins and on distinct isoforms of the ER-α protein.

Background In a global, phase III, open-label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10 years to receive approval as first-line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost-effectiveness of lenvatinib and sorafenib as a first-line therapy of unresectable HCC. Materials and methods A state-transition model of unresectable HCC was developed in the form of a cost-utility analysis. The model time horizon was 5 years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model. Results Lenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost-saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy. Conclusion Lenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost-saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost-saving if a significantly cheaper generic sorafenib becomes available. Implications for practice This analysis suggests an actionable clinical policy that will achieve cost saving. This cost-utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost-saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10 years in Canada provides an important opportunity for clinicians, researchers, and health care decision-makers to explore potential modifications in recommendations and practice guidelines.

BACKGROUND: Currently, there are no pharmacological options available for the treatment of non-alcoholic steatohepatitis (NASH). In the 18-month interim analysis of an ongoing randomized, placebo-controlled phase 3 trial (REGENERATE), early results demonstrated that obeticholic acid (OCA) 25 mg significantly improved fibrosis with no worsening of NASH among patients with NASH and fibrosis compared with placebo (PBO). This study aimed to assess the potential cost-effectiveness of OCA compared with PBO in NASH patients. METHODS: A state-transition model was developed to perform a cost-utility analysis comparing two treatment strategies, PBO and OCA 25 mg, from a Canadian public payer perspective. The model time horizon was lifetime with annual cycle lengths. Cost and utility parameters were discounted at 1.5% annually. The efficacy data were obtained from the REGENERATE trial, and costs and utilities were derived from other published literature. Probabilistic and deterministic sensitivity analyses were performed to test the robustness of the model. RESULTS: Treatment with OCA led to reductions of 3.58% in decompensated cirrhosis cases, 3.95% in hepatocellular carcinoma, 7.88% in liver transplant, and 6.01% in liver-related death. However, at an annual price of CAD $36,000, OCA failed to be cost-effective compared with PBO at an incremental cost-effectiveness ratio of $815,514 per quality-adjusted life year (QALY). An 88% reduction in drug price to an annual cost of $4,300 would make OCA cost-effective at a willingness-to-pay threshold of $50,000/QALY. CONCLUSIONS: OCA failed to be cost-effective compared with PBO, despite demonstrating clinical benefits due to a high drug cost. A significant price reduction would be needed to make the drug cost-effective.

Study Objectives To examine in a subsample at the screening phase of a clinical trial of a β-amyloid (Aβ) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer’s disease (AD). Methods Overall, 26 Aβ-positive (Aβ+) and 33 Aβ-negative (Aβ−) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR]). Results We were unable to detect any differences between Aβ+ and Aβ− participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aβ+ participants had lower activity levels than Aβ− participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aβ+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05). Conclusions Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally “local” RAR alterations in preclinical AD.

Background and Aims Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernised diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal microbiota and bile acid metabolism in mice with DCA-induced intestinal inflammation. Methods Wild-type C57BL mice, 4 weeks old, were fed with AIN-93G (control diet), AIN-93G+0.2% DCA, AIN-93G+0.2% DCA+6 weeks of fexaramine (FXR agonist), or AIN-93G+0.2% DCA+antibiotic cocktail, for 24 weeks. Histopathology, western blotting, and qPCR were performed on the intestinal tissue. Faecal microbiota was analysed by 16S rDNA sequencing. Faecal bile acid and short chain fatty acid (SCFA) levels were analysed by chromatography. Results Gut dysbiosis and enlarged bile acid pool were observed in DCA-treated mice, accompanied by a lower farnesoid X receptor (FXR) activity in the intestine. Administration of fexaramine mitigated DCA-induced intestinal injury, restored intestinal FXR activity, activated fibroblast growth factor 15, and normalised bile acid metabolism. Furthermore, fexaramine administration increased the abundance of SCFA-producing bacteria. Depletion of the commensal microbiota with antibiotics decreased the diversity of the intestinal microbiota, attenuated bile acid synthesis, and reduced intestinal inflammation induced by DCA. Conclusions DCA induced-intestinal inflammation is associated with alterations of gut microbiota and bile acid profiles. Interventions targeting the gut microbiota-FXR signalling pathway may reduce DCA-induced intestinal disease.

Introduction Patients with atrophic gastritis (AG) or gastric intestinal metaplasia (GIM) have elevated risk of gastric adenocarcinoma. Endoscopic screening and surveillance have been implemented in high incidence countries. The study aimed to evaluate the accuracy of a deep convolutional neural network (CNN) for simultaneous recognition of AG and GIM. Methods Archived endoscopic white light images with corresponding gastric biopsies were collected from 14 hospitals located in different regions of China. Corresponding images by anatomic sites containing AG, GIM, and chronic non-AG were categorized using pathology reports. The participants were randomly assigned (8:1:1) to the training cohort for developing the CNN model (TResNet), the validation cohort for fine-tuning, and the test cohort for evaluating the diagnostic accuracy. The area under the curve (AUC), sensitivity, specificity, and accuracy with 95% confidence interval (CI) were calculated. Results A total of 7,037 endoscopic images from 2,741 participants were used to develop the CNN for recognition of AG and/or GIM. The AUC for recognizing AG was 0.98 (95% CI 0.97-0.99) with sensitivity, specificity, and accuracy of 96.2% (95% CI 94.2%-97.6%), 96.4% (95% CI 94.8%-97.9%), and 96.4% (95% CI 94.4%-97.8%), respectively. The AUC for recognizing GIM was 0.99 (95% CI 0.98-1.00) with sensitivity, specificity, and accuracy of 97.9% (95% CI 96.2%-98.9%), 97.5% (95% CI 95.8%-98.6%), and 97.6% (95% CI 95.8%-98.6%), respectively. Discussion CNN using endoscopic white light images achieved high diagnostic accuracy in recognizing AG and GIM.

