IL-23 amplifies the epithelial-mesenchymal transition of mechanically conditioned alveolar epithelial cells in rheumatoid arthritis-associated interstitial lung disease through mTOR/S6 signaling.

Epithelial-mesenchymal transition (EMT) creates an environment facilitating fibrosis following alveolar epithelial cell injury. IL-23 has important roles in chronic autoimmune conditions like rheumatoid arthritis (RA), but its role in the interstitial lung disease that affects patients with RA is unclear. This study aimed to determine the profibrogenic role of IL-23 on somatic alveolar type I (ATI) epithelial cells. Primary ATI cells were isolated from rats and cultured on plastic dishes for 1-3 wk. After prolonged culture (≥14 days) on rigid culture dishes, primary ATI cells gradually acquired a mesenchymal phenotype, identified by decreased expression of caveolin-1, and reorganization of F-actin cytoskeleton, indicating the initiation of EMT by matrix stiffness. To determine how IL-23 promotes EMT in vitro, transitioning ATI cells, cultured on a stiff substrate for ≥14 days were stimulated with IL-23. The EMT phenotype was significantly enhanced by IL-23, which upregulated α-smooth muscle actin (α-SMA), collagen I/III protein, and decreased caveolin-1. Furthermore, IL-23 significantly promoted cell invasion, as well as apoptotic resistance on transitioning ATI cells. Mechanistically, IL-23-induced EMT was mammalian target of rapamycin/ribosomal protein S6 (mTOR/S6) signaling dependent and reversible by rapamycin. Transcriptional sequencing analysis of human lung fibrosis biopsy tissue revealed key roles for IL-23 in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This result was further validated by significantly upregulated IL-23 expression at the mRNA level in RA-ILD lung sections. Notably, transitioning ATI epithelial cells were abundantly detected in RA-ILD tissue. Taken together, these data support a role for IL-23 in the pathogenesis of RA lung fibrosis by promoting EMT in alveolar epithelial cells through mTOR/S6 signaling.

A novel humanized model of rheumatoid arthritis associated lung disease.

Cigarette smoking has been implicated in the pathogenesis of seropositive rheumatoid arthritis (RA), as well as RA-associated lung disease. Fibrotic interstitial lung disease as well as emphysema occur in RA and cause substantial morbidity. We used arthritis-susceptible HLA-DQ8 transgenic mice to generate RA-associated lung disease. Mice were exposed to cigarette smoke (CS) prior to induction of arthritis, and subsequently injected with a low dose of bleomycin intra-tracheally to induce lung injury. Exposure of arthritic mice to both CS and bleomycin led to a significant reduction in lung compliance consistent with development of diffuse lung disease. Morphologic evaluation of the lung demonstrated areas of emphysematous change and co-existent fibrosis, consistent with a combined pattern of fibrosis and emphysema. These changes were accompanied by inflammatory cell infiltration and upregulation of fibrosis-associated genes. This humanized mouse model can serve as a valuable research tool to understand the pathogenesis of RA associated lung disease.

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

A 3D printing replication technique for fabricating digital dentures.

Digitally fabricated dentures allow clinicians to provide new prostheses for edentulous patients in an efficient manner. One approach uses a replication technique where a prosthesis in need of minor alterations is used as a basis for the definitive prosthesis. Compared with conventional duplication techniques, this method allows for the predictable fabrication of accurate dentures in less time and with increased quality. In this clinical report, interim treatment dentures were scanned and 3D printed to make a replication denture for fabrication of a digital prosthesis with the replication technique.

Perioperative management of esophageal atresia/tracheo-esophageal fistula: An analysis of data of 101 consecutive patients.

BACKGROUND: The perioperative management of esophageal atresia/tracheo-esophageal fistula by open or thoracoscopic approach can be complicated by metabolic derangements. Little is known, however, about the severity of derangements of vital and metabolic parameters in the perioperative period. AIM: The aim of this study is to describe the perioperative courses of vital and metabolic parameters in 101 consecutive neonates undergoing surgical repair of esophageal atresia type C. METHOD: In a retrospective cohort study, we extracted all data from the electronic anesthetic and medical charts of patients who underwent esophageal atresia type C repair within 30 days of life (2007-2017). We distinguished three types of surgery: primary open, primary thoracoscopic, and primary thoracoscopic surgery converted to open surgery. Descriptive analysis was applied. RESULTS: The charts of 117 patients were reviewed: data of 101 were included. The perioperative anesthetic management was not standardized; various methods and medications were used for anesthesia induction and maintenance. Intraoperative blood gas analysis data of 72 patients were available and showed derangements regardless of type of surgery. The median pH-value decreased to 7.21 [IQR 7.14-7.30] and a pH-value below 7.20 was found in 29 patients; in four cases below 7.0, with the lowest value 6.83. The median PaCO2 reached an upper level of 7.5kPa [IQR 5.8-9.2]; in 13 cases above 10.0kPa, with a peak value of 25.8kPa. These high PaCO2 levels fluctuated with lowest measured PaCO2 of median 5.6 [IQR 4.5-6.6], with the lowest value 2.8kPa. The median PaO2 level reached an upper level of 16.9kPa [IQR 11.8-25.7], in 22 cases above 20.0kPa, with a peak value of 50.0kPa. These high levels fluctuated with lowest measured PaO2 levels of median 8.3kPa [IQR 6.73-10.5]; the lowest PaO2 value was 4.7 kPa. CONCLUSION: Open and thoracoscopic correction of esophageal atresia were associated with periods of severe metabolic derangements. These events need to be taken into account for the evaluation of esophageal atresia (surgical) care and in evaluations of short- and long-term outcomes.

Single 4.5 mg fixed-dose of rasburicase for hyperuricemia associated with tumor lysis syndrome.

Rasburicase is a recombinant urate oxidase enzyme administered for treatment of hyperuricemia associated with tumor lysis syndrome. Studies demonstrate effectiveness of single fixed-dose rasburicase as compared to the FDA-approved dose of 0.2 mg/kg intravenously daily for up to five days. Doses in these studies range from 1.5 mg to 7.5 mg. Our study evaluated outcomes in patients who received single 4.5 mg fixed-dose rasburicase. This retrospective, IRB-approved chart review evaluated adult oncology subjects who received fixed-dose rasburicase between January 2007 and April 2014. The primary outcome was percentage of patients with normalization of uric acid (level <8 mg/dL within 24 h) after a single 4.5 mg fixed-dose of rasburicase. Secondary objectives were incidence of initial failure of fixed-dose rasburicase and normalization of uric acid in overweight (body mass index ≥25 kg/m2) versus non-overweight patients. Initial failure was defined as need for additional doses or progression to dialysis within one week of the initial fixed-dose. In the 128 patients included, the mean baseline uric acid level was 14.84 mg/dL. Of the 112 patients with a follow-up uric acid level, 68% achieved normalization within 24 h of rasburicase administration. Thirty-eight patients received additional treatment: 10 received additional dose(s) and 28 underwent dialysis. Normalization of uric acid in overweight versus non-overweight patients was 66% and 73%, respectively. Overall, a single 4.5 mg fixed-dose of rasburicase effectively normalized uric acid in 68% of patients within 24 h. Further studies are needed to determine the optimal single fixed-dose necessary for treatment response across all patients.

The VCAM1-ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology.

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aß) plaque-associated ApoE, and leads to Aß clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aß-directed migration. Functional screening identified that VCAM1 directs microglial Aß chemotaxis by sensing Aß plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aß chemotaxis, resulting in decreased microglial clearance of Aß. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aß chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.

Intraventricular 4D flow cardiovascular magnetic resonance for assessing patients with heart failure with preserved ejection fraction: a pilot study.

Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. Intraventricular four-dimensional flow (4D flow) phase-contrast cardiovascular magnetic resonance (CMR) can assess different components of left ventricular (LV) flow including direct flow, delayed ejection, retained inflow and residual volume. This could be utilised to identify HFpEF. This study investigated if intraventricular 4D flow CMR could differentiate HFpEF patients from non-HFpEF and asymptomatic controls. Suspected HFpEF patients and asymptomatic controls were recruited prospectively. HFpEF patients were confirmed using European Society of Cardiology (ESC) 2021 expert recommendations. Non-HFpEF patients were diagnosed if suspected HFpEF patients did not fulfil ESC 2021 criteria. LV direct flow, delayed ejection, retained inflow and residual volume were obtained from 4D flow CMR images. Receiver operating characteristic (ROC) curves were plotted. 63 subjects (25 HFpEF patients, 22 non-HFpEF patients and 16 asymptomatic controls) were included in this study. 46% were male, mean age 69.8 ± 9.1 years. CMR 4D flow derived LV direct flow and residual volume could differentiate HFpEF vs combined group of non-HFpEF and asymptomatic controls (p < 0.001 for both) as well as HFpEF vs non-HFpEF patients (p = 0.021 and p = 0.005, respectively). Among the 4 parameters, direct flow had the largest area under curve (AUC) of 0.781 when comparing HFpEF vs combined group of non-HFpEF and asymptomatic controls, while residual volume had the largest AUC of 0.740 when comparing HFpEF and non-HFpEF patients. CMR 4D flow derived LV direct flow and residual volume show promise in differentiating HFpEF patients from non-HFpEF patients.

Macrogeometry and Bone Density Control Over the Primary Stability of 6-mm Implants: An In Vitro Study.

PURPOSE: Short implants are used in clinical conditions of insufficient vertical bone availability. This study aimed to compare the primary stability of short implants with different macrodesigns placed in different bone densities in vitro. MATERIALS AND METHODS: One hundred twenty short (6-mm) implants (20/group) were placed at the bone level in commercially available polyurethane blocks representing type I and IV bone quality. The groups were as follows: test A group (4.6-mm diameter with tapered body), test B group (4.8-mm diameter/cylindric microthreaded neck), and test C group (4.8-mm diameter, cylindric body with polished collar, three threads at the intraosseous portion). Implant primary stability was assessed using insertion torque and implant stability quotient (ISQ) values. A blinded calibrated clinician recorded all measurements. Statistical comparisons were completed using a one-way analysis of variance (ANOVA) and Bonferroni posttests. RESULTS: The insertion torque values (mean ± SD) for groups A, B, and C in type I bone were 52.50 ± 5.25, 49.00 ± 5.98, and 46.25 ± 3.93, and in type IV bone, the values were 14.00 ± 2.05, 15.50 ± 2.76, and 9.75 ± 1.11, respectively. Also, the ISQ values were 67.25 ± 2.760, 69.25 ± 1.67, and 61.80 ± 5.68 (type I bone); and 53.27 ± 1.99, 60.65 ± 2.11, and 51.97 ± 4.51 (type IV bone), respectively. The comparison showed statistical differences in ISQ (Bonferroni adjusted P < .0001) for the A and B groups but also for the A and C groups (type I bone), in soft bone between the A and B groups and between the B and C groups, and also for the insertion torque values for the A and C groups and between the B and C groups in type IV bone. CONCLUSION: Short implant macrogeometry defines primary stability. Short implants with 6-mm length and multiple threads can achieve good primary stability in vitro in type I and IV artificial bone.

Primary stability of narrow-diameter dental implants with a multiple condensing thread design placed in bone with and without osteotomes: An in vitro study.

BACKGROUND: The authors hypothesized that there is no difference in the primary stability (PS) of multiple condensing thread design (MCTD) implants placed in simulated type-IV bone with and without using osteotomes. PURPOSE: This in vitro study assessed the PS of narrow-diameter dental implants with MCTD placed in simulated soft (type-IV) bone with and without using osteotomes. MATERIALS AND METHODS: Sixty MCT-designed implants (diameter: 3.0 mm; length: 11.5 mm) were placed using 800 rpm drilling speed in cellular rigid polyurethane foam bone-blocks that simulated type-IV bone. Prior to placement, the implants were divided into three groups (20 implants per group) depending upon the protocol used for osteotomy preparation-Group-1: Conventional drilling (CD); Group-2: CD followed by osseous condensation using a chisel-shaped tapered osteotome with maximum diameter of 3 mm; and Group-3: CD followed by osseous condensation using a cylindrical osteotome with maximum diameter of 3 mm. Abutments were connected to all implants and PS was recorded using resonance frequency analysis (RFA) and the periotest (PTV). Group comparisons were performed using analysis and Bonferroni post-hoc adjustment tests. Level of significance was set at P < .05. RESULTS: There was no statistically significant difference in the RFA values for the MCT-designed implants placed in groups 1, 2, and 3 (59.85 ± 0.72, 59.67 ± 0.76 and 59.42 ± 0.92, respectively). There was no statistically significant difference in the PTV values for MCT-designed implants in groups 1, 2, and 3 (1.655 ± 0.82, 1.405 ± 0.57, and 1.078 ± 0.63, respectively). CONCLUSION: The MCTD implants with narrow diameters have a high PS in artificial soft bone in vitro. Due to the condensation effect of the thread design, there is no need for additional condensation of the peri-osteotomy bone in order to improve implant stability.