Objectives The objective of this study was to use a decision-analytic model to examine the potential economic impact of establishing a remunerated programme for pharmacists prescribing for minor ailments (PPMA) in Ontario, Canada. Methods A novel decision tool was developed to assess the economic impact of pharmacists prescribing for upper respiratory tract infections (URTIs), contact dermatitis (CD) and conjunctivitis by performing a cost-minimization analysis from a public payer perspective. Two prescribing strategies were compared: (1) PPMA, where patients may seek care from pharmacists or physicians, and (2) the usual care model (UCM), where all patients receive care from physicians. Two remuneration models for the PPMA strategy were also compared: (1) a prescription-detached scenario (PDS), where pharmacists were remunerated CAD$18.00 for each consultation, and (2) a Prescription-Attached Scenario (PAS), where pharmacists were only remunerated if a decision to prescribe was made. Key findings At a service uptake rate of 38% for the PDS, the PPMA model led to savings of $7.51, $4.08 and $5.15 per patient for URTIs, CD and conjunctivitis, respectively. Per 30 000 patients, the PPMA model for these minor ailments was projected to lead to cumulative reductions in visits to the emergency department, family physician and walk-in clinics by 799, 3677 and 5090, respectively. Conclusions The results of the study strongly suggest that enabling community pharmacists to assess and prescribe for minor ailments could potentially lead to large savings for the government in Ontario, Canada. In 100% of the PAS scenarios simulated, pharmacists as prescribers led to cost savings.

OBJECTIVES: Although early biliary drainage improves outcomes in patients with acute cholangitis, the optimal time to perform endoscopic retrograde cholangiopancreatography (ERCP) is controversial. Our aim was to evaluate the impact of timing of ERCP on mortality in hospitalized patients with acute cholangitis. METHODS: We searched PubMed, EMBASE, and The Cochrane Library (until February 2019) for studies evaluating the impact of timing of ERCP (

Outcomes of furazolidone- and amoxicillin-based quadruple therapy for Helicobacter pylori infection and predictors of failed eradication

AIM To determine whether fructo-oligosaccharide (FOS) affects visceral sensitivity, inflammation, and production of intestinal short-chain fatty acids (SCFA) in an irritable bowel syndrome (IBS) mouse model. METHODS Mice were randomly assigned to daily oral gavage of saline solution with or without FOS (8 g/kg body weight) for 14 d. Mice were further assigned to receive either daily one-hour water avoidance stress (WAS) or sham-WAS for the first 10 d. After 2 wk, visceral sensitivity was measured by abdominal withdrawal reflex in response to colorectal distension and mucosal inflammation was evaluated. Gas chromatography, real-time reverse transcription PCR, and immunohistochemistry assays were used to quantify cecal concentrations of SCFA, intestinal cytokine expression, and number of intestinal mast cells per high-power field (HPF), respectively. RESULTS Mice subjected to WAS exhibited visceral hypersensitivity and low-grade inflammation. Among mice subjected to WAS, FOS increased visceral hypersensitivity and led to higher cecal concentrations of acetic acid (2.49 ± 0.63 mmol/L vs 1.49 ± 0.72 mmol/L, P < 0.05), propionic acid (0.48 ± 0.09 mmol/L vs 0.36 ± 0.05 mmol/L, P < 0.01), butyric acid (0.28 ± 0.09 mmol/L vs 0.19 ± 0.003 mmol/L, P < 0.05), as well as total SCFA (3.62 ± 0.87 mmol/L vs 2.27 ± 0.75 mmol/L, P < 0.01) compared to saline administration. FOS also increased ileal interleukin (IL)-23 mRNA (4.71 ± 4.16 vs 1.00 ± 0.99, P < 0.05) and colonic IL-1β mRNA (2.15 ± 1.68 vs 0.88 ± 0.53, P < 0.05) expressions as well as increased mean mast cell counts in the ileum (12.3 ± 2.6 per HPF vs 8.3 ± 3.6 per HPF, P < 0.05) and colon (6.3 ± 3.2 per HPF vs 3.4 ± 1.2 per HPF, P < 0.05) compared to saline administration in mice subjected to WAS. No difference in visceral sensitivity, intestinal inflammation, or cecal SCFA levels was detected with or without FOS administration in mice subjected to sham-WAS. CONCLUSION FOS administration intensifies visceral hypersensitivity and gut inflammation in stress-induced IBS mice, but not in the control mice, and is also associated with increased intestinal SCFA production.

// Lijun Du 1 , John J. Kim 1, 2 , Binrui Chen 1 , Shuwen Zhu 1 and Ning Dai 1 1 Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, CA, USA Correspondence to: Ning Dai, email: ndaicn@zju.edu.cn Keywords: marital status; esophageal cancer; survival; surveillance; epidemiology Received: January 04, 2017 Accepted: August 23, 2017 Published: October 07, 2017 ABSTRACT The impact of marital status on survival among patients with esophageal cancer has not been evaluated in the U.S. population in depth. The aim of the study was to investigate the impact of marital status on survival among patients diagnosed with esophageal cancer. The Surveillance, Epidemiology, and End Results (SEER) database was utilized to identify patients diagnosed with esophageal cancer between 1973 and 2013. Cox regression analysis was performed to evaluate for association between marital status on both cancer-specific and overall survival. Of the 69,139 patients with esophageal cancer, 35,863 (52%) had adenocarcinoma and 21,573 (31%) had distant SEER stage. At the time of diagnosis, 39,805 (57%) patients were married, 10,116 (15%) were single, 8,417 (12%) were divorced or separated, and 10,801 (16%) were widowed. Married patients had superior cancer-specific and overall survival compared to unmarried patients. Multivariate analysis demonstrated that single (adjusted hazard ratio (HR)=1.14, 95%CI 1.11-1.17; P

// Lijun Du 1 , John J. Kim 1,2 , Jinhua Shen 1,3 , Binrui Chen 1 and Ning Dai 1 1 Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, USA 3 Department of Gastroenterology, Affiliated Hospital of Shaoxing University, Shaoxing, China Correspondence to: Ning Dai, email: // Keywords : KRAS, TP53, mutation, inflammatory bowel disease, colorectal cancer Received : September 18, 2016 Accepted : December 27, 2016 Published : January 07, 2017 Abstract Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P =0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; P