Referrals by general dental practitioners and medical practitioners to oral medicine specialists in New Zealand: a study to develop protocol guidelines.

OBJECTIVE: The aim of this study was to examine the awareness level among general dental practitioners and medical practitioners with regard to common oral mucosal diseases and orofacial pain, investigate their orofacial screening and oral medicine referral practices, assess the information to be included in the referral, and evaluate the perceived need for supplementary resources and guidelines for referral. STUDY DESIGN: In total, 51 general dental practitioners and medical practitioners were recruited to investigate their orofacial screening and oral medicine referral practices. Three oral medicine specialists were interviewed to understand the referrals received from dentists and physicians. RESULTS: Of the participants, 87.5% dentists and 52.6% physicians considered orofacial screening as treatment priority. However, 71.9% dentists performed orofacial screening routinely, whereas none of the physicians did. Of the dentists, 50% referred relevant patients to oral medicine specialists every time they encountered such cases, and 31.6% of the physicians did so. Referrals should include the patient's background and medical history, full descriptions of the lesions, and results and photos from special tests. Of the participants, 65.6% of the dentists and 78.9% of the physicians believed that continuing professional development courses in oral medicine would be beneficial, and 93.8% of the dentists and 89.5% of the physicians agreed that standardized national referral guidelines would be useful. CONCLUSIONS: Standardized national referral guidelines, as well as continuing professional development courses in oral medicine, would be helpful to dental practitioners in the management of patients.

Mechanisms of lung disease development in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and damage. Extra-articular manifestations occur in many patients and can include lung involvement in the form of airway or parenchymal inflammation and fibrosis. Although the pathophysiology of articular RA has been extensively investigated, the mechanisms causing airway and parenchymal lung disease are not well defined. Infections, cigarette-smoking, mucosal dysbiosis, host genetics and premature senescence are all potentially important contributors to the development of lung disease in patients with RA. RA-associated lung disease (which can predate the onset of articular disease by many years) probably originates from chronic airway and alveolar epithelial injury that occurs in an individual with a genetic background that permits the development of autoimmunity, leading to chronic inflammation and subsequent airway and lung parenchymal remodelling and fibrosis. Further investigations into the specific mechanisms by which lung disease develops in RA will be crucial for the development of effective therapies. Identifying mechanisms by which environmental and host factors cooperate in the induction of autoimmunity in the lung might also help to establish the order of early events in RA.

An Evaluation of a Practice-Based Minor Oral Surgery Service.

AIM To report the findings of a service evaluation of an NHS practice-based minor oral surgery service. METHOD A service evaluation including a retrospective analysis of activity and outcome data and assessment of patient and practitioner satisfaction. RESULTS 623 appointments were arranged, with a mean waiting time of 43 days. Treatment provided included: surgical removal of third molars and non-third molars, surgical endodontics and other surgical and oral medicine cases (29.7%, 44.1%, 3.0% and 23.4% of cases respectively). Antibiotics were prescribed at 16.1% of treatment appointments and 1.9% required appointments for post-operative complications. All participants reported overall satisfaction with their care and strongly agreed/agreed with positive attitudinal statements about the oral surgeon's communication/information giving, technical competence and understanding and acceptance; 77.5% were seen on time and none were seen more than 15 minutes late; 87.5% felt the standard of the service was better than expected than at a hospital and none felt it was worse. Over 80 of practitioners agreed that waiting times were better than expected at a hospital, urgent problems were seen quickly and the referral process was easy and understandable. All practitioners strongly agreed/agreed they that they were happy with the service provided. CONCLUSIONS A range of minor oral surgery procedures can be provided with low complication rates, acceptable waiting times and accessibility, and high patient and referring practitioner satisfaction from a practice-based specialist oral surgery service.

Using Semantic Web Technologies to Enable Cancer Genomics Discovery at Petabyte Scale.