Objectives Application of artificial intelligence in gastrointestinal endoscopy is increasing. The aim of the study was to examine the accuracy of convolutional neural network (CNN) using endoscopic images for evaluating Helicobacter pylori (H. pylori) infection. Methods Patients who received upper endoscopy and gastric biopsies at Sir Run Run Shaw Hospital (January 2015-June 2015) were retrospectively searched. A novel Computer-Aided Decision Support System that incorporates CNN model (ResNet-50) based on endoscopic gastric images was developed to evaluate for H. pylori infection. Diagnostic accuracy was evaluated in an independent validation cohort. H. pylori infection was defined by the presence of H. pylori on immunohistochemistry testing on gastric biopsies and/or a positive 13C-urea breath test. Results Of 1,959 patients, 1,507 (77%) including 847 (56%) with H. pylori infection (11,729 gastric images) were assigned to the derivation cohort, and 452 (23%) including 310 (69%) with H. pylori infection (3,755 images) were assigned to the validation cohort. The area under the curve for a single gastric image was 0.93 (95% confidence interval [CI] 0.92-0.94) with sensitivity, specificity, and accuracy of 81.4% (95% CI 79.8%-82.9%), 90.1% (95% CI 88.4%-91.7%), and 84.5% (95% CI 83.3%-85.7%), respectively, using an optimal cutoff value of 0.3. Area under the curve for multiple gastric images (8.3 ± 3.3) per patient was 0.97 (95% CI 0.96-0.99) with sensitivity, specificity, and accuracy of 91.6% (95% CI 88.0%-94.4%), 98.6% (95% CI 95.0%-99.8%), and 93.8% (95% CI 91.2%-95.8%), respectively, using an optimal cutoff value of 0.4. Discussion In this pilot study, CNN using multiple archived gastric images achieved high diagnostic accuracy for the evaluation of H. pylori infection.

INTRODUCTION: The prevalence and shedding of fecal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA indicate coronavirus disease 2019 (COVID-19) infection in the gastrointestinal (GI) tract and likely infectivity. We performed a systemic review and meta-analysis to evaluate the prevalence and the duration of shedding of fecal RNA in patients with COVID-19 infection. METHODS: PubMed, Embase, Web of Science, and Chinese databases Chinese National Knowledge Infrastructure and Wanfang Data up to June 2020 were searched for studies evaluating fecal SARS-CoV-2 RNA, including anal and rectal samples, in patients with confirmed COVID-19 infection. The pooled prevalence of fecal RNA in patients with detectable respiratory RNA was estimated. The days of shedding and days to loss of fecal and respiratory RNA from presentation were compared. RESULTS: Thirty-five studies (N = 1,636) met criteria. The pooled prevalence of fecal RNA in COVID-19 patients was 43% (95% confidence interval [CI] 34%–52%). Higher proportion of patients with GI symptoms (52.4% vs 25.9%, odds ratio = 2.4, 95% CI 1.2–4.7) compared with no GI symptoms, specifically diarrhea (51.6% vs 24.0%, odds ratio = 3.0, 95% CI 1.9–4.8), had detectable fecal RNA. After loss of respiratory RNA, 27% (95% CI 15%–44%) of the patients had persistent shedding of fecal RNA. Days of RNA shedding in the feces were longer than respiratory samples (21.8 vs 14.7 days, mean difference = 7.1 days, 95% CI 1.2–13.0). Furthermore, days to loss of fecal RNA lagged respiratory RNA by a mean of 4.8 days (95% CI 2.2–7.5). DISCUSSION: Fecal SARS-CoV-2 RNA is commonly detected in COVID-19 patients with a 3-fold increased risk with diarrhea. Shedding of fecal RNA lasted more than 3 weeks after presentation and a week after last detectable respiratory RNA.

Summary Background Predictors of organ failure and the impact of early endoscopic retrograde cholangiopancreatography (ERCP) on outcomes in patients with acute cholangitis are unclear. Aim To identify factors associated with persistent organ failure and assess the impact of early ERCP on outcomes in hospitalised patients with cholangitis. Methods Consecutive hospitalised patients who received ERCP at two centres for cholangitis from 4/2005–3/2013 were retrospectively reviewed. Delayed ERCP was defined as ERCP ≥48 h after hospitalisation. Primary outcome was persistent organ failure at >48 h after hospitalisation (≥1.5 times rise in creatinine levels from baseline values to ≥1.5 mg/dL or need for dialysis, mechanical ventilation and/or hypotension requiring vasopressor). Results 203 patients (mean age 59 ± 19 years) had ERCP for cholangitis: 115 with choledocholithiasis, 48 with other benign obstructions and 40 with malignant strictures. Forty-five (22%) patients had persistent organ failure at >48 h and 11 (5%) died. On multivariate analysis, Charlson Comorbidity Index >2 (OR = 4.6, 95% CI = 1.5–13.8), systemic inflammatory response syndrome (SIRS; OR = 3.2, 95% CI = 1.1–9.8), hypoalbuminemia (OR = 3.3, 95% CI = 1.4–7.9), bacteremia (OR = 2.8, 95% CI 1.3–6.2) and delayed ERCP(OR = 3.1, 95% CI: 1.4–7.0) were associated with persistent organ failure. Every 1-day delay in ERCP was associated with a 17% (95% CI = 5–29%) relative risk increase in persistent organ failure after adjusting for significant factors. Conclusions Delay in ERCP beyond 48 h was associated with persistent organ failure in hospitalised patients with acute cholangitis. Other factors included increased comorbidities, SIRS, hypoalbuminemia and bacteremia. Early ERCP performed within 48 h after presentation in patients with cholangitis may improve outcomes.