Increased efforts in cancer genomics research and bioinformatics are producing tremendous amounts of data. These data are diverse in origin, format, and content. As the amount of available sequencing data increase, technologies that make them discoverable and usable are critically needed. In response, we have developed a Semantic Web-based Data Browser, a tool allowing users to visually build and execute ontology-driven queries. This approach simplifies access to available data and improves the process of using them in analyses on the Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org). The Data Browser makes large data sets easily explorable and simplifies the retrieval of specific data of interest. Although initially implemented on top of The Cancer Genome Atlas (TCGA) data set, the Data Browser's architecture allows for seamless integration of other data sets. By deploying it on the CGC, we have enabled remote researchers to access data and perform collaborative investigations.

Cost-Effectiveness Analysis of Second-Line Chemotherapy Agents for Advanced Gastric Cancer.

STUDY OBJECTIVE: Gastric cancer is the fifth most common malignancy and second leading cause of cancer-related mortality. Chemotherapy options for patients who fail first-line treatment are limited. Thus the objective of this study was to assess the cost-effectiveness of second-line treatment options for patients with advanced or metastatic gastric cancer. DESIGN: Cost-effectiveness analysis using a Markov model to compare the cost-effectiveness of six possible second-line treatment options for patients with advanced gastric cancer who have failed previous chemotherapy: irinotecan, docetaxel, paclitaxel, ramucirumab, paclitaxel plus ramucirumab, and palliative care. MEASUREMENTS AND MAIN RESULTS: The model was performed from a third-party payer's perspective to compare lifetime costs and health benefits associated with studied second-line therapies. Costs included only relevant direct medical costs. The model assumed chemotherapy cycle lengths of 30 days and a maximum number of 24 cycles. Systematic review of literature was performed to identify clinical data sources and utility and cost data. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. The primary outcome measure for this analysis was the ICER between different therapies, where the incremental cost was divided by the number of QALYs saved. The ICER was compared with a willingness-to-pay (WTP) threshold that was set at $50,000/QALY gained, and an exploratory analysis using $160,000/QALY gained was also used. The model's robustness was tested by using 1-way sensitivity analyses and a 10,000 Monte Carlo simulation probabilistic sensitivity analysis (PSA). Irinotecan had the lowest lifetime cost and was associated with a QALY gain of 0.35 year. Docetaxel, ramucirumab alone, and palliative care were dominated strategies. Paclitaxel and the combination of paclitaxel plus ramucirumab led to higher QALYs gained, at an incremental cost of $86,815 and $1,056,125 per QALY gained, respectively. Based on our prespecified WTP threshold, our base case analysis demonstrated that irinotecan alone is the most cost-effective regimen, and both paclitaxel alone and the combination of paclitaxel and ramucirumab were not cost-effective (ICER more than $50,000). Both 1-way sensitivity analyses and PSA demonstrated the model's robustness. PSA illustrated that paclitaxel plus ramucirumab was extremely unlikely to be cost-effective at a WTP threshold less than $400,000/QALY gained. CONCLUSION: Irinotecan alone appears to be the most cost-effective second-line regimen for patients with gastric cancer. Paclitaxel may be cost-effective if the WTP threshold was set at $160,000/QALY gained.

Deep sequencing of RSV from an adult challenge study and from naturally infected infants reveals heterogeneous diversification dynamics.

As RNA virus mutation occurs during replication within host cells, we hypothesized that viral evolution during acute infections in healthy hosts reflects host immune pressure. We therefore investigated the within-host diversification of human respiratory syncytial virus (RSV), a highly prevalent cause of acute respiratory infections. We evaluated healthy adults experimentally infected with an identical inoculum and infants hospitalized with naturally acquired infections. In aggregate, viral diversification in adults peaked at day 3, with overrepresentation of diversity in the matrix protein 2 (M2) and non-structural protein 2 (NS2) genes. In one subject, delayed viral clearance was accompanied by a late peak of diversity at day 10 in known and predicted B and T cell epitopes. In contrast, infant infections showed much less viral diversity. Our findings suggest multiple overlapping mechanisms for early control of acute viral infections, which may differ between age groups and host immune responses.

Improving the Management of Patients With Low-Risk Neutropenic Fever at the Cleveland Clinic Taussig Cancer Institute.

PURPOSE: Neutropenic fever (NF) is an oncologic emergency and has resulted historically in inpatient management. The Multinational Association for Supportive Care in Cancer (MASCC) score can be used to identify patients with NF at a low risk of complications who can be managed safely as outpatients. Despite established guidelines supporting outpatient management of low-risk neutropenic fever (LRNF), provider awareness is low, and inpatient admission for intravenous antibiotics continues to be standard of care. METHODS: Inpatient provider algorithm implementation and education began in the second quarter of 2014. Providers calculated MASCC scores for patients with nonleukemia hematologic malignancies and solid tumors at admission. Data were collected in a prospectively maintained registry. Patients identified as low risk by MASCC score were placed under observation and started on oral antibiotics. If exclusion criteria and social barriers were not identified, discharge within 48 hours was planned. RESULTS: Eighty-three patients with NF were admitted to the Taussig Cancer Institute inpatient oncology unit between November 2014 and June 2015. Fifty-three patients (64%) had LRNF by MASCC score. Patients with LRNF had an average length of stay of 3.3 days, compared with 6.2 days in our historical cohort. Sixteen patients (30%) were discharged within 24 hours. Only two patients with LRNF had a culture-proven infection, both Enterococcus urinary tract infections. Three patients required nonelective readmission. There were no deaths caused by NF. CONCLUSION: This pilot study demonstrates that a formal algorithm for LRNF management combined with provider education can improve current inpatient standard of care and length of stay without an increase in morbidity.

The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized-A New Paradigm in Large-Scale Computational Research.

The Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3-6. ©2017 AACR.

Use of atropine-diphenoxylate compared with hyoscyamine to decrease rates of irinotecan-related cholinergic syndrome.

BACKGROUND: Cholinergic syndrome is a well established acute adverse reaction associated with irinotecan. Cholinergic side effects can be ameliorated or prevented with anticholinergic agents. To date, no formal studies have compared atropine-diphenoxylate and hyoscyamine as premedications for prophylaxis of the cholinergic syndrome with irinotecan infusion. OBJECTIVES: To compare the incidence of cholinergic syndrome with irinotecan using atropine-diphenoxylate or hyoscyamine as premedication. METHODS: We conducted a retrospective, single-center, nonrandomized, cohort study of adult patients treated with atropine-diphenoxylate or hyoscyamine as premedication before receiving irinotecan. For all irinotecan infusions, intravenous atropine was administered for patients experiencing any cholinergic reaction. RESULTS: A total of 532 irinotecan cycles (354 cycles for atropine-diphenoxylate group; 178 cycles for hyoscyamine group) were analyzed in 80 patients. Overall incidence of cholinergic syndrome did not differ between atropine-diphenoxylate (8.2%) and hyoscyamine (9.0%) groups (P = .76). The incidence of cholinergic syndrome after the £rst cycle of irinotecan was similar between the 2 arms, atropine-diphenoxylate (14.6%) and hyoscyamine (10.7%), with P = .74. The most common cholinergic symptoms documented were abdominal pain or cramping, and diarrhea. LIMITATIONS: This study was subjected to vulnerabilities to bias and random error because of its observational retrospective design and small number of participants. CONCLUSIONS: Lack of difference in the incidence of cholinergic syndrome observed in irinotecan-treated patients suggests atropinediphenoxylate and hyoscyamine may both be effective prophylactic options. The findings support the need for a larger, randomized study to assess and compare these agents with other potential premedications such as scopolamine and atropine in prevention of irinotecan-related cholinergic syndrome.

The interaction of ambient frequency and feature complexity in the diphthong errors of children with phonological disorders.

This study examined the interaction of ambient frequency and feature complexity in the diphthong errors produced by Cantonese-speaking children with phonological disorders. A total of 611 diphthongs produced by 13 Cantonese-speaking children with speech disorders were subjected to perceptual analysis. The percentage accuracy of production and error patterns was examined. Perceptual analysis showed that /(see text)i/ and /ui/ were most frequently in error, whereas /ei/, /ou/, and /(see text)u/ were least frequently in error. Diphthong errors (usually diphthong reduction) arise as a function of both ambient frequency and feature complexity. The combination of ambient frequency and feature complexity yields a complexity metric reflecting accuracy of production. Treatment guidelines include consideration of three basic factors: ambient frequency, feature complexity, and error patterns.