Emerging studies demonstrate the diagnostic utility of DNA methylation-based blood test for gastric cancer. The aim of the meta-analysis is to evaluate the accuracy of blood DNA methylation markers for detecting patients with gastric cancer. A systematic literature search to November 2016 that evaluated DNA methylation markers utilizing blood specimen to detect gastric cancer were selected to derive pooled sensitivities and specificities. 32 studies including 4,172 patients (gastric cancer (N = 2,098), control (N = 2,074)) met the study criteria. Overall sensitivity of DNA methylation-based blood test for detecting gastric cancer was 57% (95% CI 50-63%); specificity was 97% (95% CI 95-98%). Among patients who received plasma-based testing, sensitivity was 71% (95% CI 59-81%); specificity was 89% (95% CI 78-94%). Among patients who received serum-based testing, sensitivity was 50% (95% CI 43-58%); specificity was 98% (95% CI 96-99%). Using multiple methylated genes had sensitivity of 76% (95% CI 64-84%); specificity of 85% (95% CI 65-95%). DNA methylation test had sensitivity of 55% (95% CI 47-64%) and specificity of 96% (95% CI 92-98%) for detecting TNM stage I+II gastric cancer. In conclusion, blood-based DNA methylation test had high specificity but modest sensitivity for detecting gastric cancer. Evaluating multiple methylated genes or using plasma sample may improve the diagnostic sensitivity.

Functional dyspepsia (FD) is a functional gastrointestinal disorder diagnosed by symptom-based criteria. It has been said that duodenal immune activation plays a role in the pathogenesis of FD. The primary aims of the study were to compare the total number of duodenal eosinophil and evaluate the eosinophil degranulation rate, number of duodenal degranulated eosinophil and mast cell between patients with FD and healthy subjects. We enrolled 96 patients with FD and 24 healthy controls at Sir Run Run Shaw Hospital. The total number of eosinophil was comparable in the second portion of duodenum (D2) and duodenal bulb (D1) between patients with FD and healthy controls (all P > 0.05). Significant higher eosinophil degranulation positive rate in D2 (P = 0.003) and a trend towards higher in D1 (P = 0.084) were observed in patients with FD compared with healthy controls. Moreover, the number of duodenal degranulated eosinophil in patients with FD were significantly increased than healthy controls in D1(9.8 ± 6.3 vs 2.9 ± 2.1 per HPF, P = 0.0002) and a trend towards increase in D2 (10.7 ± 7.7 vs 5.3 ± 0.9 per HPF, P = 0.077), respectively. However, degranulated mast cells in patients with FD were almost same with healthy controls. Increased eosinophils degranulation in duodenum play an important role in pathogenesis of FD.

Cytology of sparingly available cell samples from both clinical and experimental settings would benefit from high-selectivity protein tools. To minimize cell handling losses in sparse samples, we design a multi-stage assay using a lab-on-a-disc that integrates cell handling and subsequent single-cell western blotting (scWestern). As the two-layer microfluidic device rotates, the induced centrifugal force directs dissociated cells to dams, which in turn localize the cells over microwells. Gravity-based sedimentation then settles the cells down into the microwells, where the cells are lysed and subjected to scWestern. Taking into account cell losses from capillary loading, centrifugation, and lysis-buffer exchange, our lab-on-a-disc device handles cell samples with as few as 200 cells with 75% cell settling efficiencies. Over 70% of microwells contain single cells after the centrifugation. In addition to cell settling efficiency, cell-size filtration from a mixed population of two cell lines is also realized by tuning the cell flight-of-time during centrifugation (58.4% settling efficiency with 6.4% impurity). Following the upstream cell handling, subsequent scWestern is demonstrated by detection of four proteins (GFP, β-TUB, GAPDH, and STAT3) in a glioblastoma cell line. By integrating the lab-on-a-disc cell preparation and scWestern analysis, our platform measures proteins from sparse cell samples at a single-cell resolution.

Asthma and chronic obstructive pulmonary disease (COPD) result in more than 1 million hospitalizations annually. Most hospitalized patients misuse respiratory inhalers. This misuse can be corrected with in-person education; however, this strategy is resource intensive and skills wane quickly after discharge.The objective of this study was to develop and pilot a virtual teach-to-goal™ (V-TTG™) inhaler skill training module, using innovative adaptive learning technology.Eligible adults with asthma or COPD completed a V-TTG™ metered-dose inhaler session with tailored rounds of narrated demonstration and self-assessments. The primary outcome was the proportion of participants with inhaler misuse post- versus pre-V-TTG™; secondary analyses tested mastery, self-efficacy, and perceived versus actual inhaler skills. Analyses were tested with McNemar's χAmong 90 enrolled participants, the majority were African American (94%), female (62%), and had asthma (68%), with a mean age of 48 years. Among those completing both pre- and post-V-TTG™ (n = 83), misuse was significantly lower post- versus pre-V-TTG™ (24% vs 83%, P.001). Mastery and confidence both improved significantly (46% vs 7%, P0.001; 83% vs 67%, P.001) post- versus pre-V-TTG™. After V-TTG™, there was greater congruence between perceived versus actual inhaler skills (P.01). No differences were seen in subgroup analyses for age, health literacy level, or diagnosis.This study is the first to demonstrate the efficacy of adaptive V-TTG™ learning to teach the inhaler technique. V-TTG™ improved most participants' technique to an acceptable level, reached mastery for half, and also increased self-efficacy and actualized skill. V-TTG™ has potential to improve health care across care transitions.

Prostate-associated gene 4 (PAGE4) is a cancer/testis antigen that is typically restricted to the testicular germ cells but is aberrantly expressed in cancer. Furthermore, PAGE4 is developmentally regulated with dynamic expression patterns in the developing prostate and is also a stress-response protein that is upregulated in response to cellular stress. PAGE4 interacts with c-Jun, which is activated by the stress-response kinase JNK1, and plays an important role in the development and pathology of the prostate gland. Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51. We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation. In vitro single molecule FRET indicates phosphorylation results in compaction of (still) intrinsically disordered PAGE4. Interestingly, however, while our previous observations indicated that the wild-type nonphosphorylated PAGE4 protein interacted with c-Jun [RajagopalanK. et al. (2014) Biochim, Biophys. Acta1842, 154−16324263171], here we show that phosphorylation of PAGE4 weakens its interaction with c-Jun in vitro. These data suggest that phosphorylation induces conformational changes in natively disordered PAGE4 resulting in its decreased affinity for c-Jun to promote interaction of c-Jun with another, unidentified, partner. Alternatively, phosphorylated PAGE4 may induce transcription of a novel partner, which then potentiates c-Jun transactivation. Regardless, the present results clearly implicate PAGE4 as a component of the stress-response pathway and uncover a novel link between components of this pathway and prostatic development and disease.

Summary Background Scant information is available regarding patients with upper gastrointestinal bleeding (UGIB) from tumours. Aim To determine the presentation, endoscopic findings, treatment and outcomes in patients with UGIB from malignant tumours and identify risk factors associated with rebleeding. Methods Consecutive patients who were hospitalised with haematemesis, melena or haematochezia and underwent upper endoscopy were identified retrospectively by reviewing an endoscopy database. Patients with UGIB due to biopsy-proven malignant tumours were studied. Results Tumours were the source of bleeding in 106 (5%) of 2,166 patients with UGIB. Tumours were oesophageal in 17 (16%), gastric in 77 (73%) and duodenal in 12 (11%). At presentation, 84 (79%) did not have known cancer previously, and 79 (75%) had metastatic disease. Seventy-seven (73%) received transfusions at index hospitalisation. At endoscopy, 32 (30%) had active bleeding (31 oozing, 1 spurting). Among actively bleeding patients, haemostasis was achieved in 12 (86%) of 14 receiving endoscopic therapy and all 18 not receiving endoscopic treatment. Hospitalisation for rebleeding occurred in 50 (49%) of 103 at a median of 30 days (3–885). On multivariate analysis, age ≤60 years (OR = 2.49, 95% CI 1.06–5.81) and haemodynamic instability (OR = 2.42, 95% CI 1.08–5.46) were associated with rebleeding. Conclusions Patients presenting with tumour-associated UGIB have substantial blood loss, with three-quarters requiring transfusion at presentation. Initial haemostasis occurs in almost all patients, with or without endoscopic therapy, but rebleeding requiring repeat hospitalisation occurs in approximately half the patients and is more common in patients who are ≤60 years of age and have haemodynamic instability at presentation.

Functional dyspepsia (FD) is a functional gastrointestinal disorder diagnosed by symptom-based criteria. It has been said that duodenal immune activation plays a role in the pathogenesis of FD. The primary aims of the study were to compare the total number of duodenal eosinophil and evaluate the eosinophil degranulation rate, number of duodenal degranulated eosinophil and mast cell between patients with FD and healthy subjects. We enrolled 96 patients with FD and 24 healthy controls at Sir Run Run Shaw Hospital. The total number of eosinophil was comparable in the second portion of duodenum (D2) and duodenal bulb (D1) between patients with FD and healthy controls (all P > 0.05). Significant higher eosinophil degranulation positive rate in D2 (P = 0.003) and a trend towards higher in D1 (P = 0.084) were observed in patients with FD compared with healthy controls. Moreover, the number of duodenal degranulated eosinophil in patients with FD were significantly increased than healthy controls in D1(9.8 ± 6.3 vs 2.9 ± 2.1 per HPF, P = 0.0002) and a trend towards increase in D2 (10.7 ± 7.7 vs 5.3 ± 0.9 per HPF, P = 0.077), respectively. However, degranulated mast cells in patients with FD were almost same with healthy controls. Increased eosinophils degranulation in duodenum play an important role in pathogenesis of FD.

The appropriate interval between ligation sessions for treatment of esophageal variceal bleeding is uncertain. The optimal interval would provide variceal eradication as rapidly as possible to lessen early rebleeding while minimizing ligation-induced adverse events. We randomly assigned patients hospitalized with acute esophageal variceal bleeding who had successful ligation at presentation to repeat ligation at 1-week or 2-week intervals. Beta-blocker therapy was also prescribed. Ligation was performed at the assigned interval until varices were eradicated and then at 3 and 9 months after eradication. The primary endpoint was the proportion of patients with variceal eradication at 4 weeks. Four-week variceal eradication occurred more often in the 1-week than in the 2-week group: 37/45 (82%) versus 23/45 (51%); difference = 31%, 95% confidence interval 12%-48%. Eradication occurred more rapidly in the 1-week group (18.1 versus 30.8 days, difference = −12.7 days, 95% confidence interval −20.0 to −5.4 days). The mean number of endoscopies to achieve eradication or to the last endoscopy in those not achieving eradication was comparable in the 1-week and 2-week groups (2.3 versus 2.1), with the mean number of postponed ligation sessions 0.3 versus 0.1 (difference = 0.2, 95% confidence interval −0.02 to 0.4). Rebleeding at 4 weeks (4% versus 4%) and 8 weeks (11% versus 9%), dysphagia/odynophagia/chest pain (9% versus 2%), strictures (0% versus 0%), and mortality (7% versus 7%) were similar with 1-week and 2-week intervals. Conclusion: One-week ligation intervals led to more rapid eradication than 2-week intervals without an increase in complications or number of endoscopies and without a reduction in rebleeding or other clinical outcomes; the decision regarding ligation intervals may be individualized based on patient and physician preferences and local logistics and resources. (Hepatology 2016;64:549-555)

Immunoblotting confers protein identification specificity beyond that of immunoassays by prepending protein electrophoresis (sizing) to immunoprobing. To accurately size protein targets, sample analysis includes concurrent analysis of protein markers with known molecular masses. To incorporate protein markers in single-cell western blotting, microwells are used to isolate individual cells and protein marker-coated microparticles. A magnetic field directs protein-coated microparticles to >75% of microwells, so as to 1) deliver a quantum of protein marker to each cell-laden microwell and 2) synchronize protein marker solubilization with cell lysis. Nickel-coated microparticles are designed, fabricated, and characterized, each conjugated with a mixture of histidine-tagged proteins (42.3–100 kDa). Imidazole in the cell lysis buffer solubilizes protein markers during a 30 s cell lysis step, with an observed protein marker release half-life of 4.46 s. Across hundreds of individual microwells and different microdevices, robust log-linear regression fits (R(2) > 0.97) of protein molecular mass and electrophoretic mobility are observed. The protein marker and microparticle system is applied to determine the molecular masses of five endogenous proteins in breast cancer cells (GAPDH, β-TUB, CK8, STAT3, ER-α), with

To evaluate whether Helicobacter pylori (H. pylori) eradication therapy benefits patients with functional dyspepsia (FD).Randomized controlled trials (RCTs) investigating the efficacy and safety of H. pylori eradication therapy for patients with functional dyspepsia published in English (up to May 2015) were identified by searching PubMed, EMBASE, and The Cochrane Library. Pooled estimates were measured using the fixed or random effect model. Overall effect was expressed as a pooled risk ratio (RR) or a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0.This systematic review included 25 RCTs with a total of 5555 patients with FD. Twenty-three of these studies were used to evaluate the benefits of H. pylori eradication therapy for symptom improvement; the pooled RR was 1.23 (95%CI: 1.12-1.36, P0.0001). H. pylori eradication therapy demonstrated symptom improvement during long-term follow-up at ≥ 1 year (RR = 1.24; 95%CI: 1.12-1.37, P0.0001) but not during short-term follow-up at1 year (RR = 1.26; 95%CI: 0.83-1.92, P = 0.27). Seven studies showed no benefit of H. pylori eradication therapy on quality of life with an SMD of -0.01 (95%CI: -0.11 to 0.08, P = 0.80). Six studies demonstrated that H. pylori eradication therapy reduced the development of peptic ulcer disease compared to no eradication therapy (RR = 0.35; 95%CI: 0.18-0.68, P = 0.002). Eight studies showed that H. pylori eradication therapy increased the likelihood of treatment-related side effects compared to no eradication therapy (RR = 2.02; 95%CI: 1.12-3.65, P = 0.02). Ten studies demonstrated that patients who received H. pylori eradication therapy were more likely to obtain histologic resolution of chronic gastritis compared to those who did not receive eradication therapy (RR = 7.13; 95%CI: 3.68-13.81, P0.00001).The decision to eradicate H. pylori in patients with functional dyspepsia requires individual assessment.

An epithelial to mesenchymal transition (EMT) has been shown to be a necessary precursor to prostate cancer metastasis. Additionally, the differential expression and splicing of mRNAs has been identified as a key means to distinguish epithelial from mesenchymal cells by qPCR, western blotting and immunohistochemistry. However, few markers exist to differentiate between these cells by flow cytometry. We previously developed two cell lines, PC3-Epi (epithelial) and PC3-EMT (mesenchymal). RNAseq was used to determine the differential expression of membrane proteins on PC3-Epi/EMT. We used western blotting, qPCR and flow cytometry to validate the RNAseq results. CD44 was one of six membrane proteins found to be differentially spliced between epithelial and mesenchymal PC3 cells. Although total CD44 was positive in all PC3-Epi/EMT cells, PC3-Epi cells had a higher level of CD44v6 (CD44 variant exon 6). CD44v6 was able to differentiate epithelial from mesenchymal prostate cancer cells using either flow cytometry, western blotting or qPCR. Electronic supplementary material The online version of this article (doi:10.1007/s12032-015-0593-z) contains supplementary material, which is available to authorized users.

Endoscopic tattoo with India ink injection for surveillance of premalignant gastric lesions is technically cumbersome and may not be durable. The aim of the study is to evaluate the accuracy of a novel, computer-simulated biopsy marking system (CSBMS) developed for the endoscopic marking of gastric lesions. Twenty-five patients with history of gastric intestinal metaplasia received both CSBMS-guided marking and India ink injection in five points in the stomach at index endoscopy. A second endoscopy was performed at three months. Primary outcome was accuracy of CSBMS (distance between CSBMS probe-guided site and tattoo site measured by CSBMS). The mean accuracy of CSBMS at angularis was5.3±2.2 mm, antral lesser curvature5.7±1.4 mm, antral greater curvature6.1±1.1 mm, antral anterior wall6.9±1.6 mm, and antral posterior wall6.9±1.6 mm. CSBMS (2.3±0.9versus12.5±4.6seconds;P=0.02) required less procedure time compared to endoscopic tattooing. No adverse events were encountered. CSBMS accurately identified previously marked gastric sites by endoscopic tattooing within 1 cm on follow-up endoscopy.

OBJECTIVE: To describe the resource utilization and care of chronic kidney disease (CKD) patients in a managed care plan. METHODS: This was a retrospective claims analysis of a nationwide managed care medical and pharmacy database from September 1, 1998, to July 31, 2001. Twenty-seven health plans in 19 states distributed across the Northeast, Southeast, Midwest, and Southwest United States were represented in this analysis. CKD patients were identified using ICD-9 CM, CPT-4, and HCPCS codes indicative of dialysis. Patients continuously enrolled for at least 6 months before and 3 months after an initial dialysis event were included in the study. Health care charges and associated clinical information were assessed during 3 time periods: predialysis was from the sixth through the second month before initial dialysis, peridialysis was 30 days before and 30 days after initial dialysis, and postdialysis was the second and third month after initial dialysis. The main outcome measures were total health care charges, primary diagnoses, and diagnosis-related groups (DRGs). RESULTS: The per-patient-per-month charges were $4,265 in the predialysis period (average for 5 months), $35,292 in the peridialysis period (average for 2 months), and $15,399 in the postdialysis period (average for 2 months). The most common primary diagnosis categories during all time periods were chronic renal failure and congestive heart failure. Similarly, the most common DRGs were related to renal and heart failure. A total of 38.2% of patients did not have an initial nephrologist visit until the first dialysis event. Treatments with nutritional supplements and medications such as angiotensin-converting enzyme inhibitors and erythropoietin were found to be suboptimal. CONCLUSION: CKD patients generate significant medical charges during the predialysis period and after initiation of dialysis. Further investigations are warranted to assess the impact of active management of CKD patients on CKD-related health care expenditures in kidney disease.

Background Randomized studies of implantable cardioverter defibrillators ( ICD ) have excluded sudden cardiac death survivors who had revascularization before or after an arrhythmic event. To evaluate the role of ICD and the effects of clinical variables including degree of revascularization, we studied cardiac surgery patients who had an ICD implanted for sustained perioperative ventricular arrhythmias. Methods and Results The electronic database for Southern California Kaiser Foundation hospitals was searched for patients who had cardiac surgery between 1999 and 2005 and an ICD implanted within 3 months of surgery. One hundred sixty‐four patients were identified; 93/164 had an ICD for sustained pre‐ or postoperative ventricular tachycardia or fibrillation requiring resuscitation. Records were reviewed for the following: presenting arrhythmia, ejection fraction, and degree of revascularization. The primary end point was total mortality ( TM ) and/or appropriate ICD therapy ( ICD ‐T), and secondary end points are TM and ICD ‐T. During the mean follow up of 49 months, the primary endpoint of TM + ICD ‐T and individual end points of TM and ICD ‐T were observed in 52 (56%), 35 (38%), and 28 (30%) patients, respectively, with 55% of TM , and 23% of ICD ‐T occurring within 2 years of implant. In multivariate risk analysis, none of the following was associated with any of the end points: incomplete revascularization, presenting ventricular arrhythmia, and timing of arrhythmias. Conclusion Our data supports the recent guidelines for ICD in this cohort of patients, as the presence of irreversible substrate and triggers of ventricular arrhythmias, cannot be reliably excluded even with complete revascularization. Further studies are needed to understand this complex group of patients.

We consider the problem of deciding the best action time when observations are made sequentially. Specifically we address a special type of optimal stopping problem where observations are made from state-contingent distributions and there exists uncertainty on the state. In this paper, the decision-maker's belief on state is revised sequentially based on the previous observations. By using the independence property of the observations from a given distribution, the sequential Bayesian belief revision process is represented as a simple recursive form. The methodology developed in this paper provides a new theoretical framework for addressing the uncertainty on state in the action-timing problem context. By conducting a simulation analysis, we demonstrate the value of applying Bayesian strategy which uses sequential belief revision process. In addition, we evaluate the value of perfect information to gain more insight on the effects of using Bayesian strategy in the problem.

Background The Cancer Testis Antigens (CTAs) are a group of genes that are highly expressed in the normal testis and several types of cancer. Due to their restricted expression in normal adult tissues, CTAs have been attractive targets for immunotherapy and biomarker development. In this work, we discovered that Centrin 1 (CETN1) which is found in the centrosome of all eukaryotes, may be a member of this group and is highly expressed in prostate and pancreatic cancer. Three members of the centrin family of calcium binding proteins (CETN) are localized to the centrosome in all eukaryotes with CDC31 being the sole yeast homolog. CETN1 is a retrogene that probably arose from a retrotransposition of CETN2, an X-linked gene. A previous mouse study shows that CETN1 is expressed solely in the testis, while CETN2 is expressed in all organs. Results In this work, we show that CETN1 is a new member of the growing group of CTAs. Through the mining of publicly available microarray data, we discovered that human CETN1 expression but not CETN2 or CETN3 is restricted to the testis. In fact, CETN1 is actually down-regulated in testicular malignancies compared to normal testis. Using q-PCR, CETN1 expression is shown to be highly up-regulated in cancer of the prostate and in pancreatic xenografts. Unexpectedly however, CETN1 expression was virtually absent in various cell lines until they were treated with the DNA demethylation agent 5’AZA-2’Deoxycytidine (AZA) but showed no increased expression upon incubation with Histone deacetylase inhibitor Trichostatin-A (TSA) alone. Additionally, like most CTAs, CETN1 appears to be an intrinsically disordered protein which implies that it may occupy a hub position in key protein interaction networks in cancer. Neither CETN1 nor CETN2 could compensate for loss of CDC31 expression in yeast which is analogous to published data for CETN3. Conclusions This work suggests that CETN1 is a novel CTA with expression in cancer of the prostate and pancreas. In cell lines, the expression is probably regulated by promoter methylation, while the method of regulation in normal adult tissues remains unknown.

Drug resistance is a major limitation to the successful treatment of advanced prostate cancer (PCa). Patients who have metastatic, castration-resistant PCa (mCRPC) are treated with chemotherapeutics. However, these standard therapy modalities culminate in the development of resistance. We established paclitaxel resistance in a classic, androgen-insensitive mCRPC cell line (DU145) and, using a suite of molecular and biophysical methods, characterized the structural and functional changes in vitro and in vivo that are associated with the development of drug resistance. After acquiring paclitaxel-resistance, cells exhibited an abnormal nuclear morphology with extensive chromosomal content, an increase in stiffness, and faster cytoskeletal remodeling dynamics. Compared with the parental DU145, paclitaxel-resistant (DU145-TxR) cells became highly invasive and motile in vitro, exercised greater cell traction forces, and formed larger and rapidly growing tumors in mouse xenografts. Furthermore, DU145-TxR cells showed a discrete loss of keratins but a distinct gain of ZEB1, Vimentin and Snail, suggesting an epithelial-to-mesenchymal transition. These findings demonstrate, for the first time, that paclitaxel resistance in PCa is associated with a trans-differentiation of epithelial cell machinery that enables more aggressive and invasive phenotype and portend new strategies for developing novel biomarkers and effective treatment modalities for PCa patients.

Aims To assess clinical markers that can be used in predicting the outcome and role of implantable cardioverter defibrillators (ICD) in coronary artery bypass surgery (CABG) patients with severely depressed left ventricular ejection fraction (LVEF), independent of time from revascularization. Methods and results The database was searched for patients who had CABG surgery and had an ICD within 4 months of surgery, between 1999 and 2005. The records were reviewed for LVEF, status of revascularization, programmed electrical stimulation results, and medications. The primary endpoints were: combined total mortality (TM) and appropriate ICD therapy (ICD-T), and the individual outcomes of TM and ICD-T. One hundred and sixty-four patients were identified, 69 had an ICD implanted for primary prevention of sudden cardiac death and were followed till June 2009. The mean pre- and post-operative LVEFs were 29 and 33%, 46 (67%) had incomplete revascularization, and 38 (55%) had inducible ventricular arrhythmias. Over the mean follow-up of 40 months, 20 patients (29%) died and 18 (26%) had ICD-T. In the Cox proportional hazard model, the following variables were significant at the 0.05 level; for the combined outcome TM and ICD-T: congestive heart failure (CHF) class III/IV and coronary artery disease (CAD) + valvular disease; for ICD-T outcome: CAD + valvular disease; for TM outcome: female gender, LVEF

The English past tense system has recently been used to argue that formal grammatical categories (such as root, rule, and lexical item) may not be necessary to explain the acquisition and knowledge of language. Rumelhart and McClelland (1986) devised a connectionist model relying solely on phonological information; it is often suggested that any deficiencies of such a model can be remedied by supplying it with semantic information. These proposals are incorrect: Grammatical categories and abstract morphological structure are indispensable and cannot be replaced with semantics while preserving the patterns of psychological generalization in the system. Linguists have noted that irregular past tense mappings (e.g., fly/flew; stick/stuck) apply only when a verb's root is marked in the lexicon as having an irregular past. Because nouns are never so marked, verbs with noun roots—denominal verbs—are regular even if they are phonologically identical to irregular verbs, hence: flied out/*flew out to center field; high-sticked/*high-stuck the goalie. Experiment 1 shows that adult subjects are highly sensitive to this principle when rating regular and irregular past tense forms of novel versions of irregular sounding verbs: New verbs formed from nouns were judged as better with a regular past tense (e.g., line-drived was the preferred past of “to hit a line drive”): new verbs formed from verbs were judged as better with an irregular past tense (e.g., line-drove was the preferred past of “to drive along a line”). Experiment 2 replicated the results with noncollege-educated adults, showing that the effect is not due to prescriptive language training. Experiment 3 tested an alternative to the formal grammatical account proposed by Lakoff (1987): When a verb has two meanings, one with an irregular past and one with a regular past, the irregular will belong to the meaning that is more central. Using regression techniques and ratings data, we disconfirm this prediction: In the data from Experiment 1, judgments of regular and irregular forms of a new verb are shown to be affected by whether the verb is derived from a noun or a verb, but not by whether its new sense is near the center or the periphery of the sense of the word it was derived from. Experiments 4 and 5 explain the few apparent counter-examples by gathering independent evidence for a short-circuiting process: When a denominal verb appears to have an irregular past tense form, it is because speakers sometimes interpret such verbs as having been derived directly from a related irregular verb root, bypassing the relevant noun. The experiments serve as a straightforward demonstration that representations of formal grammatical categories and structures are powerful determinants of linguistic behavior, and are not reducible to semantics, phonology, or prescriptive training.

BackgroundGood to excellent short-term results have been reported for the surgical treatment of lateral epicondylitis using various surgical techniques.HypothesisSurgical treatment for lateral epicondylitis using the mini-open Nirschl surgical technique will lead to durable results at long-term follow-up.Study DesignCase series; Level of evidence, 4.MethodsRecords from 139 consecutive surgical procedures (130 patients) for lateral epicondylitis performed by 1 surgeon between 1991 and 1994 were retrospectively reviewed. Eighty-three patients (92 elbows) were available by telephone for a mean follow-up of 12.6 years (range, 10–14 years). Outcome measures included the Numeric Pain Intensity Scale, Nirschl and Verhaar tennis elbow–specific scoring systems, and American Shoulder and Elbow Surgeons elbow form. Preoperative data were collected retrospectively.ResultsThe mean age of the study group was 46 years (range, 23–70 years) with 45 men and 38 women. Eighty-seven of the procedures were primary, and 5 were revision tennis elbow surgeries. Concomitant procedures were performed in 30 patients including ulnar nerve release in 24 patients, medial tennis elbow procedures in 23 patients, shoulder arthroscopy in 2 patients, carpal tunnel release in 1 patient, and triceps debridement and osteophyte excision in 1 patient. The mean duration of preoperative symptoms was 2.2 years (range, 2 months to 10 years). The mean Nirschl tennis elbow score improved from 23.0 to 71.0, and the mean American Shoulder and Elbow Surgeons score improved from 34.3 to 87.7 at a minimum of 10-year follow-up ( P < .05). The Numeric Pain Intensity Scale pain score improved from 8.4 preoperatively to 2.1 ( P < .05). Results were rated as excellent in 71 elbows, good in 6 elbows, fair in 9 elbows, and poor in 6 elbows by the Nirschl tennis elbow score. By the criteria of Verhaar et al, the results were excellent in 45 elbows, good in 32 elbows, fair in 8 elbows, and poor in 7 elbows. Eighty-four percent good to excellent results were achieved using both scoring systems. Ninety-two percent of the patients reported normal elbow range of motion. The overall improvement rate was 97%. Patient satisfaction averaged 8.9 of 10. Ninety-three percent of those available at a minimum of 10-year follow-up reported returning to their sports.ConclusionThe mini-open Nirschl surgical technique with accurate resection of the tendinosis tissue remains highly successful in the long term.

Background Cell shape changes during cytokinesis and chemotaxis require regulation of the actin cytoskeletal network. Dynacortin, an actin cross-linking protein, localizes to the cell cortex and contributes to cortical resistance, thereby helping to define the cell shape changes of cytokinesis. Dynacortin also becomes highly enriched in cortical protrusions, which are sites of new actin assembly. Results We studied the effect of dynacortin on cell motility during chemotaxis and on actin dynamics in vivo and in vitro. Dynacortin enriches with the actin, particularly at the leading edge of chemotaxing cells. Cells devoid of dynacortin do not become as polarized as wild-type control cells but move with similar velocities as wild-type cells. In particular, they send out multiple pseudopods that radiate at a broader distribution of angles relative to the chemoattractant gradient. Wild-type cells typically only send out one pseudopod at a time that does not diverge much from 0° on average relative to the gradient. Though dynacortin-deficient cells show normal bulk (whole-cell) actin assembly upon chemoattractant stimulation, dynacortin can promote actin assembly in vitro. By fluorescence spectroscopy, co-sedimentation and transmission electron microscopy, dynacortin acts as an actin scaffolder in which it assembles actin monomers into polymers with a stoichiometry of 1 Dyn2:1 actin under salt conditions that disfavor polymer assembly. Conclusion Dynacortin contributes to cell polarization during chemotaxis. By cross-linking and possibly stabilizing actin polymers, dynacortin also contributes to cortical viscoelasticity, which may be critical for establishing cell polarity. Though not essential for directional sensing or motility, dynacortin is required to establish cell polarity, the third core feature of chemotaxis.